Abstract

Fibrosis, characterized by aberrant tissue scarring from activated myofibroblasts, is often untreatable. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues affect myofibroblast differentiation in 3D is poorly understood. Here, we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure of interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness but positively correlated with matrix fibers. Using a multistep bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix metalloproteinase activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis and identifying antifibrotic therapeutics.

Fibrosis is implicated in nearly 45% of all deaths in the developed world and plays a role in numerous pathologies, including pulmonary fibrosis, cardiac disease, atherosclerosis, and cancer (1). In particular, interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are fatal and incurable with a median survival of only 2 to 5 years (2). Often described as dysregulated or incessant wound healing, fibrosis involves persistent cycles of tissue injury and deposition of extracellular matrix (ECM) by myofibroblasts (MFs). These critical cellular mediators of fibrogenesis are primarily derived from tissue-resident fibroblasts (1). MFs drive eventual organ failure through excessive fibrous ECM deposition, force generation and tissue contraction, and eventual disruption of parenchymal tissue function (1). As organ transplantation remains the only curative option for late-stage disease, effective antifibrotic therapeutics that slow MF expansion or even reverse fibrosed tissue remain a major unmet clinical need. Undoubtedly, the limited efficacy of antifibrotic drugs at present underscores limitations of existing models for identifying therapeutics, the complexity of the disease, and an incomplete understanding of MF biology.

A strong correlation between lung tissue stiffening and worse patient outcomes suggests an important role for matrix mechanosensing in fibrotic disease progression (3). Preclinical models of fibrosis in mice have supported the link between tissue stiffening and disease progression. However, a precise understanding of how physical cues from the microenvironment influence MF differentiation in vivo is confounded by concurrent structural (e.g., collagen density and laminin/elastin degradation) and biochemical (e.g., matrix composition and inflammatory) changes to the microenvironment (4). Consequently, natural and synthetic in vitro tissue models have provided great utility for the study of MF mechanobiology. Seminal studies using natural type I collagen gels have elucidated the role of profibrotic soluble cues [e.g., transforming growth factor1 (TGF-1)] in promoting cell contractility, ECM compaction, and MF differentiation, and more recently, precision-cut lung slices, have emerged as a powerful tool to study the complexity of the pulmonary microenvironment in IPF (4, 5). However, their utility in identifying physical microenvironmental determinants of MF differentiation suffers from an intrinsic coupling of multiple biochemical and mechanical material properties (6). Rapid degradation kinetics (1 to 3 days) and resulting issues with material stability (1 to 2 weeks) further impede the use of natural materials for studying fibrogenic events and drug responses, which occur over weeks to months in in vivo models or years in patients (7, 8).

Synthetic hydrogels that are more resistant to cell-mediated degradation have provided a better controlled setting for long-term studies of disease-related processes (9). For example, synthetic hydrogel-based cell culture substrates with tunable stiffness have helped establish a paradigm for mechanosensing during MF differentiation in two-dimensions (2D), where compliant matrices maintain fibroblast quiescence in contrast to stiffer matrices that promote MF differentiation (10, 11). Extensive findings in 2D suggest a causal role for matrix mechanics (e.g., stiffness) during MF differentiation in vitro and potentially in human disease, but these models lack the 3D nature of interstitial spaces where fibrosis originates (12). The interstitium surrounding alveoli is structurally composed of two key components: networks of fibrous ECM proteins (namely, type I collagen fibers) and interpenetrating ground substance, an amorphous hydrogel network rich in glycosaminoglycans such as heparan sulfate proteoglycan. Mechanical cues from fibrotic ECM that promote MF differentiation may arise from changes to the collagen fiber architecture or the gel-like ground substance; whether matrix stiffness is a prerequisite for MF differentiation in 3D fibrous interstitial spaces remains unclear (13). Furthermore, the limited efficacy of antifibrotic therapies identified in preclinical and in vitro models of IPF motivates the development of 3D tissue-engineered systems with improved structural and mechanical biomimicry, relevant pharmacokinetics, and the potential to incorporate patient cells (9). Furthermore, recapitulating key features of the fibrotic progression in an in vitro setting that better approximates interstitial tissues could (i) improve our current understanding of MF mechanobiology and (ii) serve as a more suitable test bed for potential antifibrotic therapeutics.

Accordingly, here, we describe a microengineered pulmonary interstitial matrix that recapitulates mechanical and structural features of fibrotic tissue as well as key biological events observed during IPF progression. Design parameters of these engineered microenvironments were informed by mechanical and structural characterization of fibrotic lung tissue from a bleomycin mouse model. We then investigated the influence of dimensionality, matrix cross-linking/stiffness, and fiber density on TGF-1induced MF differentiation in our pulmonary interstitial matrices. Increased hydrogel cross-linking/stiffness substantially hindered MF differentiation in 3D in contrast to findings in 2D, while fibrotic matrix architecture (i.e., high fiber density) potently promoted fibroblast proliferation and differentiation into MFs. Long-term (21 days) culture of hydrogels with a fibrotic architecture engendered tissue stiffening, collagen deposition, and secretion of profibrotic cytokines, implicating fiber density as a potent fibrogenic cue in 3D microenvironments. Pharmacologic screening in fibrotic pulmonary interstitial matrices revealed matrix metalloproteinase (MMP) activity and hydrogel remodeling as a key step during 3D fibrogenesis, but not in traditional 2D settings. To explore the clinical relevance of our findings, we leveraged a multistep bioinformatics analysis of transcriptional profiles from 231 patients, highlighting increased MMP gene expression and enriched signaling domains associated with matrix degradation in patients with IPF. Together, these results highlight the utility of studying fibrogenesis in a physiologically relevant 3D hydrogel model, underscore the requirement of matrix remodeling in IPF, and establish a new platform for screening antifibrotic therapies.

To inform key design criteria for our pulmonary interstitial matrices, we began by characterizing mechanical properties of fibrotic interstitial tissue in a bleomycin-induced lung injury model in mouse. Nave C57BL/6 mice were intratracheally challenged with bleomycin to induce lung injury and subsequent fibro-proliferative repair, with saline-treated animals maintained as a control group. After 2 weeks, animals were sacrificed and lung tissue was dissected out, sectioned and stained, and then mechanically tested by atomic force microscopy (AFM) nanoindentation to map the stiffness of interstitial tissue surrounding alveoli. While single-dose bleomycin administration does not recapitulate human IPF, the fibro-proliferative response is well characterized and leads to MF differentiation, collagen deposition, and lung stiffening events that are reminiscent of what occurs in human disease over longer time scales. As previously documented (14), bleomycin treatment corresponded to an increase in the thickness of interstitial tissue regions surrounding alveoli, a structural change that occurred alongside matrix stiffening (Fig. 1, A and B); bleomycin-treated lungs had elastic moduli nearly fivefold greater than healthy control tissues. To generate synthetic hydrogels with elastic moduli tunable over this range, we functionalized a biocompatible and protein-resistant polysaccharide, dextran, with pendant vinyl sulfone groups amenable to peptide conjugation (termed DexVS; Fig. 1C). To permit cell-mediated proteolytic hydrogel degradation and thus spreading of encapsulated cells, we cross-linked DexVS with a bifunctional peptide (GCVPMSMRGGCG, abbreviated VPMS) primarily sensitive to MMP9 and MMP14, two MMPs implicated in fibrosis-associated matrix remodeling (15, 16). Tuning input VPMS cross-linker concentration yielded stable hydrogels spanning the full range of elastic moduli we measured by AFM nanoindentation of lung tissue (Fig. 1D). Additional functionalization with cell-adhesive moieties (CGRGDS, abbreviated RGD) facilitated adhesion of primary normal human lung fibroblasts (NHLFs) (Fig. 1E).

(A) Histological preparations of healthy control and bleomycin-treated murine lung tissue (n = 3 mice per group) stained for collagen by picrosirius red (scale bar, 100 m). (B) Youngs modulus of mouse lung tissue as measured by AFM nanoindentation, with data fit to the Hertz contact model to determine Youngs modulus (n = 3 mice per group, n = 50 indentations per group on n = 9 tissue sections). (C) Schematic of proteolytically sensitive, cell-adhesive DexVS-VPMS bulk hydrogels. (D) Youngs modulus determined by AFM nanoindentation of DexVS-VPMS hydrogels formed with different concentrations of VPMS cross-linker (n = 4 samples per group, n = 20 total indentations per group). (E and F) Representative images of F-actin (cyan), nuclei (yellow), and -SMA (magenta); image-based quantification of -SMA expression (left axis, magenta bars, day 9) and nuclear Ki67 (right axis, gray bars, day 5) in 2D and 3D (n = 4 samples per group, n = 10 fields of view per group, n > 50 cells per field of view; scale bars, 200 m). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way analysis of variance (ANOVA). AU, arbitrary units.

To confirm the role of matrix mechanics on cell proliferation and MF differentiation, we seeded patient-derived NHLFs on 2D DexVS protease-sensitive hydrogel surfaces varying in VPMS cross-linker density and resulting stiffness and stimulated cultures with TGF-1 to promote MF differentiation. In accordance with previous literature, we observed a stiffness-dependent stepwise increase in cell proliferation (day 5) and MF differentiation (day 9) as measured by Ki67 and -smooth muscle actin (-SMA) immunofluorescence, respectively (Fig. 1E) (11). As the influence of matrix elasticity on MF differentiation in 3D synthetic matrices has not previously been documented, we also encapsulated NHLFs in 3D within identical DexVS hydrogels. The opposing trend with respect to stiffness was noted for cells encapsulated in 3D; compliant (E = 560 Pa) hydrogels that limited -SMA expression in 2D plated cells instead exhibited the highest levels of MF differentiation in 3D (Fig. 1F). Decreasing proliferation and cell-cell contact formation as a function of increasing hydrogel stiffness were also noted in 3D matrices and may be one reason why rigid hydrogels limit differentiation in 3D. Similar findings have been reported for mesenchymal stem cells encapsulated in hyaluronic acid matrices, where compliant gels promoted stem cell proliferation and yes-associated protein (YAP) activity in 3D, yet inhibited YAP activity and proliferation in 2D (17). These results suggest that while stiff, cross-linked 2D surfaces promote cell spreading, proliferation, and MF differentiation, an equivalent relationship does not directly translate to 3D settings. High cross-linking and stiffness (E = 6.1 kPa) in 3D matrices sterically hinder cell spreading, proliferation, and the formation of cell-cell contacts, all well-established promoters of MF differentiation (18).

Cell-degradable synthetic hydrogels with elastic moduli approximating that of fibrotic tissue proved nonpermissive to MF differentiation in 3D. Although matrix cross-linking and densification of ground substance has previously been implicated in fibrotic tissue stiffening, remodeled collagenous architecture can also engender changes in tissue mechanics and may modulate MF development in IPF independently. To characterize the fibrous matrix architecture within healthy and fibrotic lung interstitium, we used second-harmonic generation (SHG) microscopy to visualize collagen microstructure in saline- and bleomycin-treated lungs, respectively. Per previous literature, saline-treated lungs contained limited numbers of micrometer-scale (~1-m-diameter) collagen fibers, primarily localized to the interstitial spaces supporting the alveoli (Fig. 2A) (19). In contrast, bleomycin-treated lungs had, on average, fourfold higher overall SHG intensity, with collagen fibers localized to both an expanded interstitial region and in disrupted alveolar networks. While no difference in fiber diameter was noted with bleomycin treatment, we did observe thick (~2- to 5-m) collagen bundles containing numerous individual fibers in fibrotic lungs, potentially arising from physical remodeling by resident fibroblasts (Fig. 2A and fig. S1). Given that typical synthetic hydrogels amenable to cell encapsulation (as in Fig. 1) lack fibrous architecture, we leveraged a previously established methodology for generating fiber-reinforced hydrogel composites (20). Electrospun DexVS fibers approximating the diameter of collagen fibers characterized by SHG imaging (fig. S1) were co-encapsulated alongside NHLFs in DexVS-VPMS hydrogel matrices, yielding a 3D interpenetrating network of DexVS fibers ensconced within proteolytically cleavable DexVS hydrogel (Fig. 2B). To recapitulate the adhesive nature of collagen and fibronectin fibers within interstitial tissues, we functionalized DexVS fibers with RGD to support integrin engagement and 3D cell spreading. While increasing the weight % of type I collagen matrices increases collagen fiber density and simultaneously increases hydrogel stiffness (fig. S2), our synthetic matrix platform enables changes to fiber density (0.0 to 5.0%) without altering mechanical properties assessed by AFM nanoindentation (Fig. 2C), likely due to the constant weight percentage of DexVS and VPMS cross-linker within the bulk hydrogel.

(A) SHG imaging of collagen microstructure within healthy and bleomycin-treated lungs on day 14, with quantification of average signal intensity (arrows indicate interstitial tissue regions adjacent to alveoli; n = 3 mice per group, n = 10 fields of view per group; scale bar, 100 m). (B) Schematic depicting polymer cross-linking and functionalization for generating fibrous DexVS hydrogel composites to model changes in fiber density within lung interstitial tissue ECM. (C) Images and intensity quantification of fluorophore-labeled fibers within composites varying in fiber density (n = 4 samples per group, n = 10 fields of view per group; scale bar, 100 m). Youngs modulus determined by AFM nanoindentation of fibrous composites formed with different concentrations of VPMS cross-linker (n = 4 samples per group, n = 20 measurements per group). (D) Representative high-resolution images of NHLFs on day 1 in fibrous composites formed with bulk hydrogels (12.5 mM VPMS) functionalized with integrin ligand arginylglycylaspartic acid (RGD) or heparin-binding peptide (HBP) [F-actin (cyan), nuclei (yellow), and DexVS fibers (magenta); scale bar, 50 m]. Quantification of fiber recruitment as measured by contact between cells and DexVS fibers (n = 10 fields of view per group, n > 25 cells analyzed). (E) Representative high-resolution images of NHLF on day 1 fibrous composites formed with bulk hydrogels functionalized with integrin ligand RGD or HBP [F-actin (cyan), fibronectin (yellow), and DexVS fibers (magenta); scale bar, 5 m]. Quantification of fibronectin deposition into tshe hydrogel matrix as measured by immunostain intensity (n = 10 fields of view per group, n > 25 cells analyzed). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA or Students t test, where appropriate; NS denotes nonsignificant comparison.

Beyond recapitulating the multiphase structural composition of interstitial ECM, we also sought to mimic the adhesive ligand presentation and protein sequestration functions of native interstitial tissue. More specifically, the gel-like ground substance within fibrotic tissue intrinsically lacks integrin-binding moieties and is increasingly rich in heparan sulfate proteoglycans, primarily serving as a local reservoir for nascent ECM proteins, growth factors, and profibrotic cytokines. In contrast, synthetic hydrogels are often intentionally designed to have minimal interactions with secreted proteins and require uniform functionalization with a cell-adhesive ligand to support cell attachment and mechanosensing. We hypothesized that RGD-presenting fibers alone would support cell spreading (20), enabling the use of a nonadhesive bulk DexVS hydrogel functionalized with heparin-binding peptide (HBP; CGFAKLAARLYRKAG) (21). While both RGD- and HBP-functionalized bulk DexVS gels supported cell spreading upon incorporation of RGD-presenting fibers, HBP-functionalized hydrogels encouraged matrix remodeling in the form of cell-mediated fiber recruitment (Fig. 2D) and enhanced the deposition of fibronectin fibrils into the adjacent matrix (Fig. 2E). Given the multiphase structure of lung interstitium, changes in collagen fiber density noted with fibrotic progression, and the importance of physical and biochemical matrix remodeling to fibrogenesis, we used HBP-tethered 560-Pa DexVS-VPMS bulk hydrogels with tunable density of RGD-presenting fibers in all subsequent studies.

We next investigated whether changes in fiber density reflecting fibrosis-associated alterations to matrix architecture could influence MF differentiation in our 3D model. NHLFs were encapsulated in compliant DexVS-VPMS hydrogels ranging in fiber density (E = 560 Pa, 0.0 to 5.0 volume % fibers). Examining cell morphology after 3 days of culture, we noted increased cell spreading (Fig. 3, A and B) and evident F-actin stress fibers (fig. S3) in fibrous conditions compared to nonfibrous controls. Increased frequency of direct cell-cell interactions was also observed as a function of fiber density, as evidenced by higher area:perimeter ratios and the number of fibroblasts per contiguous multicellular cluster (Fig. 3A and fig. S3). As evidenced by changes in the ratio of nuclear to cytosolic YAP localization, we detected changes in mechanosensing as a function of fiber density, with the highest nuclear ratio measured in samples containing the highest fiber density examined. Given that nuclear YAP activity (a transcriptional coactivator required for downstream mechanotransduction) has been implicated as a promoter of MF differentiation (22), we also assayed other markers associated with fibroblast activation. With increases in fiber density, we found significant increases in cell proliferation and local fibronectin deposition (Fig. 3, A and B). Luminex quantification of cytokine secretion at this time point revealed elevated secretion of inflammatory and profibrotic cytokines (Fig. 3C), suggesting that matrix fibers may modulate the soluble milieu known to regulate the response to tissue damage and repair in vivo (2325). While no -SMA expression or collagen deposition was observed at this early time point, F-actin stress fibers, YAP activity, and fibronectin expression have been previously established as proto-MF markers in vivo (26), suggesting that physical interactions with matrix fibers prime fibroblasts for activation into MFs. Supplying the profibrotic soluble factor TGF-1 prompted increases in the expression of various profibrotic YAP-target genes (ACTA2, COL1A1, FN1, CD11, and CTGF) relative to nonfibrous (FD 0.0%) controls at day 5 (Fig. 3D). Together, these data suggest that heightened fiber density promotes a fibrotic phenotype (Fig. 3, A to C) and gene expression (Fig. 3D), despite the absence of a stiff surrounding hydrogel.

(A) Immunofluorescence images of NHLFs in hydrogel composites over a range of fiber densities after 3 days of culture [F-actin (cyan), fibronectin (FN, yellow), YAP (magenta), Ki67 (white), and nuclei (blue); scale bars, 100 m (F-actin), 20 m (FN), 20 m (YAP), and 100 m (Ki67/nuclei)]. (B) Corresponding image-based quantification of cell area, deposited FN, YAP nuclear to cytosolic ratio, and % of proliferating cells (n = 4 samples per group; for cell spread area analysis, n > 50 cells per group; for FN, YAP, and Ki67 analyses, n = 10 fields of view per group and n > 25 cells per field of view). (C) Cytokine secretion into culture medium on day 3 (all data were normalized to background levels in control medium, n = 4 samples per condition). (D) Expression of MF-related genes in NHLFs stimulated with TGF-1 on day 3, in either highly fibrous (FD 5.0%) or nonfibrous (FD 0.0%) hydrogels (data presented are GAPDH-normalized fold changes relative to NHLFs within an FD 0% hydrogel lacking TGF-1 supplementation). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA or Students t test where appropriate.

To explore whether fibrotic matrix cues in the form of heightened fiber density could promote 3D MF differentiation over longer-term culture, NHLFs were encapsulated within hydrogels varying in fiber density and maintained in medium supplemented with TGF-1 beginning on day 1. Immunofluorescent imaging and cytokine quantification were performed on days 3, 5, 7, and 9 to capture dynamic changes in cellular phenotype and secretion, respectively. No -SMApositive stress fibers or changes in total cytokine secretion were observed on day 3 or 5. On day 7, we noted the sparse appearance of -SMApositive cells alongside increased total cytokine secretion (Fig. 4D) in FD 5.0% conditions containing TGF-1, indicating the beginning of a potential phenotypic shift. Extensive MF differentiation (designated by -SMApositive cells) and a sixfold increase in total cytokine secretion occurred rapidly between days 7 and 9 (Fig. 4, B, D, and E) in the highest fiber density (FD 5.0%) condition. Despite the high proliferation within high fiber density hydrogels (Fig. 4C), -SMApositive cells were not evident in samples lacking exogenous TGF-1 supplementation. Moreover, -SMApositive cells were also absent in TGF-1 supplemented conditions that lacked fibrous architecture, indicating a requirement for both soluble and physical fibrogenic cues in 3D. Furthermore, inhibiting integrin engagement by incorporating fibers lacking RGD also abrogated MF differentiation and proliferation despite the presence of TGF-1 (Fig. 4, A and B), suggesting that a fibrotic matrix architecture drives -SMA expression primarily through integrin engagement and downstream mechanosensing pathways. These results were replicated with primary human dermal fibroblasts and mammary fibroblasts, where similar trends with -SMA expression as a function of fiber density were observed (fig. S4). While high fiber density promoted proliferation in dermal fibroblasts, mammary fibroblasts underwent MF differentiation in the absence of higher proliferation rates, demonstrating intrinsic differences between cell populations originating from different tissues. Nevertheless, these results suggest that fibrotic matrix architecture may be promoting MF differentiation in other pathologies, namely, dermal scarring in systemic sclerosis and desmoplasia in breast cancer.

(A) Representative immunofluorescence images of NHLFs in microenvironmental conditions leading to low (top row) or high (bottom row) MF differentiation after 9 days in culture [-SMA (magenta) and nuclei (cyan); n = 4 samples per group, n = 10 fields of view per group, and n > 50 cells per field of view; scale bar, 200 m], with corresponding image-based quantification in (B) and (C). Insets depict representative fiber densities. (D) Measurement of total cytokine secretion over time as a function of fiber density (n = 4 samples per condition; * indicates significant differences between FD 5.0% and all other groups at a given time point; NS denotes nonsignificant comparison). (E) Secretion of specific cytokines and chemoattractants as a function of fiber density on day 9 (n = 4 samples per condition). (F) Representative images and quantification of tissue contraction within day 14 fibroblast-laden hydrogels of varying fiber density (n = 4 samples per group, dashed line indicates initial diameter of 5 mm). Photo credit: Daniel Matera, University of Michigan. (G) AFM measurements of day 14 fibroblast-laden hydrogels of varying fiber density (n = 20 measurements from n = 4 samples per group). Dashed line indicates original hydrogel stiffness. (H) SHG images of fibrous collagen within fibroblast-laden hydrogels after 21 days of culture in medium supplemented with ascorbic acid (scale bar, 100 m). (I) Measurement of total collagen content within digested DexVS hydrogels at day 21 as measured by biochemical assay (n = 4 samples per group). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA; NS denotes nonsignificant comparison.

While proliferation and -SMA expression are accepted markers of activated fibroblasts, fibrotic lesions contribute to patient mortality through airway inflammation, collagen secretion, tissue contraction, and lung stiffeningpathogenic events that hinder the physical process of respiration (27). Luminex screening of 41 cytokines and chemokines within hydrogel supernatant revealed elevated total cytokine secretion as a function of fiber density over time (Fig. 4D), many of which were soluble mediators known to regulate airway inflammation (Fig. 4E) (23). Numerous other cytokines were additionally secreted at day 9 but did not change as a function of fiber density despite differences in cell number at this time point (fig. S5), suggesting that cell number alone cannot account for the increased cytokine secretion in high fiber density conditions. By generating free-floating hydrogels that allow contraction over time, we also examined macroscale changes in tissue geometry. Consistent with the influence of fiber density on -SMA expression, hydrogels containing high fiber densities underwent greater hydrogel contraction compared to nonfibrous or low fiber density conditions (Fig. 4F). Day 14 fibrotic hydrogels (FD 5.0%) were also fourfold stiffer (2.0 versus 0.5 kPa) as measured by AFM nanoindentation (Fig. 4G) compared to conditions that yielded low rates of MF differentiation in shorter-term studies (i.e., FD 0.0 or FD 0.5% in Fig. 4, A and B). When medium was supplemented with ascorbic acid to permit procollagen hydroxylation, collagen deposition into the surrounding matrix was evident by SHG microscopy by day 21 in high fiber density hydrogels (Fig. 4H) as compared to nonfibrous controls. Further biochemical analysis of hydrogel collagen content confirmed a stepwise increase in collagen production as a function of fiber density (Fig. 4I). Together, these findings demonstrate a clear influence of fiber density on MF differentiation and phenotype in 3D and furthermore suggest that this in vitro model recapitulates key pathogenic events associated with the progression of fibrosis in vivo.

Having established microenvironmental cues that promote robust 3D MF differentiation, we next evaluated the potential of our fibrous hydrogel model for use as an antifibrotic drug screening platform. Nintedanib, a broad-spectrum receptor tyrosine kinase inhibitor, and pirfenidone, an inhibitor of the mitogen-activated protein kinase (MAPK)/nuclear factor B (NF-B) pathway, were selected due to their recent Food and Drug Administration approval for use in patients with IPF (28). We also included dimethyl fumarate, an inhibitor of the YAP/TAZ pathway clinically approved for treatment of systemic sclerosis, and marimastat, a broad-spectrum MMP inhibitor that has shown efficacy in murine preclinical models of fibrosis (29, 30). We generated fibrotic matrices (560-Pa DexVS-VPMS-HBP bulk hydrogels containing 5.0 volume % DexVS-RGD fibers) that elicited the highest levels of MF differentiation, matrix contraction, and collagen secretion in our previous studies (Fig. 4). As a comparison to the current standard for high-throughput compound screening, we also seeded identical numbers of NHLFs on 2D tissue culture plastic in parallel. Cultures were stimulated with TGF-1 on day 1, and pharmacologic treatments were added on day 3, following extensive fibroblast spreading, cell-cell junction formation, and proliferation (Fig. 3A).

As in our earlier studies, TGF-1 supplementation promoted proliferation and -SMA expression within 3D constructs as well as on rigid tissue culture plastic (Fig. 5A). Nintedanib and pirfenidone had differential effects on NHLFs depending on culture format; NHLFs on 2D tissue culture plastic were resistant to pirfenidone/nintedanib treatment with no difference in proliferation or -SMA expression relative to vehicle controls, whereas modest but significant decreases in -SMA expression (pirfenidone and nintedanib) and proliferation (nintedanib) were detected in 3D (Fig. 5, A to E). Combined treatment with pirfenidone and nintedanib provided an antifibrotic effect only in fibrotic matrices, supporting ongoing clinical studies exploring their use as a combinatorial therapy (ClinicalTrials.gov identifier NCT03939520). Dimethyl fumarate abrogated cell proliferation and -SMA expression across all conditions, suggesting that inhibition of downstream mechanosensing inhibits MF differentiation in both 2D and 3D contexts in support of the general requirement for mechanosensing during MF differentiation independent of culture substrate (11). Inhibition of YAP activity in vivo has been shown to mitigate fibrosis and may be an advantageous therapeutic target (22). Blockade of MMP activity via marimastat treatment proved ineffectual in reducing -SMA expression or proliferation on 2D tissue culture plastic, but surprisingly fully abrogated the proliferation and differentiation response in 3D fibrotic matrices (Fig. 5, A to E). Given the role of protease activity in tissue remodeling in vivo (30) and in cellular outgrowth within 3D hydrogels (17, 31), our data suggest that degradative matrix remodeling is a requirement for MF differentiation in 3D, but not in more simplified 2D settings. To summarize, multiple antifibrotic agents (pirfenidone, nintedanib, dimethyl fumarate, and marimastat) demonstrating efficacy in clinical literature elicited an antifibrotic effect in our engineered fibrotic pulmonary interstitial matrices, but not in the 2D tissue culture plastic contexts traditionally used for compound screening.

(A) Representative confocal images stained for -SMA (magenta), F-actin (cyan), and nuclei (yellow) of NHLFs after 9 days of culture on tissue culture plastic (TCP) (top row) or 3D fibrotic matrices (bottom row) with pharmacologic treatment indicated from days 3 to 9 (scale bar, 100 m). Imaged regions were selected to maximize the number of -SMA+ cells per field of view within each sample. (B) Quantification of -SMA and (C) total cell count within 2D NHLF cultures. (D) Quantification of -SMA and (E) total cell count within 3D fibrotic matrices (n = 4 samples per group, n = 10 fields of view per group, and n > 50 cells per field of view). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA; NS denotes nonsignificant comparison.

As the protease inhibitor marimastat fully ablated TGF-1induced -SMA expression and proliferation in our 3D fibrotic matrices, we leveraged bioinformatics methodologies to investigate the role of matrix proteases in patients with IPF on a network (Reactome) and protein (STRING) basis. Differential expression analysis of microarray data within the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (dataset #GSE47460) was used to generate an uncurated/unbiased dataset composed of the top 1000 differentially regulated genes in IPF, revealing MMP1 as the most up-regulated gene in patients with IPF, with other matrix proteases (MMP1, MMP3, MMP7, MMP9, MMP10, MMP11, and MMP12) and matrix remodeling proteins (COL1A2, LOX, ACAN, DCN, and HS6ST2) similarly up-regulated (Fig. 6B, table S1, and data file S1). To focus on genes associated with MF differentiation for subsequent analyses, we performed Gene Ontology (GO) term enrichment (via GEO2R) to compile a curated dataset containing 188 key genes associated with MF differentiation (data file S1) and used Reactome and STRING analyses to investigate network signaling within both the uncurated and curated datasets. Analyses revealed 103 (uncurated) and 89 (curated) enriched signaling pathways in IPF (data file S1). The top 3/5 (uncurated) and 5/5 (curated) significantly enriched pathways in IPF involved matrix degradation and remodeling (Fig. 6C). Subsequent STRING protein-protein interaction analysis of datasets revealed that top signaling nodes were MMPs (uncurated: MMP1 and MMP3; Fig. 6D), fibrous collagens (uncurated: COL1A2 and COL3A1), or cytokines (curated: IL6, VEGFA, IL1B, and IGF1; Fig. 6D) known to increase MMP expression in fibroblasts (3235). These results emphasize the interdependence between MMP activity and systems-level pathogenic signaling in IPF and, in combination with our 3D drug screening results, highlight fibroblast-specific protease activity as a potential therapeutic target. Furthermore, given that protease inhibition had no effect on MF differentiation in 2D culture, these data also support the growing sentiment that simplified 2D screening models may be masking the identification of potentially viable antifibrotics.

(A) Schematic representation of bioinformatics workflow: Whole-genome transcriptomes from 91 healthy and 140 patients with lung fibrosis were fetched from the NCBI GEO. Differential expression analysis was used to assemble an uncurated list of the top 1000 differentially expressed genes. GO enrichment of choice biological pathways was used to assemble a curated list of genes associated with MF differentiation. Datasets were fed through a previous knowledgebased analysis pipeline to identify enriched signaling pathways (Reactome) and key protein signaling nodes (STRING) within patients with IPF. (B) Heatmaps of the top 20 differentially expressed genes within specified GO categories, which were manually selected for curated analysis. CN values indicate a high degree of interaction between proteins selected for curated analysis. Colors are based on differential expression values that were not log-normalized. (C) Summary of the top 5 significantly enriched pathways in the curated and uncurated gene set. (D) Representative STRING diagram depicting protein interactions within the curated dataset, with summary of the top 5 signaling nodes in the uncurated and curated gene set. Blue nodes and edges represent interactions within the top 5 signaling nodes for the curated dataset.

Despite fibrosis widely contributing to mortality worldwide, inadequate understanding of fibrotic disease pathogenesis has limited the development of efficacious therapies (12). Preclinical studies in vivo, while indispensable, often fail to translate to clinical settings as evidenced by the failure of ~90% of drugs identified in animal studies (36). In addition, limitations in current technologies (e.g., the embryonic lethality of many genetic ECM knockouts and the limited resolution/imaging depth of intravital microscopy) have hindered the application of preclinical in vivo models for the study of cell-ECM interactions that underlie fibrogenesis (37). In contrast, existing in vitro models use patient-derived cells that are affordable, scalable, and amenable to microscopy, but often fail to recapitulate the complex 3D matrix structure of the interstitial tissue regions where fibrotic diseases such as IPF originate. We leveraged electrospinning and bio-orthogonal chemistries to engineer novel pulmonary interstitial matrices that are 3D and have fibrous architecture with biomimetic ligand presentation. In the presence of profibrotic soluble factors, these settings reproduce hallmarks of fibrosis at cellular and tissue levels (Figs. 2 to 4). Examining the influence of physical microenvironmental cues (cross-linking/stiffness and fiber density) on MF differentiation, we find that cross-linking/stiffness has opposing effects on MF differentiation in 2D versus 3D (Fig. 1) and that incorporation of a fibrous architecture in 3D is a prerequisite to MF differentiation (Fig. 4). Furthermore, supported by the importance of protease signaling in IPF (Fig. 6), we performed proof-of-concept pharmacologic screening within our 3D fibrotic matrices (Fig. 5) and highlighted enhanced biomimicry as compared to traditional 2D drug screening substrates where matrix remodeling appears to be dispensable for MF differentiation.

While tunable synthetic hydrogels have identified mechanosensing pathways critical to MF differentiation in 2D, these observations have yet to be translated to 3D fibrous settings relevant to the interstitial spaces where fibrosis originates. Given that late-stage IPF progresses in the absence of external tissue damage, current dogma implicates fibrotic matrix stiffness as the continual driver of MF differentiation in vivo (10, 11, 38). While we cannot disregard this hypothesis, our work elucidates a contrasting MMP-dependent mechanism at play in 3D, whereby a compliant, degradable, and fibrous matrix architecture supports MF differentiation, with matrix contraction and stiffening occurring downstream of -SMA expression, nearly a week later. Given numerous 2D studies indicating matrix stiffness as a driver of MF differentiation, the finding that a compliant matrix promotes MF differentiation may appear counterintuitive (10, 11). However, MF accumulation has been documented before tissue stiffening in human disease (3), and a recent phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT01769196) targeting the LOX pathway (the family of enzymes responsible for matrix stiffening in vivo) failed to prevent disease progression in patients with IPF and was terminated due to lack of efficacy (39). Furthermore, compelling recent work by Fiore et al. (3) combined immunohistochemistry with high-resolution AFM to characterize human IPF tissue mechanics and found that regions of active fibrogenesis were highly fibrous but had a similar Youngs modulus as healthy tissue. In concert with our in vitro data, these findings suggest that MF differentiation is possible within soft provisional ECM in vivo and that the initiation of fibrogenesis may not be dependent on heightened tissue stiffness so long as matrix fibers and appropriate soluble cues (e.g., TGF-1) are present.

Consequently, understanding the source of profibrotic soluble cues in vivo is of critical importance when identifying therapeutic targets for IPF. Luminex screening of supernatant from 3D fibrotic matrices revealed sixfold increases in cytokine secretion during fibrogenesis, most of which were potent inflammatory factors [e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, and vascular endothelial growth factor A (VEGF-A)] and chemoattractants (e.g., CCL2, CCL7, CCL11, and CXCL1) (Fig. 4E). Furthermore, IL-6 and VEGF-A were found to be major signaling nodes in patients with IPF (Fig. 6D). While not typically regarded as an immunomodulatory cell population, these findings suggest that MFs may maintain localized inflammation to support continual fibrogenesis. Mitogens such as IL-6 and IL-8 promote endothelial- and epithelial-to-mesenchymal transition, a process that gives rise to matrix-producing MF-like cells in IPF (40). CCR2 (CCL2 and CCL7) and CXCR1 (CXCL1 and IL-8) ligation facilitates macrophage chemotaxis, potentially leading to a sustained influx of TGF-1producing cells in IPF, and glycoproteins such as GM-CSF inhibit caspase activity in mononuclear cells, potentially preventing apoptotic events required for the resolution of wound repair and return to homeostasis (23, 41). In addition, secretion of nearly all cytokines was increased as a function of fiber density, highlighting a potential feed-forward loop distinct from canonical TGF-1 signaling. Further model development (e.g., coculture platforms) will be required to examine these hypotheses and the role of MF-derived cytokines in persistent inflammation and fibrosis.

In addition to documenting the role of fibrotic matrix architecture in 3D fibrogenesis, we demonstrate proof-of-concept pharmacologic screening within our synthetic pulmonary interstitial matrices and highlight their improved relevance to human disease. Previous work in vitro has documented profound reductions in MF differentiation after treatment with clinically approved antifibrotics (pirfenidone and nintedanib), whereas in the clinic, pirfenidone and nintedanib impede disease progression but are far from curative (4, 28, 42, 43). Pirfenidone or nintedanib had insignificant effects in 2D settings in our hands and only modest effects in 3D (Fig. 5). One reason for this discrepancy may be the use of supraphysiologic pirfenidone and nintedanib concentrations in previous in vitro studies, whereas we selected dosages based on plasma concentrations in patients with IPF (44). Differences in pharmacokinetics, nutrient/growth factor diffusion, and cell metabolism between 2D and 3D tissue constructs likely also play a role. Furthermore, as evidenced by the preventative effect of the protease inhibitor marimastat in 3D hydrogels but not 2D settings (Fig. 5), pharmacologics that influence matrix degradation and remodeling are likely to have a minimized effect in 2D settings due to the less dynamic nature of tissue culture plastic and flat hydrogels (45). Nintedanib and pirfenidone have been shown to influence protease activity and matrix remodeling in vivo (16), and may be mediating their effects within fibrotic matrices through modulation of ECM remodeling. Given the identification of numerous potential antifibrotic agents (microRNA, TGF-1 inhibitors, IL-4, IL-13 neutralizing antibodies, and integrin blockers) in preclinical models, application of the system described here could elucidate how choice pharmacologics affect MF differentiation and matrix remodeling processes that are difficult to recapitulate in 2D culture. Further development of our interstitial matrices as an arrayed platform, as has been elegantly implemented with collagen matrices (42), is a critical next step to moving this technology toward high-throughput screening applications.

It is important to note that this work has several potential limitations. Our material approach allows facile control of initial microenvironmental conditions (e.g., dimensionality, fiber density, ligand density, and elastic modulus), and of note, composites of RGD-bearing nondegradable fibers and degradable bulk hydrogel decouple degradation-induced changes in matrix mechanics and ligand availability. However, we have no experimental control over subsequent dynamic cell-driven remodeling events (e.g., MMP-mediated hydrogel softening, fibronectin and collagen deposition, and hydrogel contraction/stiffening from resident cells) that likely affect local matrix mechanics, cellular mechanosensing, and MF differentiation. Exciting recent technologies such as 3D traction force microscopy (TFM) and magnetic bead microrheology could enable future examination of how these dynamic changes in cell-scale mechanics potentiate MF differentiation in 3D. Along similar lines, although our study suggests a requirement for initial adhesion to the surrounding matrix, how the dynamics of ligand presentation due to matrix remodeling regulates mechanosensing was not explored here. We present this platform as a reductionist approach to modeling the activation of fibroblasts within the 3D fibrous interstitia associated with fibrosis, a pathology that develops over years in vivo and involves multiple cell types. Human pulmonary tissue and fibrotic foci, in particular, also have viscoelastic and nonlinear mechanical behaviors (3, 46) that were not explored in our AFM measurements of murine lung or hydrogel composites. Given the important role such mechanical features can play in ECM mechanosensing, incorporating new synthetic material strategies in combination with cell-scale mechanical measurements will be essential to modeling physiologic complexity. Given that the development of lung organoids is still in its infancy, decellularized precision-cut lung slices currently represent the best culture platform to capture the full complexity of the lung microenvironment (5).

In summary, we designed a tunable 3D and fibrous hydrogel model that recapitulates dynamic physical (e.g., stiffening and contraction) and biochemical (e.g., secretion of fibronectin, collagen, and cytokines) alterations to the microenvironment observed during the progression of IPF. Implementation of our model allowed us to establish a developing mechanism for MF differentiation in 3D compliant environments, whereby cell spreading upon matrix fibers drives YAP activity, cytokine release, and proteolysis-dependent MF differentiation. Furthermore, we leveraged bioinformatics techniques to explore protease signaling in clinical IPF and, in concert with our therapeutic screening data, establish a strong role for proteases during IPF pathogenesis and in 3D MF differentiation. Whether protease activity promoted MF differentiation directly through modulation of intracellular signaling or indirectly through affects on the local matrix environment has yet to be explored in these settings but will be the focus of future efforts. Consequently, these results highlight critical design parameters (3D degradability and matrix architecture) frequently overlooked in established synthetic models of MF differentiation. Future work incorporating macrophages, endothelial cells, and epithelial cells may expand current understanding of how developing MF populations influence otherwise homeostatic cells and how matrix remodeling influences paracrine signaling networks and corresponding drug response. Given the low translation rate of drugs identified in high-throughput screening assays, we show that the application and development of engineered biomimetics, in combination with preclinical models, can improve drug discovery and pathophysiological understanding.

All reagents were purchased from Sigma-Aldrich and used as received, unless otherwise stated.

Dextran vinyl sulfone. A previously described protocol for vinyl sulfonating polysaccharides was adapted for use with linear highmolecular weight (MW) dextran (MW 86,000 Da; MP Biomedicals, Santa Ana, CA) (20). Briefly, pure divinyl sulfone (12.5 ml; Thermo Fisher Scientific, Hampton, NH) was added to a sodium hydroxide solution (0.1 M, 250 ml) containing dextran (5 g). This reaction was carried out at 1500 rpm for 3.5 min, after which the reaction was terminated by adjusting the pH to 5.0 via the addition of hydrochloric acid. A lower functionalization of DexVS was used for hydrogels, where the volume of divinyl sulfone reagent was reduced to 3.875 ml. All reaction products were dialyzed for 5 days against Milli-Q ultrapure water, with two water exchanges daily, and then lyophilized for 3 days to obtain the pure product. Functionalization of DexVS was characterized by 1H nuclear magnetic resonance (NMR) spectroscopy in D2O and was calculated as the ratio of the proton integral [6.91 parts per million (ppm)] and the anomeric proton of the glucopyranosyl ring (5.166 and 4.923 ppm); here, vinyl sulfone/dextran repeat unit ratios of 0.376 and 0.156 were determined for electrospinning and hydrogel DexVS polymers, respectively.

DexVS was dissolved at 0.6 g ml1 in a 1:1 mixture of Milli-Q ultrapure water and dimethylformamide with 0.015% Irgacure 2959 photoinitiator. Methacrylated rhodamine (0.5 mM; Polysciences Inc., Warrington, PA) was incorporated into the electrospinning solution to fluorescently visualize fibers under 555 laser. This polymer solution was used for electrospinning within an environment-controlled glovebox held at 21C and 30% relative humidity. Electrospinning was performed at a flow rate of 0.3 ml hour1, gap distance of 5 cm, and voltage of 10.0 kV onto a grounded collecting surface attached to a linear actuator. Fiber layers were collected on glass slabs and primary cross-linked under ultraviolet light (100 mW cm2) and then secondary cross-linked (100 mW cm2) in an Irgacure 2959 solution (1 mg ml1). After polymerization, fiber segments were resuspended in a known volume of phosphate-buffered saline (PBS) (typically 3 ml). The total volume of fibers was then calculated via a conservation of volume equation: total resulting solution volume = volume of fibers + volume of PBS (3 ml). After calculating total fiber volume, solutions were re-centrifuged, supernatant was removed, and fiber pellets were resuspended to create a 10 volume % fiber solution, which were then aliquoted and stored at 4C. To support cell adhesion, 2.0 mM RGD was coupled to vinyl sulfone groups along the DexVS backbone via Michael-type addition chemistry for 30 min, followed by quenching of excess VS groups in a 300 mM cysteine solution for 30 min.

DexVS gels were formed via a thiol-ene click reaction at 3.3% (w/v) (pH 7.4, 37C, 45 min) with VPMS cross-linker (12.5, 20, and 27.5 mM) (GCRDVPMSMRGGDRCG, GenScript, George Town, KY) in the presence of varying amounts of arginylglycylaspartic acid (RGD, CGRGDS, 2.0 mM; GenScript, George Town, KY), HBP (GCGAFAKLAARLYRKA, 1.0 mM; GenScript, George Town, KY), and fiber segments (0.0 to 5.0%, v/v). For experiments comparing hydrogels of varying ligand type (1 mM HBP versus 2 mM RGD), cysteine was added to precursor solutions to maintain a final vinyl sulfone concentration of 60 mM. All hydrogel and peptide precursor solutions were made in PBS containing 50 mM Hepes. To create fibrous hydrogels, a defined stock solution (10% v/v) of suspended fibers in PBS/Hepes was mixed into hydrogel precursor solutions before gelation. By controlling the dilution of the fiber suspension, fiber density was readily tuned within the hydrogel at a constant hydrogel weight percentage. For gel contraction experiments, DexVS was polymerized within a 5-mm-diameter polydimethylsiloxane (PDMS) gasket to ensure consistent hydrogel area on day 0.

NHLFs (University of Michigan Central Biorepository), normal human dermal fibroblasts (Lonza, Basel, Switzerland), and normal human mammary fibroblasts (Sciencal, Carlsbad, CA) were cultured in Dulbeccos modified Eagles medium containing 1% penicillin/streptomycin, l-glutamine, and 10% fetal bovine serum (Atlanta Biologicals, Flowery Branch, GA). NHLFs derived from three separate donors were used for experiments. Cells were passaged upon achieving 90% confluency at a 1:4 ratio and used for studies until passage 7. For all hydrogel studies, cells were trypsinized, counted and either encapsulated into or seeded onto 25-l hydrogels at a density of 1,000,000 cells ml1 of hydrogel, and subsequently cultured at 37C and 5% CO2 in serum-containing medium. For studies comparing 3D hydrogels to tissue culture plastic, the number of cells seeded into 2D conditions was analogous to the total cell number within hydrogel matrices. Medium was refreshed the day after encapsulation and every 2 days after. In selected experiments, recombinant human TGF-1 (5 ng/ml; PeproTech, Rocky Hill, NJ) was supplemented into the medium at 5 ng ml1. For pharmacological studies, nintedanib (50 nM; Thermo Fisher Scientific, Hampton, NH), pirfenidone (100 M; Thermo Fisher Scientific, Hampton, NH), marimastat (1.0 M), and dimethyl fumarate (100 nM) were supplemented in serum-containing medium and refreshed every 2 days.

Cultures were fixed with 4% paraformaldehyde for 30 min at room temperature. To stain the actin cytoskeleton and nuclei, samples were permeabilized in PBS solution containing Triton X-100 (5%, v/v), sucrose (10%, w/v), and magnesium chloride (0.6%, w/v); blocked in 1% bovine serum albumin (BSA); and stained simultaneously with phalloidin and 4,6-diamidino-2-phenylindole (DAPI). For immunostaining, samples were permeabilized, blocked for 8 hours in 1% (w/v) BSA, and incubated with mouse monoclonal anti-YAP antibody (1:1000; Santa Cruz Biotechnology, SC-101199), mouse monoclonal anti-fibronectin antibody (FN, 1:2000; Sigma-Aldrich, #F6140), rabbit monoclonal anti-Ki67 (1:500; Sigma-Aldrich #PIMA514520), or mouse monoclonal anti-SMA (1:2000; Sigma-Aldrich, #A2547) followed by secondary antibody for 6 hours each at room temperature with 3 PBS washes in between. High-resolution images of YAP, FN, and actin morphology were acquired with a 40 objective. Unless otherwise specified, images are presented as maximum intensity projections of 100-m Z-stacks. Hydrogel samples were imaged on a Zeiss LSM 800 laser scanning confocal microscope. SHG imaging of lung tissue was conducted on a Leica SPX8 laser scanning confocal microscope with an excitation wavelength of 820 nm and a collection window of 400 to 440 nm. Single-cell morphometric analyses (cell spread area) were performed using custom Matlab scripts with sample sizes >50 cells per group, while YAP, -SMA, Ki67, and FN immunostains were quantified on an image basis with a total of 10 frames of view. MFs were denoted as nucleated, F-actin+, -SMA+ cells. For cell density (number of nuclei) calculations, DAPI-stained cell nuclei were thresholded and counted in six separate 600 m 600 m 200 m image volumes, allowing us to calculate a total number of cells per mm3 of gel. Fiber recruitment analysis was conducted via a custom Matlab script; briefly, cell outlines were created via actin masking and total fiber fluorescence was quantified under each actin mask on a per-cell basis. A similar analysis method using Matlab was used for cell-cell junction analysis as published previously, with higher area:perimeter ratios and clusters/cell indicative as more pronounced network formation (47).

For all experiments, additional hydrogel replicates were finely minced and degraded in dextranase solution (4 IU/ml; Sigma-Aldrich) for 20 min and homogenized in buffer RLT (Qiagen, Venlo, The Netherlands), and RNA was isolated according to the manufacturers protocols. Complementary DNA (cDNA) was generated from deoxyribonuclease (DNase)free RNA and amplified, and gene expression was normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Experiments were run with technical triplicates across three individual biological experiments. For a complete list of primers, see table S2.

To determine the elastic modulus of lung tissue and DexVS hydrogels, indentation tests were used with a Nanosurf FlexBio AFM (Nanosurf, Liestal, Switzerland). Samples were indented via a 5-m bead at a depth of 10 m and an indentation rate of 0.333 m/s. Resulting force-displacement curves were fit to a spherical Hertz model using AtomicJ. Poissons ratios of 0.5 and 0.4 were used for hydrogels and lung tissue, respectively.

All animal studies were approved by the Animal Care and Use Committee at the University of Michigan. Bleomycin (0.025 U; Sigma-Aldrich) was instilled intratracheally in C57BL6 mice (8 weeks of age; The Jackson Laboratory, Bar Harbor, ME, USA) on day 0. Briefly, mice were anesthetized with sodium pentobarbital, the trachea was exposed and entered with a 30-gauge needle under direct visualization, and a single 30-l injection containing 0.025 U of bleomycin (Sigma-Aldrich) diluted in normal saline was injected. Lungs were collected on day 14 for mechanical and histological analysis. For histology samples, lungs were perfused with saline and inflated with 4% paraformaldehyde, sectioned, and stained with picrosirius red. For mechanical characterization via AFM, lungs were perfused with saline, infused with OCT (optimal cutting temperature) compound (Thermo Fisher Scientific), and flash-frozen in a slurry of dry ice and ethanol. Sections were mechanically tested via AFM nanoindentation immediately upon thawing.

To characterize the inflammatory secretome associated with various DexVS-VPMS environments, medium was collected from NHLF cultures 3, 5, 7, and 9 days after encapsulation. A Luminex FlexMAP 3D (Luminex Corporation, Austin, TX) systems technology was used to measure 41 cytokines/chemokines (HCTYMAG-60 K-PX41, Milliplex, EMD Millipore Corporation) in the medium samples according to the manufacturers instructions. Total secretion was reported as the sum of all 41 analytes measured for each respective condition. Cell-secreted collagen was measured using the established colorimetric Sircol assay in hydrogels cultured with serum-free medium in the presence of ascorbic acid (25 g ml1).

The NCBI GEO database was consulted [dataset GSE47460 (GP14550)] to fetch gene expression data from 91 healthy patients and 140 patients with IPF; patients with chronic obstructive pulmonary disease and nonidiopathic fibrotic lung diseases were excluded from the analysis (48). GEO2R (www.ncbi.nlm.nih.gov/geo/geo2r/) software was used for GO term enrichment, with keywords ECM, MMP, integrin, cytoskeleton, cytokine, chemokine, and MAPK used as search terms for dataset curation (48). Noncurated datasets were composed of the top 1000 differentially expressed genes between healthy and interstitial lung disease (ILD) conditions. Differential expression was calculated on the basis of subtracting normalized expression values between diseased and healthy patients. All genes were normalized before analysis with GEO2R via a pairwise cyclic losses approach. For pathway and protein-protein enrichment analyses, a curated pathway database [Reactome (49)] and Search Tool for Retrieval of Interacting Genes/Proteins [STRING (50)] methodology were consulted, respectively. For STRING analyses, up-regulated genes within the druggable genome were focused upon. A tabulated list of top genes, pathways, and nodes can be seen in data file S1.

Statistical significance was determined by one-way analysis of variance (ANOVA) or Students t test where appropriate, with significance indicated by P < 0.05. All data are presented as means SD.

Acknowledgments: We thank E. S. White (University of Michigan) for providing patient-derived lung fibroblasts used in these studies. Funding: This work was supported, in part, by the NIH (HL124322, R35HL144481). D.L.M. and C.D.D. acknowledge financial support from the NSF Graduate Research Fellowship Program (DGE1256260). Author contributions: D.L.M. and B.M.B. conceived and supervised the project. D.L.M. designed and performed the experiments. K.M.D. and K.B.A. performed and aided in analysis of the Luminex experiments. M.R.S. and C.D.D. helped with data analysis. R.P. and M.S. aided in polymer syntheses and microfiber fabrication. I.M.L. provided equipment for and assisted in polymerase chain reaction experiments. C.A.W. and B.B.M. helped perform the animal experiments for the bleomycin-induced lung fibrosis model. All authors edited and approved the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation - Science...

Recommendation and review posted by Bethany Smith

There is no silver bullet at the moment, and there might never be, said World Health Organization Director-General Tedros Adhanom at a virtual press conference at the beginning of August. While it was this bleak sound bite that made the headlines, Tedros also had words of praise for the progress made towards identifying treatments that aid the recovery of COVID-19 patients with the most serious forms of the disease.Research towards treatments for COVID-19 has been developing at a phenomenal speed, even though it feels as though solutions cant come soon enough; the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had significant health, economic and social impacts across the globe, and as of September 8th more than 27 million cases and 890,000 deaths have been recorded in 188 countries.

Research groups across the world have set about identifying drugs for the treatment of COVID-19, by screening both novel and existing drugs for their ability to alleviate symptoms and stem viral replication. Here, we provide an update on ongoing global efforts to develop and test drugs for the treatment of COVID-19 and explore the range of strategies being employed.

COVID-19 is a disease which can leave you with anything between a mild sniffle to an unpleasant combination of high fever, heavy fatigue, and lung inflammation and damage. The drivers of clinical symptoms can be roughly divided into two categories: the virus itself and the hyperinflammatory response to the virus that occurs in the most severely ill people. Consequently, efforts to identify appropriate treatments are often focused on one category, and sometimes, a particular patient group or stage of disease. Given the nature of COVID-19, it is highly likely that a combination of drugs (drug cocktail) will be needed to both neutralize the virus and suppress the symptoms of COVID-19. Antiviral treatments may target viral components directly, or other cellular processes involved in viral infection or replication. To date, interventional studies for COVID-19 have attempted to achieve a wide range of goals, including:

Addressing the threat of new and potentially life-threatening pathogens requires deep understanding and accurate, reproducible techniques for developing better tests, vaccines, and treatments. Agilent provides the complete breadth of systems, consumables, software, services, and knowledge you need to support your success.

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Meet the scientists on the frontline with coronavirus. Video credit: Sanford Burnham Prebys Medical Discovery Institute

Of the ~12,000 compounds screened, 100 inhibited SARS-CoV-2 replication in mammalian cells, 21 of which did so in a dose-response fashion. Achieving a sufficiently high dose concentration to elicit antiviral effects in vivo was predicted to be practical and possible for 13 of these compounds based on EC50 values in various cell lines. The most potent of these were evaluated for antiviral activity in human induced pluripotent stems cell (iPSC)-derived pneumocyte-like cells (five candidates) and in an ex vivo lung culture system (one candidate). The latter candidate is called apilimod, a small molecule inhibitor of an enzyme (phosphoinositide 5-kinase or PIKfyve, an endosomal lipid kinase) important to the endocytic pathway in which SARS-CoV-2 travels along during its journey through the cell. Encouragingly, apilimod potently antagonized viral replication in these tissues, and the findings are in agreement with those of another research group. This month, Kang et al. published an article in PNAS, describing the potent inhibition of SARS-CoV-2 by apilimod, providing further evidence to suggest PIKfyve-inhibition as a potential strategy that could limit infection and disease pathogenesis. The authors also noted that apilimod has passed safety tests in previous clinical trials for nonviral indications.

Chanda highlights the incredible pace at which this work was produced. Typically, a project like this would take years, rather than months. He points out that by wanting to do something quickly, there were sacrifices (and not just weekends). For example, they ran with the assay and the cell lines that allowed them to produce results quickly. This is the reason we put the entire dataset out there not one/three/20 molecules, we put all 100 molecules out there. These are the ones we found because of our experimental system, but please keep testing the others because youll probably find other things that work, said Chanda.

To design multiple peptide sequences that can competitively bind to the SARS-CoV-2 receptor binding domain, the University of Michigan research group used a protein design system called EvoDesign.EvoDesign is the first de novo protein design protocol developed in our lab; it performs design simulation by combining the evolution-based information collected from protein databases and an accurate physics- and knowledge-based energy function, namely EvoEF2, for computing atomic interactions such as van der Waals forces, electrostatics, hydrogen bonding, and desolvation energies, said Huang.

Overall, these sophisticated computational tools represent a promising new avenue for the de novo development of drug discovery studies.

Michele Wilson is a freelance science writer for Choice Science Writing.

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COVID-19 Drug Discovery and Development Why Diverse Strategies Are Critical - Technology Networks

Recommendation and review posted by Bethany Smith

A piercing smile that beams out of his photos is not the only legacy left behind by much-loved Joe Brown.

At just 29, his life was cut short, but not before he made a decision that would save the lives of three other people.

Prior to his untimely death, the avid gamer signed up to donate all his organs to help those waiting for a life-saving transplant.

For his mother and siblings, nothing could prepare them for losing "kind and generous" Joe so suddenly, but they have found solace in knowing part of him lives on.

Big sister, Louise Edwards, told Black Country Live: "He had opted to donate all his organs. Initially, my mum struggled with this decision but its what he wanted.

"He saved two 29-year-old men who had been waiting nearly two years for a life-saving transplant and he also helped a lady in her 50s.

Joes liver and kidneys were donated shortly after his death at Walsall Manor Hospital on July 23 this year.

Louise said: "My brother was a caring person and, even on his deathbed, he wanted to help. He chose to do it so we had to support it. He agreed to have his stem cells taken to help children. Although he is no longer here, he is still helping people.

"Its comforting to know he saved the lives of three people and his legacy lives on."

According to figures released by the NHS blood and transplant service, there are currently around 6,000 people on the UK transplant waiting list.

Last year, more than 350 people died while waiting for a transplant. Just eight per cent of organs donated were from those of African, Caribbean or Asian heritage.

While his final gesture represented the gift of life, Joe was hiding a silent battle with mental health.

An inquest hearing held at Black Country Coroners Court decided he had tragically taken his own life.

Louise said: "He didnt talk about his struggles with mental health, he always said he didnt want to be a burden. He had stopped talking to us, we only got him back two weeks before his death."

During the inquest, it was revealed that, in the weeks before Joe's death, he had tried to contact the emergency mental health crisis team but was denied a face-to-face appointment because of the COVID-19 outbreak.

"He only used to confide in his friends on the Xbox, he talked about his past, his troubles in his relationship and previous suicide attempts, his sister continued.

She added: "He was a family person, he was a kind and generous person, thats the legacy that he left behind. More than 200 people came to pay their respects at his funeral, he didnt know how loved he was.

"To those struggling with mental health, speak out. It doesnt make you weak to speak out. If he had told us how he was feeling we could have helped to get him the help he needed.

Samaritans (116 123) samaritans.org operates a 24-hour service available every day of the year. If you prefer to write down how youre feeling, or if youre worried about being overheard on the phone, you can email Samaritans at jo@samaritans.org , write to Freepost RSRB-KKBY-CYJK, PO Box 9090, STIRLING, FK8 2SA and visit http://www.samaritans.org/branches to find your nearest branch.

CALM (0800 58 58 58) thecalmzone.net has a helpline is for men who are down or have hit a wall for any reason, who need to talk or find information and support. They're open 5pm to midnight, 365 days a year.

Childline (0800 1111 ) runs a helpline for children and young people in the UK. Calls are free and the number wont show up on your phone bill. PAPYRUS (0800 068 41 41) is a voluntary organisation supporting teenagers and young adults who are feeling suicidal.

Depression Alliance is a charity for people with depression. It doesnt have a helpline, but offers a wide range of useful resources and links to other relevant information depressionalliance.org Students Against Depression is a website for students who are depressed, have a low mood or are having suicidal thoughts. Bullying UK is a website for both children and adults affected by bullying studentsagainstdepression.org The Sanctuary (0300 003 7029 ) helps people who are struggling to cope - experiencing depression, anxiety, panic attacks or in crisis. You can call them between 8pm and 6am every night.There are other depression charities.

"The family are distraught, my kids and the younger siblings dont understand why Joe isnt here. Im the oldest and I never thought he would be gone before me."

At the hearing, coroner, Joanne Lees, told the court that Joe had been found unresponsive in his room by his ex-girlfriend on July 20, 2020.

Paramedics were able to resuscitate him and he was rushed to Walsall Manor Hospital but, due to a cardiac arrest, he suffered a brain injury which led to his death.

Fondly recalling her sons warm character, Vicky Spriggs told the court: "He was a happy go lucky person who didnt believe in mental health, he would always say, 'suck it up' or 'man up'.

"He was bubbly and outgoing. Joe was always smiling and joking around.

Ms Lees recorded a verdict of suicide and offered her condolences to the family.

The rest is here:
Much-loved son Joe Brown saved three lives after tragic death at just 29 - Birmingham Live

Recommendation and review posted by Bethany Smith

WASHINGTON, Sept. 4, 2020 /PRNewswire/ -- During the COVID-19 pandemic, many stem cell transplant centers including guidance from the National Marrow Donor Program (NMDP) recommend that stem cell products be frozen for preservation. However, a new study in Blood Advances suggests that the freezing process can decrease the quality of stem cells, particularly if they were manipulated before being preserved, if they had high white blood cell content, or if they were stored for a long period of time.

Stem cells can develop into many different types of cells, so they are often used in treatment to replace or repair damaged organs or tissues. Allogeneic stem cell transplantation, which involves transferring stem cells from a healthy donor to a patient, can treat a variety of diseases, including leukemia, lymphoma, myeloma, thalassemia, and sickle cell disease.

Before the coronavirus outbreak, it was not common to freeze allogeneic donor stem cells prior to infusion. However, due to COVID-19's effects on donor and hospital availability, as well as new travel and transportation restrictions, more transplant centers including the NMDP are recommending cryopreservation.

"Prior to COVID-19, the donor and transplant systems were well coordinated and effective. Now, with irregular flights and closed borders, travel and transportation are not assured," said lead study author Duncan Purtill, MD, of Fiona Stanley Hospital in Western Australia. "Five to seven days before stem cell transplant, the recipient usually starts chemotherapy to remove all their bone marrow cells. Without a healthy transplant to replace the cells on the same day, they would be left with no functioning bone marrow, which would of course be very high risk and carry a poor prognosis. Life literally depends on the safe arrival and immediate infusion of stem cells."

Dr. Purtill and his team analyzed 305 samples of allogeneic stem cell products that were cryopreserved at participating Australian cell processing labs between 2015 and 2019. They found that, on average, the recovery of the stem cell products was 74%. This is considered an acceptable, viable recovery, enabling the cells to be used in transplantation. However, some products did not recover to that level: around 15% of the surveyed products had a cell recovery of less than 50%. In fact, the study found that quality recovery could range as low as just 6%. Such a significant cell loss after thawing may mean that the remaining cells may be too few, or too damaged, to achieve timely bone marrow recovery in the patient after infusion.

"It seems that there is variability in recovery and more work needs to be done to determine why," said Dr. Purtill. "When we freeze stem cells and then thaw them afterwards, we sometimes get unexpected results. In this study we identified some possible factors influencing that variability."

The research team pointed to three possible reasons for the loss of quality in some of the stem cells products they analyzed. First, they noted that prolonged transportation and storage time prior to cryopreservation was associated with a loss of quality. They also found that higher white cell concentration of the product affected its quality. It was thought that the presence of other white cells could adversely affect the stem cells, either by releasing damaging enzymes or chemicals, or else by consuming nutritional elements within the product and resulting in less healthy stem cells. And finally, they pointed out that a small proportion of cells which underwent complex manipulation before being frozen also suffered quality loss for instance, when the cell processing lab removed lymphocytes or washed the product to remove plasma and other noncellular components.

Dr. Purtill and his collaborators expressed hope that their findings could serve to inform and improve stem cell transplantation, collection, and processing procedures. "Our findings could be a note of caution for transplant centers to not take for granted that the frozen product they have received will show perfect recovery once thawed," said Dr. Purtill. "I hope centers will insist on receiving a pilot vial which has been frozen and transported in the same way. They can assess the pilot vial to determine its viability before they use the full product and start chemotherapy for the patient."

Blood Advancesis a peer-reviewed, online only, open access journal of the American Society of Hematology (ASH), the world's largest professional society concerned with the causes and treatment of blood disorders.

Blood Advances is a registered trademark of the American Society of Hematology.

SOURCE Blood Advances

http://www.bloodadvances.org

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Study: Cryopreservation Associated with Loss of Quality in Donor Stem Cell Products - PRNewswire

Recommendation and review posted by Bethany Smith

PHOENIX, Sept. 8, 2020 /PRNewswire/ --(OTC CELZ) -- Creative Medical Technology Holdings Inc. announced today receipt of a Notice of Allowance from the United States Patent and Trademark Office for its patent application, "Perispinal Perfusion by Administration of T Regulatory Cells Alone or in Combination with Angiogenic Cell Therapies."

The patent covers the use of activated T regulatory cells for inducing an increase in blood circulation in areas surrounding the disc of patients with lower back pain. It is believed that a significant proportion of patients suffering from lower back pain have abnormally poor circulation, which does not effectively remove waste products and irritants. Restoration of circulation in the lower back is associated with reduction of pain.

The Company acquired a previously granted US Patent # 9,598,673 covering use of various types of stem cells, autologous and allogeneic, for treating lower back pain. The Company has completed an autologous cell therapy pilot study in the area of lower back pain utilizing this patented technology and is currently in the process of assembling data for publication.

"Creative Medical Technology Holdings is developing a critical mass of issued intellectual property covering multiple cell therapy treatments of lower back pain as well as other indications," said Timothy Warbington, President and CEO of the Company. "Testimony to the size of the lower back pain market is the $1 Billion Mesoblast-Grunenthal deal for a pre-review cell therapy product1. We are enthusiastic to add this new therapy to our expanding portfolio of rapid-to-commercialize cellular therapies."

Creative Medical Technology Holdings has previously commercialized its CaverStemR technology involving personalized bone marrow cellular therapy for erectile dysfunction. This technology is covered by issued patent # 8,372,797 and a clinical trial demonstrating safety with signals of efficacy published in the peer-reviewed literature2.

"Immunotherapy is one segment of the biotechnology industry that is expanding at an exponential rate," said Donald Dickerson, CFO of the Company. "The recent Nobel Prize in the area of Immunotherapy of Cancer, as well as the current valuations of immunotherapy companies, validates the approaches that we have been developing, and now patenting. Essentially our approach is to use stem cells, or immunotherapy to enable the body to heal itself."

"The Company welcomes the biotechnology/life sciences community and key opinion leaders to contact us to discuss potential collaboration on our patented technologies in this amazing space," Mr. Warbington said further.

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visit http://www.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website at http://www.sec.gov.

Creativemedicaltechnology.comwww.StemSpine.com http://www.Caverstem.com http://www.Femcelz.com

1 https://www.biopharma-reporter.com/Article/2019/09/12/Gruenenthal-partners-with-Mesoblast-for-back-pain-cell-therapy#:~:text=Gr%C3%BCnenthal%20agrees%20deal%20with%20Mesoblast,disease%20in%20previously%20treated%20patients.

2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958721/

SOURCE Creative Medical Technology Holdings, Inc.

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Application of Immunotherapy to $7 Billion Lower Back Pain Market Patented by Creative Medical Technology Holdings - PRNewswire

Recommendation and review posted by Bethany Smith

Hematopoietic stem cells are young or immature blood cells found to be living in bone marrow. These blood cells on mature in bone marrow and only a small number of these cells get to enter blood stream. These cells that enter blood stream are called as peripheral blood stems cells. Hematopoietic stem cells transplantation is replacement of absent, diseased or damaged hematopoietic stem cells due to chemotherapy or radiation, with healthy hematopoietic stem cells. Over last 30 years hematopoietic stem cells transplantation market seen rapid expansion and constant expansion with lifesaving technological advances. Hematopoietic stem cells transplantation is also known blood and marrow transplantation which brings about reestablishment of the patients immune and medullary function while treating varied range of about 70 hematological and non-hematological disorders. In general hematopoietic stem cells transplantation is used in treatment of hereditary, oncological, immunological and malignant and non-malignant hematological diseases.

There are two types of peripheral blood stem cell transplants mainly autologous and allogeneic transplantation. In autologous transplants patients own hematopoietic stem cells are harvested or removed before the high-dose treatment that might destroy the patients hematopoietic stem cells. While in allogeneic transplants stem cells are obtained from a tissue type of matched or mismatched donor. Hematopoietic stem cells are harvested from blood or bone marrow and is then frozen to use later. Depending upon the source of hematopoietic stem cells, worldwide there are three types of hematopoietic stem cells transplants namely bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. Major drivers in the hematopoietic stem cells transplantation market are establishment of strong and well developed network of hematopoietic stem cells transplantation organizations having global reach and presence has recognized NGO named Worldwide Network for Blood and Marrow Transplantation Group (WBMT) in official relation with World Health Organization (WHO) and rapid increase in number of transplants. Major restraints in hematopoietic stem cells transplantation market is high cost of transplantation and lack of funding for WBMT and other organizations such as regional, national and donor.

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The global market for Hematopoietic stem cells transplantation market is segmented on basis of transplant type, application, disease indication, end user and geography:

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Based on transplantation type, hematopoietic stem cells transplantation market is segmented into allogeneic and autologous. Hematopoietic stem cells transplantation market is also segmented by application type into bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. The market for hematopoietic stem cells transplantation is majorly driven by bone marrow transplant (BMT) segment. Based on end user hematopoietic stem cells transplantation market is segmented into hospitals and specialty centers. Peripheral blood stem cell transplant type holds the largest market for hematopoietic stem cells transplantation. Hematopoietic stem cells transplantation market is further segmented by disease indication into three main categories i.e. lymphoproliferative disorders, leukemia, and non-malignant disorders. Segment lymphoproliferative disorder holds largest share amongst the three in Hematopoietic stem cells transplantation market. On the basis of regional presence, global hematopoietic stem cells transplantation market is segmented into five key regions viz. North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. Europe leads the global hematopoietic stem cells transplantation market followed by U.S. due to easy technological applications, funding and high income populations. Other reasons for rise in hematopoietic stem cells transplantation market is high prevalence of lymphoproliferative disorders and leukemia; demand for better treatment options; and easy accessibility and acceptance of population to new technological advances. Transplantation rates in high income countries are increasing at a greater extent but continued rise is also seen in low income countries and expected to rise more. Hematopoietic stem cells transplantation market will have its potential in near future as being a perfect alternative to traditional system in many congenital and acquired hematopoietic disorders management. While India, China and Japan will be emerging as potential markets. An excellent and long term alternative to relief by side effects of chemotherapy, radiotherapy and immune-sensitive malignancies is another driver for hematopoietic stem cells transplantation market. The key players in global hematopoietic stem cells transplantation market are Lonza, Escape Therapeutics, Cesca Therapeutics Inc., Regen BioPharma, Inc., Invitrx Inc, StemGenex, Lion Biotechnologies, Inc., CellGenix GmbH, Actinium Pharmaceuticals, Inc., Pluristem, Kite Pharma, Novartis AG.You Can Request for TOC Here @ https://www.persistencemarketresearch.com/toc/14563

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Global Hematopoietic Stem Cells Transplantation Market to Witness Rapid Development During the Period 2017 2025 - The News Brok

Recommendation and review posted by Bethany Smith

A novel Bcl-2 inhibitor, APG-2575, has been granted an Orphan Drug designation (ODD) by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL), announced Ascentage Pharma in a press release.1

This marks the second ODD for APG-2575, after 1 was granted to the drug in July 2020 for the treatment of Waldenstrm Macroglobulinemia (WM).2

At present, CLL still presents considerable unmet medical needs. APG-2575 is a key drug candidate in Ascentage Pharma's pipeline targeting apoptosis. The APG-2575 received this ODD from the FDA shortly after the first ODD in WM, and this designation will be helpful in enhancing our communication with the FDA and expediting our development of APG-2575 in these rare cancer diseases," said Yifan Zhai, MD, PhD, chief medical officer, Ascentage Pharma, in a statement.1 All the policy support and incentives as a result of this ODD will help us accelerate the global clinical development of APG-2575, which we hope will soon offer additional treatment options for patients with CLL."

In hematologic malignancies, APG-2575 may selectively block Bcl-2 as a way to renew the apoptosis process in cancer cells. The first study of APG-2575 in CLL, as well as in small lymphocytic leukemia (SLL), is currently recruiting 35 patients with relapsed or refractory disease. In the phase 1b dose-escalation study (NCT04215809), patients will receive APG-2575 alone or in combination with other therapeutic agents. The primary end point of the study is dose-limiting toxicity, and the secondary end point is the maximum tolerated dose of APG-2575.

The study will follow a non-randomized 3 + 3 design at a starting dose of 200 mg given on day 1 of a 28-day cycle. The dose will be increased to 400 mg, followed by 600 mg, 800 mg, and 1200 mg.

To be included in the trial, patients must be 18 years or older with a histologically confirmed diagnosis of CLL/SLL, and ECOG performance status of 2 or lower, adequate bone marrow function, and a serum creatinine level of 1.5upper limit of normal. In part 1, patients will be eligible for dose escalation if they have received 3 or fewer prior lines of systemic therapy. Female patients are required to be postmenopausal for 2 years or surgically sterile prior to beginning treatment in the study.

Patients are excluded from this study if they have undergone allogeneic stem cell transplant within 90 days of joining the study, have active graft-versus-host-disease or are in need of immunosuppressive therapy, and/or have Richter's syndrome. The study also excludes patients with certain prior therapies and comorbidities that may interfere with APG-2575 treatment.

Multiple cancer centers in the United States are involved in the phase 1b study of APG-2575 including the Mayo Clinic in Scottsdale Arizona, City of Hope in Duarte, California, Dana-Farber Cancer Institute in Boston, Massachusetts, Novant Health in Charlotte, North Carolina, Grabrail Cancer Center in Canton, Ohio, Cleveland Clinic in Cleveland, Ohio, and Swedish Health in Seattle, Washington.

Outside of the realm CLL/SLL, APG-2575 is being investigated in other hematologic malignancies like WM, AML, and T-cell prolymphocytic leukemia. Studies of APG-2575 in these disease states are currently recruiting patients in centers in the United States, Australia, and China.

References:

1. Ascentage Pharma's Bcl-2 inhibitor apg-2575 granted Orphan Drug designation by the FDA for the treatment of chronic lymphocytic leukemia. News release. Ascentage Pharmaceuticals. September 7, 2020. Accessed September 8, 2020. https://prn.to/2ZiOqFJ

2. Ascentage Pharmas Bcl-2 inhibitor apg-2575 granted Orphan Drug Designation by the FDA for the treatment of waldenstrm macroglobulinemia. News release. Ascentage Pharmaceuticals. July 15, 2020. Accessed September 8, 2020. https://bit.ly/329A5gL

Excerpt from:
FDA Grants Orphan Drug Designation to Novel Bcl-2 inhibitor in CLL - Targeted Oncology

Recommendation and review posted by Bethany Smith

Skin fibroblasts were successfully reprogrammed into the smooth muscle cells (red) and endothelial cells (white) which surround blood vessels. The cells nuclei are shown in blue. Credit: Bersini, Schulte et al. CC by 4.0

Salk study is the first to reveal ways cells from the human circulatory system change with age and age-related diseases.

Salk scientists have used skin cells called fibroblasts from young and old patients to successfully create blood vessels cells that retain their molecular markers of age. The teams approach, described in the journal eLife on September 8, 2020, revealed clues as to why blood vessels tend to become leaky and hardened with aging, and lets researchers identify new molecular targets to potentially slow aging in vascular cells.

The vasculature is extremely important for aging but its impact has been underestimated because it has been difficult to study how these cells age, says Martin Hetzer, the papers senior author and Salks vice president and chief science officer.

Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. So, most knowledge about how blood vessel cells age comes from observations of how the blood vessels themselves change over time: veins and arteries become less elastic, thickening and stiffening. These changes can contribute to blood pressure increases and a heightened risk of heart disease with age.

From left: Martin Hetzer and Simone Bersini. Credit: Salk Institute

In 2015, Hetzer was part of the team led by Salk President Rusty Gage to show that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age.

In the new work, Hetzer and his colleagues applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.

We are among the first to use this technique to study the aging of the vascular system, says Roberta Schulte, the Hetzer lab coordinator and co-first author of the paper. The idea of developing both of these cell types from fibroblasts was out there, but we tweaked the techniques to suit our needs.

The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging.

The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation. In patients with HGPS, some genes reflected the same expression patterns usually seen in older people, while other patterns were unique. In particular, levels of BMP-4 protein, which is known to play a role in the calcification of blood vessel, were slightly higher in aged cells compared to younger cells, but more significantly higher in smooth muscle cells from progeria patients. This suggests that the protein is particularly important in accelerated aging.

The results not only hinted at how and why blood vessels change with age, but confirmed that the direct-conversion method of creating vascular endothelial and smooth muscle cells from patient fibroblasts allowed the cells to retain any age-related changes.

One of the biggest theoretical implications of this study is that we now know we can longitudinally study a single patient during aging or during the course of a treatment and study how their vasculature is changing and how we might be able to target that, says Simone Bersini, a Salk postdoctoral fellow and co-first author of the paper.

To test the utility of the new observations, the researchers tested whether blocking BMP4 which had been present at higher levels in smooth muscle cells developed from people with HGPS could help treat aging blood vessels. In smooth muscle cells from donors with vascular disease, antibodies blocking BMP4 lowered levels of vascular leakiness one of the changes that occurs in vessels with aging.

The findings point toward new therapeutic targets for treating both progeria and the normal age-related changes that can occur in the human vascular system. They also illustrate that the direct conversion of fibroblasts to other mature cell types previously successful in neurons and, now, in vascular cells is likely useful for studying a wide range of aging processes in the body.

By repeating what was done with neurons, weve demonstrated that this direct reprogramming is a powerful tool that can likely be applied to many cell types to study aging mechanisms in all sorts of other human tissues, says Hetzer, holder of the Jesse and Caryl Philips Foundation Chair.

The team is planning future studies to probe the exact molecular mechanisms by which some of the genes they found to change with age control the changes seen in the vasculature.

Reference: Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome by Simone Bersini, Roberta Schulte, Ling Huang, Hannah Tsai and Martin W Hetzer, 8 September 2020, eLife.DOI: 10.7554/eLife.54383

Other researchers on the study were Ling Huang and Hannah Tsai of Salk. The work was supported by grants from the National Institutes of Health, the NOMIS Foundation and an AHA-Allen Initiative in Brain Health and Cognitive Impairment award made jointly through the American Heart Association and the Paul G. Allen Frontiers Group. Simone Bersini was supported by the Paul F. Glenn Center for Biology of Aging Research at the Salk Institute.

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Scientists May Have Discovered a Way to to Slow Aging by Direct Reprogramming of Human Cells - SciTechDaily

Recommendation and review posted by Bethany Smith

Im not saying my skin has aged significantly this year but my six-year-old recently asked me why I had asix-pack on my forehead. After six months of stressful days, sleepless nights and home-school nightmares, its become apparent that matters need taking in hand. And theres something about the early autumn, with its nip in the air, and its new-found appreciation for proper, non-negotiable routines that feels right for a skincare overhaul.

Fortunately, the seasons big skincare launches abound with new ways to reset your skin, from serious, sleeves-rolled-up jump-starting regimens, which last up to a month and deliver a rapid burst of intense reconditioning, to new strategies that claim todetoxify your daily regime without your having to somuch as cut down on caffeine.

Sorting out most modern-day skincare complaints from sluggish cell turnover caused by tiredness and stress to overstimulated skin (a result of using products not suited to one another), to undeserved lacklustre complexions caused by outdated products requires a bit of areboot. It could be a facial; it could be a peel. But inthedays when weve all become beauty hobbyists, performing DIY facials like pros, it could also be a pleasurable at-home experience for the price of a couple ofdecent salon treatments.

Dr Anita Sturnham, a London-based GP specialising in dermatology who launched her own excellent skincare line,Decree, last year, became so aware of how many of herpatients especially those suffering with breakouts, pigmentation and dehydration needed a thorough overhaul that she recently launched her own two-week Skin Reset Kit. Sturnham believes 90 per cent of the skin issues she sees are self-inflicted simply by using the wrong products and that stripping your skincare right back is an essential step for getting the best from your skin.

Another recent reset kit is Budapest brand Omoroviczas The Cure programme, which in nine days cycles through anacid phase (to resurface), a remineralise phase (tostimulate microcirculation) and a reconstruct phase (forrenewed elasticity). You can repeat it every three months, ideally to coincide with the change of seasons.

One of the best known brands for an intensive treatment is that of anthropologist-turned-dermatologist Dr Phillip Levy. A Geneva-based wound-healing specialist,he believes that only via resetting can you achieve some of the most visible anti-ageing results andhis Ultimate Stem Cell Spring Homecure (the springmeans spring clean but it can bestarted any time)is legendary. Manyofthe cures we have studied over the years seem to be everyday products nicely repackaged, he says.But to have something truly transformational, theyneed go deep enough to stimulate your own collagen, elastin and hyaluronic acid production, and last four weeks or even eight or more.

Its true that these regimes work best when they feel elevated from the everyday. And when it comes to products with a built-in sense of occasion, no one does it better than Sisley. Even before you get to the science and the scents, and the textures it has a particular French earnestness that makes every product feel like an event. Which must make LIntgral Anti-Age La Cure, its new skin-resetting regimen, at 775 for a four-week supply, a veritable tapis rouge.

For each of the four week-long phases Impulse, Reset, Consolidate, Renaissance theres a phial of creamy serum, about the size of an eye cream. You use each one for seven days, applying eight pumps of product morning and night (this feels a lot, and it takes a few minutes to properly sink in). You can follow with eye cream or moisturiser if you want to, but I didnt feel the need. The bottles have been slightly overfilled so as to ensure you dont run out, but when you get to the end of the seventh day, you must start the next one nonetheless. (This feels wasteful, but I was assured by Sisleys training manager Lorna Green that I could save up these last drops and use them a couple of weeks after the course, as a further boost).

The formulation works on the skins mitochondria the batteries where cellular energy is stored. Theylose the ability to restore themselves over time, particularly during intense periods of stress and hormonal changes, so following either one of those would be an ideal time to try it. The breakthrough wasthe discovery of the mechanisms of a process called autophagy (for which Japanese biologist Yoshinori Ohsumi won the Nobel Prize for medicine in2016), whereby damaged cell components such as mitochondria destroy themselves to protect the rest ofthe cell. La Cure boosts the elimination of these wasteelements, allowing the healthy cells left behind tosoak up energy and regenerate promoting the appearanceof healthier, more youthful skin. In skincare terms, this is no mean feat.

Where the real technology is happening, it wont be long before they eclipse the big jars of moisturiser completely

It sounds intense and its certainly super-active: by the end of the first week I had a small, yet determined, spot on my chin (which I cannot believe was a coincidence) and a little more redness than usual, too. The following week, cell detoxification week, my skin was starting to feel unusually smooth. By the end of the fourth week, my skin was smoother and clearer than I can ever remember. Its also, though, a real example of skincare as self-care: as much as the thought of a radically rejuvenated complexion, the daily reminder that youve sidelined your usual clutter of products in favour of something exceptional is almost enough to bring on a glow.

With any reset complete, the focus should then be on keeping your skin detoxified and renewed. One update worth looking at is a serum. Whereas the luxurious facecream at the end of your regime used to be the jewel in any skincare crown, these dayslightweight serums are where the real technology ishappening, and it wont be long before they eclipse thebig jars of moisturiser completely.

While serums used to be a targeted addition to your face cream specifically for age spots, say, or wrinkles the best new ones are genuinely impressive all-rounders. Este Lauder has just revamped Advanced Night Repair, one of the first ever mainstream skin serums and a product so ubiquitous that among beauty editors it has acronym status. (See also: Cliniques DDML, aka Dramatically Different Moisturizing Lotion). And in October, Suqqu, which hails from Japan where serums have been the mainstay of skincare much longer than here will launch Vialume, its most advanced line yet, containing glucosamine and amino-acid derivatives designed to targetall five key characteristics of great skin: moisture, firmness, smoothness, translucency and brightness.

Another product gaining increasingly scientific status is face oil, which should no longer be dismissed as the preserve of the militantly natural beauty brigade. Augustinus Bader, the world-leading wound-healing specialist whose Rich Cream was the runaway skincare success of 2018, has just launched The Face Oil, which contains a slew of delicious-sounding oils argan, babassu, hazelnut, karanja as wellas a healthy dose of TFC8, the complex of vitamins, amino acids and synthesised molecules that has made Baders products famous. Meanwhile, RVive Glow Elixir Hydrating Radiance Oil is bronze in colour and slightly shimmering although unusually, it leaves no evidence of glittery particles. Alongside a cocktail of seed oils, it contains the brands signature Bio-Renewal Protein, rendering it a real skincare/make-up hybrid and a great transitional product for this time of year.

Another need-to-know and a great option particularly for younger skin is Rihannas new Fenty Skin line. Theres Total Cleansr, which would work especially well as the first step of a double-cleanse, and Fat Water, which Ri-Ri calls a toner-serum hybrid but its the Hydra Vizor daily moisturiser that triumphs. This so-called Invisible Moisturizer has an SPF30 that leaves no white cast to the skin whatsoever, primarily because the product has a gorgeous pinkish hue and a blurring effect. The ghostly pallor left behind by so many SPF products is a particular challenge to people of colour and this range was designed to work seamlessly with make-up on all skin tones. It also smells great juicy with just the slightest medicinal tinge and comes in a refillable tube.

The recently launched skincare brand U Beauty wants to reset not just your skin, but the way you think about your whole regime. Were all doing too much, says founder Tina Craig, who until two years ago was working as an influencer/ambassador for the worlds biggest skincare brands but admits being as confused as anyone about what to use; she had ended up with a 13-step skincare routine. I started noticing that everyone Iknew had skin that looked translucent, which is not how it should look, she says. Then I looked at my grandma and relatives in Asia, and their skin was not like that. It was thick. Dense. Firm.

U Beauty is her answer to what she calls the cosmeticconfusion. Its first product, the Resurfacing Compound (which sold out three times on UK stockist Net-aPorter), was designed to replace toner, vitamin C, hyaluronicacid, AHAs, physical exfoliants, antioxidant serums and retinol products. From this month, theres alsoSuper Smart Hydrator, a moisturising serum that seeks out damaged cells and only treats the skin where itneeds it. Bookend these two with cleanser and SPF, saysCraig, and youre good to go.

Finally, could we reset the way we use products altogether? New brand Noble Panacea is overseenby ascientific heavyweight: Sir Fraser Stoddart, who was awarded the 2016 Nobel Prize in chemistry. A microscopic delivery system releases its active ingredients into the skinin a programmed sequence, and it comes in individualdoses packed in mini sachets to ensure the optimal amount of these ingredients stays potent until theminute it reaches your skin.

On the one hand, they feel counter to the idea of luxury face creams more like a free sample from a beauty hall but on the other, the boxes made from renewable materials and ultra-hygienic 0.5ml doses feel modern and Covid-safe. (You can send them for recyling in a complimentary envelope to TerraCycle, with which the brand has partnered). And if nothing else, as its global ambassador ithas snapped up the actress Jodie Comer, who must havebeen pursued by every beauty company under the sun and as far as I can tell, theres no sign of a six-pack on her forehead.

Read the original here:
The great beauty reset: how to reboot your skin - Financial Times

Recommendation and review posted by Bethany Smith

The one thing all beauty therapists should know about exfoliatingWhen were young, our cells typically take 28 days to complete the cell turnover cycle. This begins in the lowest layer of the epidermis the stratum germinativum where the stem cells are housed. From here the skin cells migrate through each layer of the epidermis until they reach the outermost layer the stratum corneum.

This process takes about 14 days, after which the cells stay in the stratum corneum for approximately another 14 days for a 28 day total cycle. At this point, the skin begins to slough off these dead skin cells, which will be replaced by new ones a process known as desquamation.

As we age, the desquamation cycle naturally slows down and leaves us with a build-up of dull, dry and dehydrated cells. Exfoliation helps speed up desquamation, making it an essential part of every clients skin care regimen.

Chemical and physical exfoliants both remove the dulling, dead skin cells that accumulate on skins surface, revealing brighter, fresher-looking skin. Regular exfoliation can also help stimulate skin cell renewal, encouraging the cells to come to skins surface more quickly.

Additionally, removing dead cells serves to increase the penetration of hydrating ingredients and other targeted treatments.

While this is common knowledge among beauty therapists, clients are often unaware of this benefit. For example, if youve ever heard a client say that their skincare products arent working anymore, its likely that a build-up of dead skin cells is preventing active ingredients from being absorbed and acting effectively on the skin. The solution: regular exfoliation.

If your clients suffer with dull, flaky skin, dryness or dehydration, then you may reach for a hydrating masque in treatment to remedy these symptoms, but if you havent exfoliated first, then dead cell build-up can act as a barrier, stopping hydrating ingredients from being effectively absorbed.

The quickest way to smooth and renew your skin is with an exfoliant. However, did you know that its critical to replenish lost moisture in the barrier within 60 seconds after exfoliating or skin will become dehydrated? WithDermalogicas Hydro Masque Exfoliantyou dont need to worry about applying two separate formulas as it combines both regimen steps in one.

DermalogicasHydro Masque Exfoliantisa hydrating and exfoliating five-minute masque that smooths and renews for healthy looking skinand offers a personalised way to exfoliate via unique touch-activated bamboo spheres.

The spheres can be moved to the areas you think clients need more exfoliation where the skin is drier or rougher in texture. The ultra-fine bamboo filled spheres dissolve upon application of light pressure, delivering a gentle level of physical exfoliation. The spheres also contain a hydrating polysaccharide and glycerin to protect the skins moisture barrier, usually depleted by exfoliating. This allows a customised exfoliating experience in contrast to dual action formulas that have no isolation of the exfoliating actives.

Another unique aspect ofthe product isthat it delivers instant and long-lasting hydration immediately as you exfoliate. The hydro-cream base of the masque contains lots of hydrating ingredients to deliver moisture and barrier restoring properties.

Snow mushroom holds 450 times its weight in water, infusing skin with hydration, and it is also rich in antioxidants and Vitamin D. The masque also contains jojoba ester and amino acids derived from sugar beets to hydrate and strengthen the skins natural barrier, with cucumber extract providing a soothing, refreshing finish.

In clinical studies,Hydro Masque Exfoliantis proven to give a smoother feeling and more hydrated skin after just one use, with 80% of consumers saying their skin felt smoother and they liked the appearance of their skin.

Exfoliation is an important regimen step for healthier, more luminous skin, just dont forget to hydrate too.

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The one thing all beauty therapists should know about exfoliating - Professional Beauty

Recommendation and review posted by Bethany Smith

As we move into spring, the seasonal change and being indoors more often can leave our skin feeling a little lacklustre.

If you've also got uneven skin tone, you might find yourself reaching for vitamin C products to bring that long-lost glow back to your skin. (I know I have.)

Yep, you know what I mean - dull spots or patches that make an unwelcome visit on your face. Somuch fun.

You've probably seen a few skincare ranges with vitamin C as a key ingredient, but some have harsh and unnatural chemicals too. In fact, slathering harsh chemicals on your face to try achieve a more radiant, even complexion can do more harm than good if you're not exactly sure what you're putting onto your skin.

That's why Andalou Naturals' Brightening range is the perfect example of a high-performance cult natural skincare range that addresses concerns like uneven skin tone and pigmentation, all while using potent, vitamin C-rich ingredients that pack some serious punch. Oh, it's cruelty-free too.

Andalou Clementine + C Illuminating Toner. Image: Supplied

According to a recent trial*, 86 per cent of people saw a more radiant and luminous complexion, while 73 per cent saw a more even skin tone and reduced pigmentation in 28 days when using Andalou's Brightening Range.

It's been so high in demand that the famous Brightening Pumpkin Honey Glycolic Face Mask, which Mamamia reviewed back in April, recently sold out on their website(it's back now, thankfully). While they can't make their pumpkins grow any faster, if you can't get it online you can also get it from your local Chemist Warehouse or Priceline.

You've probably seen the Andalou's Brightening Range popping up on your Instagram, with model Natalia Kalinowski, author and lifestlye influencer Sjana Elise Earp, and model and lifestyle influencer Ruby Tuesday Matthews, all singing its praises.

See the article here:
Got uneven skin tone? There's a cult natural range with vitamin C that's changing the game. - Mamamia

Recommendation and review posted by Bethany Smith

Medical skin care products are used for beautifying or to address some other skin care problems. The cosmetic industry is booming and skin care forms a very huge part of this industry. The aesthetic appearance is so important that people spend a lot on skin care products and treatment. People being more technologically aware of the various new skin care products trending in the market. In addition to the aesthetic application, the medical skin care products are also used to address issues such as acne, pimples or scars.

Medical Skin Care Products Market: Drivers and Restraints

The medical skin care products is primarily driven by the need of natural based active ingredients products which are now trending in the market. Consumers demand medical skin care products which favor health and environment. Moreover, the consumers are updated with the trends so that various companies end up providing such products to satisfy the customers. For instance, a single product face mask has thousands of different variants. This offers consumers different options to select the product depending on the skin type. Moreover, the market players catering to the medical skin care products are offering products with advanced technologies. For instance, Santinov launched the CICABEL mask using stem cell material based on advanced technologies. The stem cells used in the skin care product helps to to protect and activate the cells and promote the proliferation of skin epidermal cells and the anagenesis of skin fibrosis.

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Medical Skin Care Products Market: Segmentation

On the basis of product type the medical skin care products market can be segmented as:

On the basis of application, the medical skin care products market can be segment as:

On the basis of distribution channel, the medical skin care products market can be segment as:

Medical Skin Care Products Market: Overview

Medical skin care products are used to address basic skin problems ranging from acne to scars. There are various advancements in the ingredients used to offer skin care products to the consumers. For instance, the use of hyaluronic acid and retinoids is the latest development in the industry. The anti-aging creams are at the forefront as the help treating issues such as wrinkles, scars, acne, and sun damage. Another, product in demand is the probiotic skincare which include lactobacillus and bifidobacterium.

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Medical Skin Care Products Market: Region-wise Outlook

In terms of geography, medical skin care products market has been divided into five regions including North- America, Asia- Pacific, Middle-East & Africa, Latin America and Europe. North America dominated the global medical skin care products market as international players are acquiring domestic companies to make their hold strong in the U.S. LOral is accelerating its U.S. market by signing a definitive agreement with Valeant Pharmaceuticals International Inc. to acquire CeraVe, AcneFree and Ambi skin-care brands for US$ 1.3 billion. The acquisition is expected LOreal to get hold of the brands in the price-accessible segment. Asia Pacific is expected to be the fastest growing region owing to the increasing disposable income and rising awareness towards the skin care products.

Medical Skin Care Products Market: Key Market Participants

Some of the medical skin care products market participants are Avon Products Inc., Beiersdorf AG, Colgate-Palmolive Company, Kao Corporation, LOral S.A., Procter & Gamble, Shiseido Company, The Estee Lauder Companies Inc., Unilever PLC, Revlon, Clinique Laboratories, llc., Murad, LLC., SkinCeuticals, RMS Beauty, J.R. Watkins and 100% PURE.

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Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics andmarket research methodologyto help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

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Read more:
Demand for Medical Skin Care Products Market to Witness Rapid Surge During the Period 2017 2025 - The News Brok

Recommendation and review posted by Bethany Smith

Ultas 21 Days of Beauty sale is in full swing, which means for the next couple of weeks, you can save 50% off a selection of bestselling skincare and must-have makeup. What better reason to refresh your beauty collection?

The biannual event began on Sunday, August 30, and runs through Saturday, September 19, and the daily deals include a number of of celebrity favorites from Kylie Cosmetics, Skyn Iceland, Benefit and Anastasia Beverly Hills, to name but a few.

Below, the A-list-approved beauty deals that are definitely worth your dollars.

Date: Tuesday, September 8

Loved by Gwyneth Paltrow whose partnered with Juice Beauty in 2016 to launch Goops own skincare line this vegan and cruelty-free cream is made with a proprietary blend of fruit stem cells and vitamin C infused into a resveratrol-rich grape formula. The lines booster serum will be half-off on September 8 as well.

$35 (usually $70)

Date: Thursday, September 10

I love a good summer tan, but the sun can be so damaging to your skin, Kim Kardashian wrote on her namesake app in 2018. I always wear SPF to protect my skin, but I also like to use self-tanners as safe alternative to tanning outside. She named this lightweight product as her formula of choice.

$22 (usually $44)

Date: Saturday, September 12

Speaking of the Kardashian-Jenners, you wont want to miss the chance to stock up on beauty mogul Kylies bestselling lip kits for a steal. Not a fan of the matte finish? The companys velvet version will also be half-off on September 12.

$14.50 (usually $29)

Date: Saturday, September 12

Kylie Jenner, Lili Reinhart, Bella Hadid and Rosie Huntington-Whiteley are just a few of the many celebs who love this brands signature pink drying lotion. Snag a travel-friendly version of the blemish-busting solution in this kit, along with Badescus equally popular rosewater facial spray.

$11 (usually $22)

Date: Sunday, September 13

Goldie Hawn, Kristen Bell and Julia Louis-Dreyfus cant get enough of these patches, which boast cooling and de-puffing powers. A travel-sized box with four pairs instead of the usual eight will also be half-off on September 13.

$16 (usually $32)

Date: Tuesday, September 15

This brands cult favorite Good Genes All-In-One Lactic Acid Treatment revitalizes the look of dull, congested and sun-damaged skin and comes approved by Jourdan Dunn and Helen Mirren. This handy kit includes a mini size, along with one of Sunday Rileys popular Ceramic Slip Cleanser to round out your skincare routine.

$12.50 (usually $25)

Date: Friday, September 18

Available in a range of shades, this bronzers beloved by the likes of Julianne Hough, Selena Gomez and Ariana Grande.

$15 (usually $30)

Date: Friday, September 18

Anastasia Soare is the eyebrow whisperer behind the flawless arches of stars including Kim Kardashian, Jennifer Lopez, Victoria Beckham and Amal Clooney, to name just a few. This kit comes with mini sizes of everything you need to maintain your brows at home, from Soares smash-hit Brow Wiz pencil to her Dipbrow taming gel.

$19 (usually $38)

Read the original post:
Ulta's 21 Days of Beauty sale is full of celebrity-loved makeup and skincare - Page Six

Recommendation and review posted by Bethany Smith

We love these products, and we hope you do too. E! has affiliate relationships, so we may get a small share of the revenue from your purchases. Items are sold by the retailer, not E!.

It's time for the shopping event skincare fanatics and makeup addicts have been waiting for:Ulta Beauty's 21 Days of Beauty is here!

From now until Saturday, September 19th, shoppers can stock up on an array of makeup and skincare products at up to 50% off. You can expect amazing buys from brands such asUrban Decay,Mario Badescu,KKW Beauty,Kylie Cosmeticsand many more! And if you're not sure about what you're buying, try before you buy with GLAMlab, Ulta Beauty's virtual product try-on (it's free on the brand's app). Just remember: you only have one day to shop each deal, so if you spot something you can't live without, make sure you grab it before it's gone!

For today's deal, you can get 50% off select faux mink lashesand 50% off Juice Beauty's Anti-Wrinkle Moisturizer and Booster Serum! Check out our faves below!

View original post here:
Ulta Beautys 21 Days of Beauty Deal of the Day: 50% Off Juice Beauty and Select Faux Mink Lashes! - E! NEWS

Recommendation and review posted by Bethany Smith

Well, weve made it more than halfway through the yearcan you believe it? Schools are once again starting up (online and in-person), the weather is crisper (and drier), election season is in full throttle (register to vote!), and the global pandemic continues to ravage (please wear a mask!). As we begin to settle into September, its more important than ever to take care of our bodies and minds so we can show up at full capacity for ourselves in the present. Take a moment and check-in with yourself today, whether its with a calming, immune-boosting coffee mix-in or a CBD-infused bath soak. Wake me up when September (and 2020) ends!

1. African Botanics Revitalizing Therapy GelHunched over your laptop all day? Aside from investing in a laptop stand, utilize this invigorating gel from South African-made, eco-luxury skincare brand African Botanics to soothe neck and shoulder aches. This miracle-in-a-chic-tube promises to reduce swelling, promote circulation, and provide a cooling, thermal feeling so you can restore muscles for the next workday.

2. Clevr Golden SuperLatteCancel the caffeine jitters and opt for a turmeric-and-oat-milk latte. Naturally sweetened with monk fruit and chock-full of warming spices, this Clevr spin on trendy golden milk lattes hits the spot for a comforting, post-lunch pick-me-up.

3. OUAI Chill PillsIts Friday night and youre not going anywhere, so whats there to do? Light some candles, play some jazz, draw a hot bath, and drop in these adorable OUAI Chill Pills for some seriously luxurious me-time. Each jasmine-and-rose-scented vegan tablet is filled with hemp, jojoba, and safflower seed oil to leave skin ultra moisturized.

4. Apothkary Chill The F* Out Herbal SupplementAs fall seeps in and we get closer to peppermint mocha season, this stress-reducing, serotonin-boosting elixir from Apothkary tastes like a peppermint hot chocolate mix. While we reminisce of the snowy holidays ahead, two powerhouse adaptogensreishi and ashwagandhawork wonders to relieve our pent-up anxiety.

5. Shanti Rejuvenate Roll On With Hemp CBDAyurvedic essential oils and Colorado-sourced hemp blend seamlessly to bring clarity to stressed-out brains in this Shanti Wellness roll-on. The small, easy-to-use packaging provides relief for those on-the-go so you can be chill whatever the occasion (long lines for the grocery store, strangers refusing to wear a mask, disposable gloves all over the ground the usual).

6. Activist Skincare Healing Water Toning MistThe vegan skincare connoisseurs at Activist believe self-care is fuel for the activism we should all be doing every day. So while youre making calls, advocating for marginalized communities, and attending protests (safely and with a mask), remember to take a moment for yourself. Add this hydrating, hyaluronic mist to your desk essentials for a small, calming break. The matte glass, recyclable bottle adds an elegant design to your workstation and the refreshing scent of cucumbers instantly calms.

7. Tata Harper Aromatic Irritability TreatmentIs your work-from-home buddy chewing their cereal as loudly as possible before youve had your cup of coffee? Instead of blasting your headphones, try this essential oil blend from natural beauty queen Tata Harper. Dab a few drops onto palms, rub together, and inhale deeply for an instant mood-lifting hit of balancing jasmine, fresh geranium, and soothing cypress.

8. Facialworks Sonic Wave + Coast Is Clear DuoMissing your monthly facials? Orange County-based, non-toxic spa specialists Facialworks brings the expertise straight to your home. With its extraction duo, you can prepare skin for a painless mini-facial and use the ultrasonic skin spatula to cleanse, get rid of blackheads or pimples, and infuse serums for maximum absorption. Clear skin, here we come!

9. The Good Patch Be Calm PatchPatches are the new It item for wellness brandsfrom pimple zappers to calming mood boosters like this menthol-infused stick-on from The Good Patch. Simply peel and stick on your wrist (or other veiny part of your skin) for over eight hours and feel nerves calm by the mix of hemp and other natural ingredients.

10.ORPHEUS Resurrection All-In-One SerumInspired by the regenerative powers of the haberlea rhodopensis flower found in the mountains of Bulgaria, family-run business ORPHEUS spent more than 20 years researching the properties of the rare blossom. Now, theyve packed the unique plants stem cells into this all-in-one serum to craft a richly intensive, calming experience for stressed-out skin. Thats pretty much all you could ask for in a bottle.

11. Missionary Chocolates CBD TrufflesA chocolate a day keeps the doctor away or something like that. Naturopathic physician Melissa Berrys Portland-based Missionary Chocolates crafts the meltiest hemp-derived fair-trade chocolates for the ultimate mid-day pick-me-up. Plus, with its cute packaging, you can send your loved ones a treat to get through the hard days.

12. The Nue Co Magnesium SprayStaring at the ceiling for hours when bedtime rolls around? Its cooljust spray this sleep aid spray from The Nue Co. made with high-quality magnesiuma mineral that is essential for over 325 biochemical reactions in the bodyand youll soon stop counting sheep. You can also use it as a post-workout aid for faster muscle recovery.

13. Life & Apples Wellness Journal Planners are a useful tool to track your busy schedule, but they can also be beneficial for checking in with yourself. Made of eco-friendly, vegan materials, this 90-day rose gold journal makes it simple to track habits, plan healthy meals, and set weekly goals. Plus, you can write down what youre grateful for to begin day on a bright note.

14. Four Sigmatic Lions Mane ElixirCaffeine levels through the roof? Same here. Thats why Im turning to lions mane, a favorite mushroom among researchers and herbalists touting benefits such as boosting mood, supporting cognitive function, and providing physical energy. Add to smoothies, decaf coffee, and tea to get a boost of brain-healthy nootropics.

15. Derma-E Vitamin C Bright Eyes Hydro Gel PatchesNon-stop screen-time is sure to wreak havoc on your eye health. When suffering from tired, baggy eyes, turn to Derma-Es moisture-intensive gel patches before your morning Zoom call. These sparkly yellow gels contain allantoin to increase smoothness, caffeine to reduce puffiness, and vitamins C and B3 to target fine lines, wrinkles, and dullness.

16. Rosebud Awaken CBD Bath SoakIf youre one of the rare types that like to take baths in the mornings, this uplifting, magnesium-rich soak is for you. With notes of bergamot and orange essential oils, 50mg of CBD, and calming Epsom salts, heck, Im considering waking up an hour earlier (wish me luck) to run a warm bath and start the day on a much chiller note.

17. REN Clean Skincare Atlantic Kelp and Magnesium Salt Anti-Fatigue Exfoliating Body ScrubExfoliate your hard-working body with a fresh body scrub from sustainability-focused REN Clean Skincare designed to gently polish and smooth skin with fresh sea and Epsom salts. Breathe in sage, cypress, geranium, and rosemary for an uplifting start to the day.

18. No B.S. Charcoal Detox Peel-Off MaskTheres just something so satisfying about a peel-off mask, but when it takes forever to take off while also causing wincing pain, wed rather avoid it altogether. Enter: cruelty-free and vegan skincare brand No B.S.s purifying, activated charcoal mask. In less than 20 minutes, watch the clean, pH-balanced formulation gently peel away the days impurities and reveal smooth, bright skin.

19. Buddha Teas Peppermint CBD TeaRather than using hemp oil like many other CBD teas, Buddha Teas figured out a way to use dispersible water-soluble CBD, ensuring optimal bioavailability and maximum absorption of the calming, non-psychoactive compound. With flavors such as Turmeric & Ginger, Matcha Green, and Peppermint, grab your tea setsits time for relaxation!

20. Pacifica Overnight Vegan Collagen Recovery CreamYour skin repairs itself at night, making the products used for your nighttime ritual all the more important. For those needing a little more glow, this Pacifica recovery cream infuses vegan collagen, essential lipids, antioxidants, and flower extracts to work some magic during your beauty sleep. Glowing, radiant skin, were dreaming of you!

21. Future Kind Vegan Sleep SupplementsStress hits hard at night when youre trying to get your Zzzs, which is why brothers and nutritionists Shaun & Eliot Cunningham developed Future Kinds eight-ingredient, all-natural sleep supplement that promises to have you feeling energized the next morningnot sluggishthanks to the addition of L-theanine.

22. Peak + Valley Balance My Stress BlendThrough the use of adaptogens such as reishi mushroom, eleuthero root, and ashwagandha, Black-owned wellness brand Peak + Valleys chocolaty, earthy stress blend pairs well with an afternoon tea or a warm cup of oat milk to protect the immune system and decrease fatigue.

23. HERBIVORE CALM Soaking SaltsEveryones favorite Himalayan pink salt blends with ylang-ylang and vanilla to soothe the body with this bath soak from plant-based, sustainable skincare brand HERBIVORE. Dont forget to recycle the chic glass bottle to reduce waste.

24. Heartsong Herbs Anxiety Away SupplementUsing regenerative growing practices to preserve soil and create stronger, more potent plants, small farm Heartsong Herbs takes its agriculture seriously. Crafting high-quality tinctures, the apothecarys Anxiety Away pairs herbs such as skullcap, passionflower, blue vervain, and lemon balm to ease away worries and help you feel grounded.

25. Kin Euphorics High RhodeNot in the mood for another lengthy Zoom happy hour and the inevitable hangover in the A.M.? Dont fret, you can still catch up with friends without the pressure. Grab a can of non-alcoholic High Rhodean herbaceous drink promising a state of bliss through a holistic mix of adaptogens, nootropics, and botanics. Kiss the morning-after headaches goodbye!

26. Naipo Massage GunWe cant go to a spa for an hour-long deep-tissue massage, so why not bring it home? This Naipo massager puts in the work and all you have to do is hold it over tense muscles to alleviate stiffness and relieve any pain. The portable design plus long battery life means you can keep it near you at all times for when the soreness starts to set in.

27. Asop Istros Aromatique Room Spray Weve all had to keep our imaginations alive during the months-long quarantine, so spend a few minutes daydreaming a walk through a lively, smoky Greek bazaar to get the creative juices flowing during a mid-day slump. Cult-favorite plant-based skincare brand Asops room spray should help with notes of pink pepper, lavender, tobacco.

Aruka Sanchir (@arukasanchir)is the Beauty & Style Editor at VegNews and shes always trying out new calming products to find her ultimate Zen.

Please support independent vegan media and get the very best in news, recipes, travel, beauty, products, and more.Subscribe now to the worlds #1 plant-based magazine!

See more here:
27 De-Stressing Vegan Products to Help You Get Through The Rest of 2020 - VegNews

Recommendation and review posted by Bethany Smith

Reportspedia announces a new report titled GlobalSkin Care Cosmetic Market, which outlines the rationale standpoint of the unpretentious forces of the market. It announces the addition of another new dimension to this industry explaining the performance of the major players. The Skin Care Cosmetic Market has also been segmented on the basis of the provincial players, out of which some are well established while some have newly entered the global market. These players have established actions such as research and development, determined to bring in new services that can efficiently compete with the other established players.

Get a sample of Skin Care Cosmetic Market @

https://www.reportspedia.com/report/life-sciences/2015-2027-global-skin-care-cosmetic-industry-market-research-report,-segment-by-player,-type,-application,-marketing-channel,-and-region/59849#request_sample

Top Key Players:

The Body Shop International PLCKao CorporationUnilever PLCAvon Products IncJohnson & JohnsonProcter & GambleBeiersdorf AGLOreal S.A.The Estee Lauder Companies Inc

Geographically, the following regions are covered in this report:

United States, Canada, Germany, UK, France, Spain, Russia, Turkey, Switzerland, Sweden, Poland, Belgium, China, Japan, South Korea, Australia, India, Taiwan, Indonesia, Thailand, Philippines, Malaysia, Brazil, Mexico, Argentina, Columbia, Chile, Saudi Arabia, UAE, Egypt, Nigeria, South Africa and Rest of the World

The global Skin Care Cosmetic Market report covers the market landscape and its growth over the upcoming years and discussion of the Prominent Companies effective in this market. This report has been organized based on a detailed market analysis with inputs from industry experts. The report delivers a 360-degree overview of the market, listing numerous factors limiting, driving the market during the forecast period.

Get a Huge discount on this Skin Care Cosmetic Market Research Report:

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Skin Care Cosmetic Market Segment by Type:

Sensitive Skin CareDry Skin CareInfants Skin CareOthers

Skin Care Cosmetic Market Segment by Application:

Stem Cells Protection Against UVFlakiness ReductionRehydrate the Skin SurfaceMinimize wrinklesIncrease the viscosity of Aqueous

The global Skin Care Cosmetic Market is predicted to witness of enormous growth in the next six years. The growing level of competition among the players and the growing focus on the advance of new products are likely to offer promising growth during the prediction period. The research study on the global Skin Care Cosmetic Market deals with a complete overview, highlighting the key aspects that are projected to surge the growth of the market in the near future.

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Key Takeaways of the report

Some Points from Table of Contents

Global Skin Care Cosmetic Market Insight and Forecast to 2027

Chapter 1Skin Care Cosmetic Market Report Overview

Chapter 2Global Growth Trends

Chapter 3Market Competition by Manufacturers

Chapter 4Skin Care Cosmetic by Regions

Chapter 5Skin Care Cosmetic by Region

Chapter 6Skin Care Cosmetic Market by Type (2020-2027)

Chapter 7Skin Care Cosmetic Market by Application (2020-2027)

strong>Chapter 8Company Profiles and Key Figures in Skin Care Cosmetic Business

Chapter 9Production and Supply Forecast

Chapter 10 Marketing Channel, Distributors, and Customers

Chapter 11 Industry Trends and Advanced Strategy

Chapter 12Conclusions

Chapter 13Appendix

Get a Complete Table of Content, Just click on the below link @:

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Here is the original post:
Global Skin Care Cosmetic Market 2020-2026 is Growing Rapidly and Expected to Witness a Sustainable Growth over 2027 - Scientect

Recommendation and review posted by Bethany Smith

Seeing a child debilitated by illness is never easy.

When doctors tell youthere is nothing they nor you can do to help ease yourbaby's suffering, well, parents who know that type of helplessness often find it hard to describe.

We were told to take my son home and love him, becausehe probably wouldnt live past his second birthday, said Pace father Todd Hamrick. But, were way past that birthday now.

Hamricks son, Alek, was diagnosed at six months old with spinal muscular atrophy and not expected to live long enough to toddle. ButAlek, now 3, has beaten the odds and outlived that initial, bleak prognosis.

His parents attribute much of his success to his doctor, Richard Finkel, who entered Alek into a clinical trial for what they believe has been a wonder drug for their little boy, Evrysdi, which was recently approved by the Food and Drug Administration.

Whats hard to even get around is that people even bothered to research it, Todd Hamrick said. Its just a small amount of the population that has SMA. Its not like researching a blood pressure medication.

Spinal muscular atrophy, or SMA,is a genetic disorder caused by a loss of nerve cells that effect human motor function.

Essentially, those afflicted by SMA are made weak. Their muscleswaste away. In many cases, eventually, a person loses their ability to walk, to eat andevento breathe, and they die.

Aleks mother, Iwona Hamrick, is a nurse at a local hospital and wellremembers the moment she heardher sons diagnosis.

It was unimaginable. His pregnancy was normal, she said. We did genetic testing and it was negative. Unfortunately, at that time, they were not screening for his disease. So, from a healthy baby to a dying baby, you know?

The parents felt they had to travel, in more ways than one, to find the places and help that they could for their Alek.

Todd Hamrick said that he and wife decided to move from Gulf Breeze to Pace after Aleks diagnosis after feeling ostracized by many of their former acquaintances. The parents felt like some people who they used to know were made uncomfortable by their son's illness.

The area is very in-the-dark when it comes to children with issues, Todd Hamrick said. If your kids are healthy and you'rehealthy, its a great area. But, it doesnt attract the greatest talent or best and biggest facilities or endowments.

So, Alek traveled with his family to meet his future doctor, Finkel, at the Nemours Children's Hospital in Orlando.

Alekwas first treated with a gene therapy drug, and he made some response with that, Finkel told the News Journal. But more recently, he started on a second drug, which seems to be having an enhanced effect, I must say.

Finkel, an expert in the field of pediatric neurologic disorders, left Florida in March for a position leading the new Center for Experimental Neurotherapeutics at St. Jude Childrens Research Hospital in Memphis, Tennessee. Buthe has continued to monitor Aleks progress via video.

Both of the drugs he has received, the gene therapy and this new drug, Evrysdi, are designed to increase a certain protein in Aleks body that is deficient because of his genetic disorder, he explained. But they do it in different ways. The potential advantage of his new drug, Evrysdi because its an oral drug; you take it by mouth it goes into the stomach and into the bloodstream, and from there, it goes to all the tissues of the body.

And, we think that there is an enhanced effect, becauseit gets into the muscle tissue, Finkel continued. "These are very, very, early daysin trying to make assessments, soI dont want to say that we can come to any kind of conclusions yet."

However the cutting-edge drug works doesnt matter to a mother, whos just glad that it isworking.

It gave us hope. Thats for sure, Iwona Hamrick said. Becausewe felt helpless.

Since Alek started his new treatment last November, his strength has increased tremendously.

His muscle tone got better, Iwona Hamrick said. He is much stronger in the upper body, so much so, he is pushing his little wheelchair.

Alek can now cruise around his Pace home in an extraordinarily lite-weight wheelchair designed by a Swedish inventor who alsohas a child with SMA.

Alek had a lot of trouble before starting this medication even pushing it, Iwona Hamrick said. Sonowhe is just rolling around the house. Also, he is barring more weight on his legs.

Recently, Alek has started to be able to walk in a pool a huge milestone for the toddler.

But some worries remain the same.

Every day, Alek must use a type of breathing machine.

Its a cough assist machine, Todd Hamrick explained. We use it two times a day, when hes healthy. Becausewhere we can just clear our throats when we cough, he doesnt have that strength no lung strength.

Alek attends physical therapy, aqua-therapy,hippotherapy, occupational therapy and speech therapy sessions every week to try and ensure he remains healthy and continues to properly develop.

My worries have changed a lot, Todd Hamrick said. I used to worry my child was going to die. Now, Im worrying about if other kids will bully him at school.

"But that'sa great worry to have," he continued. "Compared to how it use to be, getting picked on is a great thing to worry about.

Colin Warren-Hicks can be reached at colinwarrenhicks@pnj.com or 850-435-8680.

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Pace toddler wasn't supposed to survive. Thanks to wonder drug, parents say he's thriving - Pensacola News Journal

Recommendation and review posted by Bethany Smith

Equipment required for reactor pressure vessel annealing has been delivered to the Armenian nuclear power plant.

The annealing will be carried out as part of the project to modernise and extend the life of unit 2 of the Armenian NPP. The plant will be prepared for the final part of the work on extending its service life, which will take place in 2021 - the reactor will be annealed, which will allow it to return to 80-85% of its original state by, the press service of Rosatom reported on 4 September.

This is an important science-intensive work to improve plant safety. Annealing will restore the characteristics of the metal of the reactor vessel, which will allow it to be safely operated in the future, said Yuri Sviridenko, manager for the life extension project.

The vessel will be annealed after the fuel assemblies have been unloaded into the used fuel pool. The vessel will be inspected and the equipment installed in the reactor. Using an annealing unit, the reactor vessel will be heated to a temperature of 475 degrees Celsius, kept at this temperature for several days, after which it will slowly cool down.

The procedure will be carried out by several Rosatom organisations, each of which is responsible for its own segment of the work.

This technology for recovery annealing of the reactor vessel metal was first applied in 1987 at Novovoronezh 3. Now this procedure is carried out at all plants requiring service life extension. Reactor pressure vessel annealing has already been completed at VVER-440 reactors at Kola in Russia, Rovno in Ukraine, Kozloduy in Bulgaria and Loviisa in Finland.

Unit 2 of Armenian nuclear power plant was reconnected to the grid on 1 September after being closed for scheduled repairs, Rosatom said.

The work performed has made it possible to significantly increase the level of safety and reliability of the power unit. Preventive maintenance at the Armenian NPP was completed 12 days ahead of schedule, Rosatom said. This was possible due to the efficient organisation of the process, the focus of the personnel of the Armenian NPP on results, as well as mutual understanding and effective business relations with the involved organisations that were developed during the joint work."

Rusatom Service, part of Rosatoms electric power division, was the general contractor for the work. For the fifth year now, the Armenian NPP has been combining maintenance work with the implementation of a programme to extend the life of the plant, since most of the activities in this direction are technologically available only when the unit is shut down, Rosatom noted. After completion of the maintenance activities, life extension work continues.

Armenias state programme provides for the extension of the operating life of the existing NPP unit until 2026, as well as the phased commissioning of new units. Funding was provided by a Russian state export loan of $270 million and a grant of $30 million for up to 15 years. However, earlier this year Armenia refused to extend the loan preferring to finance further work at its own expense. The Armenian government provided a budgetary loan to the Armenian NPP in the amount of $131.38 million for 2020-22, while the cost of the agreement with Rusatom Service is limited to $40.255 million.

The two-unit Armenian nuclear plant was built in the 1970s, but was closed following the Spitak earthquake in 1988. Metsamor 2 restarted with Russian assistance in 1995 in the face of severe energy shortages.

Link:
Key life extension equipment delivered to Armenian NPP - Nuclear Engineering

Recommendation and review posted by Bethany Smith

A landfill site owners plan to add 15 years to the life of its contentious commercial and municipal waste tip has been thrown out.

FCC Environment runs the Bletchley Landfill Site, near Newton Leys, and it applied to Milton Keynes Council to add another 15 years to its operational life.

The tip is due to close in 2022 under permission granted in 2002, but the application would see it taking commercial and council waste until 2037 with another two years to finish off restoration work.

One of the objectors, resident Ethan Kelly-Wilson told Thursdays development control committee that he would be nearing retirement, and his child would be grown up before the site would be returned to nature.

Other objectors also made the case that residents, especially in Newton Leys, had brought their new homes on the understanding that they would only have to put up with the site for a few more years.

Adding 15 years would have a devastating impact, said Bletchley and Fenny Town councillor Ed Hume.

Mat Nicholson, the estates manager for owner FCC Environment, said he had concerns over the manner which some of the information was presented to the committee.

He claimed that it was in a manner not to give the full picture.

He said that the site, which employs 15 people, is regionally important, making up one quarter of the landfill space that is left in the whole of the south east of England.

Mr Nicholson said none of the statutory consultees had objected but that was not highlighted to the committee.

He claimed that consultees like the Environment Agency and the councils own environmental health officers were not given equal weight to other issues.

He admitted there had been a large number of recent complaints but claimed there is a disparity between complaints and reality.

Mr Nicholson added that if the life of the site was not extended then it would not be possible to restore the site as agreed. And he said it would cause issues with site gases and water.

But Tracy Darke, the councils director of economy, growth and culture, said councillors had to make a judgement on where the planning balance lies by taking everything into account.

Residents expected to have a country park in 2023 but in 2035 we could be in exactly the same position.

There is no clarity around when we get to the end date anyway.

Ward councillor Emily Darlington (Lab, Bletchley East) said having a landfill site in Milton Keynes until 2037 would go against the citys aim to be the greenest city.

And other speakers said they did not want Milton Keynes to be an exporter of other peoples rubbish when the council is aiming to send nothing at all to landfill.

Cllr Paul Trendall (Lib Dem, Campbell Park & Old Woughton) said: MK isnt everyones dumping ground.

Councillors voted unanimously to reject the application. FCC Environment will have the opportunity to appeal to the Government to get an inspector to overturn the committees decision.

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Committee rejects owner's case to throw out 15 year landfill site life extension plan in Milton Keynes - MKFM

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The most recent research released provided interesting results. Quite interesting.

Of all of the countries in the world all of them where do you think the United States ranks with respect to the increase in human longevity? That is, in which countries are people living longer. (This came out pre-virus.)

It might be significant to point out that both individually and in the aggregate, the U.S. ranks first by a healthy margin in money spent on health care. Then, it might not.

You see, as a country we rank 45th overall in life extension.

Of utmost significance, experts say the primary cause of this less than stellar ranking is, in a word diet.

Thats right, diet. What we eat. How its prepared and seasoned. (Think animal fat, fried, fast foods.) And individual amounts. How much, that is.

Just look at us, folks. Overweight or obese is almost standard. Especially is this so in places such as where we live. In rural areas. In the South. Not an opinion. A fact.

Lets not just say diet and leave it at that. It is estimated that 68 percent of adults are overweight and 34 percent are obese.

An ideal heart-healthy diet as defined by the American Heart Association entails that saturated and trans-fat should be limited to less than seven percent and one percent of your daily calories, respectively Additionally, physical activity can help control weight and improve cardiovascular health. It is recommended to exercise 30 minutes a day, five days a week. (Rony L. Shammas, MD, FACC, FASE, FSCAI, Vidant Medical Center)

Smoking? We dont even need to go there. We all know that it is a strong risk factor for heart attack, stroke and cancer.

Then, we could cite grim warnings about cholesterol, high blood pressure and diabetes, of course. But most of us have long known about all of this. Some are in denial, and some are going to do what they want to do, all information and warnings be damned. And that includes those now who also dont respect the coronavirus.

A good friend of mine would often say that You cant save people from themselves.

And that, friends, is the way it is.

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Write Again ... The primary cause - Washington Daily News - thewashingtondailynews.com

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Greece and Turkey have a long history of animosity despite both being NATO members. However, theres a real concern that the current spike in tensions mainly related to control of oil and gas reserves and maritime rights in the eastern Mediterranean could escalate. If they do, the respective air arms of the two countries are likely to be heavily engaged, so its a good time to take a detailed look at their respective assets and how their capabilities compare.

Its worth noting here that the Hellenic and Turkish Air Forces regularly spar over the Aegean Sea. Turkey and Greece broadly have a long history of confrontation, including an all-out war fought in support of competing factions in Cyprus in 1974. That independent Mediterranean island, which is still divided between areas under the control of ethnic Greek and Turkish Cypriots to this day, remains a focus of antagonism between the two countries. However, current developments in the region have caused alarm in both NATO and the European Union.

The background to the current dispute surrounds the race to exploit energy reserves in the eastern Mediterranean. The two countries have claims on overlapping areas containing undersea oil and gas fields. In July, Turkey announced it was sending its research vessel Oru Reis to carry out a drilling survey in disputed waters off the coast of southwest Turkey, but close to the Greek island of Kastellorizo. The Greek military was put on alert and the vessel eventually left port on August 10, 2020.

NormanEinstein/wikicommons

The illegal and provocative behavior of Turkey has a serious backlash not only to peace and stability in the eastern Mediterranean but to the cohesion of NATO and to its relations with the European Union, said Greek Foreign Minister Nikos Dendias, in response to the Turkish drilling mission.

Greece claims 40,000 square kilometers of maritime jurisdiction area due to this tiny island [Kastellorizo] and attempts to stop the Oru Reis and block Turkey in the eastern Mediterranean, declared aatay Erciyes, Director General at the Turkish Ministry of Foreign Affairs.

The build-up to the latest phase in the standoff included a collision between Greek and Turkish frigates on August 12, 2020. The Turkish warship involved was one of five escorting the research vessel OruReis. The Greek frigate Limnos made contact with its Turkish counterpart Kemal Reis and the resulting damage was apparently confirmed by photos published soon afterward in the Greek media.

Complicating matters, some of the recent exercises in the area have involved foreign participation, including French Air Force Rafale fighter jets that arrived at Souda-Chania Air Base on Crete for joint training with Greek F-16s on August 13, 2020. The French Ministry of Defense described the deployment as a temporarily strengthening [of] their presence in the eastern Mediterranean. Souda then received four F-16E/F Desert Falcons from the United Arab Emirates, which had touched down at the Greek base by August 27 to take part in further joint exercises.

On August 26, Greece began a naval exercise south of Cyprus involving forces from Cyprus, France, and Italy. At the same time, warships from Turkey and the United States were taking part in separate drills in the same area. The U.S. Navy has taken part in maneuvers with both the Greek and Turkish navies in recent weeks, including involvement from Greek F-16s and the U.S. Navy Arleigh Burke-class destroyer USS Winston S. Churchill.

U.S. NAVY/MASS COMMUNICATION SPECIALIST 3RD CLASS LOUIS THOMPSON STAATS IV

The Arleigh Burke-class guided-missile destroyer USS Winston S. Churchill (DDG 81) executes drills with the Hellenic Navy frigate Aigaion (F 460) in the Mediterranean, August 24, 2020.

As well as a war of words and aggressive acts between ships, there have been other examples of direct posturing, too. The Turkish Ministry of Defense released what it claims is footage from the head-up display (HUD) of one of its F-16 fighters showing an incident that occurred on August 27, 2020, in which six Greek F-16s were supposedly warded off by Turkish Vipers. According to a statement from the ministry, the Greek fighters launched from Crete and were heading towards southern Cyprus when they approached an area in which Turkey had previously declared a restricted zone for a naval exercise.

The Turkish Ministry of Defense said the Greek jets were removed from the region and local media reported that the Oru Reis was also active in the area at the time. The supplied HUD footage shows F-16s in a turning fight at close quarters and includes several tone alerts indicating that the Turkish pilots AIM-9 Sidewinder air-to-air missile (AAM) was locked on to the opposing F-16. The full story behind the incident is unclear, but encounters of this kind are not uncommon over the contested waters of the Aegean. However, by posting the video now, the Turkish Ministry of Defense seems keen to display its willingness and ability to take on Greek airpower to protect its interests in the region.

The most recent altercations between Greek and Turkish forces, and the soaring rhetoric that has come with them, have been met with concern among the wider European Union, of which Greece is a member. The German Defense Minister, Annegret Kramp-Karrenbauer, has called for the situation in the Aegean to be defused and criticized the latest rounds of potentially provocative naval exercises staged by both countries in the area. Kramp-Karrenbauers words suggest theres now a wider recognition that another incident could put Greece and Turkey on a more serious collision course again, including in the air.

NATO Secretary General Jens Stoltenberg spoke with Turkish President Recep Tayyip Erdoan on August 28, 2020, to talk about developments in the eastern Mediterranean. Stoltenberg stressed dialogue and de-escalation and the two discussed deconfliction mechanisms to prevent further incidents. For NATO, any tensions between Greece and Turkey threaten the solidarity of the alliance, potentially diminishing its ability to confront common security challenges.

Were urging everyone to stand down to reduce tensions and begin to have diplomatic discussions added U.S. Secretary of State Mike Pompeo. It is not useful to increase military tensions in the region.

After examining the background to the latest standoff, lets look at the key combat aircraft types that make up the two countries respective air arms.

The two countries air forces are spearheaded today by Lockheed Martin F-16 Viper fleets, which have now recorded three decades of service in Greece and Turkey. In both cases, the fighter jets were primarily purchased to replace aging F-104 Starfighters and F-5 Freedom Fighters.

The Hellenic Air Force (HAF, or Elliniki Polemiki Aeroporia) received 170 F-16s of various types between 1989 and 2010 and, with a large-scale modernization program underway, the Viper will remain the backbone of the air arm for many years to come.

HELLENIC AIR FORCE

A Hellenic Air Force F-16C Block 50 in the markings of 341 Mira and armed with AGM-88 HARMs.

Greek Vipers were acquired via Foreign Military Sales (FMS) channels, through the Peace Xenia program, which included four distinct phases.

Peace Xenia I provided 34 single-seat F-16C and six two-seat F-16D Block 30 jets delivered between 1988 and 1990.

Peace Xenia II added another 32 F-16C and eight F-16D Block 50 aircraft. These jets are capable of night attack missions with the LANTIRN targeting pod and have AGM-88 High-speed Anti-Radiation Missile (HARM) capability, making them suitable for the suppression/destruction of enemy air defenses (SEAD/DEAD) mission.

Peace Xenia III provided 40 F-16C and 20 F-16D Block 52+ jets, all equipped with conformal fuel tanks for extended range. These were delivered between 2003 and 2004.

After scrapping plans to purchase the Eurofighter Typhoon, the Greek government instead opted for another Viper order, under Peace Xenia IV, to replace the veteran fleet of A-7H/TA-7H Corsair II attack jets. The deal covered 20 F-16C and 10 F-16D Block 52+ Advanced versions, also sometimes referred to as Block 52M aircraft, and was signed in December 2005.

The HAFs aging F-16 Block 30s are now consolidated with a single squadron, 330 Mira, and the jets have undergone the Falcon UP service-life extension, work being undertaken locally by Hellenic Aerospace Industry (HAI).

Of the 150 or so Vipers still operational, the bulk is divided among eight operational squadrons based at Araxos, Lrisa, Na Anghialos, and Souda-Chania, but the HAF also maintains a number of rotational detachments on islands in the Aegean. All HAF F-16 squadrons maintain a full air-to-air capability and undertake quick reaction alert (QRA) readiness duties to counter potential Turkish airspace violations, despite the fact that some are specialized air-to-ground squadrons.

The Collins Aerospace DB-110 reconnaissance pod is available to Greek F-16s for reconnaissance missions, and additional weapons options include the AIM-120C AMRAAM, AGM-154C Joint Stand-Off Weapon (JSOW), Joint Direct Attack Munition (JDAM), and reportedly Wind Corrected Munitions Dispensers (WCMD). Unusually, the HAF has opted for the pan-European IRIS-T as the primary short-range AAM for the Viper, rather than the AIM-9X Sidewinder.

Eyeing a longer-term modernization for its Vipers, Greece selected the F-16V upgrade that will bring 84 aircraft all of them Block 52+ and Block 52+ Advanced jets to Block 70/72 standard, including the AN/APG-83 Scalable Agile Beam Radar (SABR) with active electronically scanned array (AESA), Raytheon Modular Mission Computer, remodeled cockpit including the second-generation Joint Helmet Mounted Cueing System (JHMCS ), and the Link 16 data link, among other enhancements. Most of the work will be undertaken by HAI in Greece. There have been suggestions that the remaining 38 Block 50 jets could also undergo an upgrade, bringing them to a so-called Block 50+ Advanced standard, but this hasnt been contracted. The fate of the Block 30 aircraft is unclear, but they could be sold off, or perhaps used as aggressors for air defense training.

TURKISH MINISTRY OF NATIONAL DEFENSE

A Turkish Air Force F-16 pair heads out for a training mission, led by an F-16C Block 50.

On the other side, the Turkish Air Force, or Trk Hava Kuvvetleri (THK), is the worlds third-largest Viper operator, with a total of 270 aircraft delivered in successively more capable Block 30, Block 50 and Block 50+ configurations.

Local industry also plays a significant part in the Turkish Viper program, with involvement from Turkish Aerospace Industries (TAI) from the outset, including local assembly of aircraft and production of center/aft fuselage sections and wings.

The Turkish Viper procurement took place in four phases: Peace Onyx I to IV.

Under Peace Onyx I, Turkey received 136 F-16Cs and 24 F-16Ds, of which the first 44 were completed to Block 30 standard. The next 116 aircraft within Peace Onyx I were Block 40-standard jets that included the provision for LANTIRN pods. Deliveries took place from 1987.

Peace Onyx II covered 60 F-16C and 20 F-16D Block 50 aircraft, which were delivered between 1996 and 1999. Like the HAF Vipers, Turkish F-16 Block 50s were provided with the AGM-88 HARM anti-radiation missile.

The Peace Onyx III contract provided the Common Configuration Implementation Program (CCIP) upgrade. As well as adding more sophisticated weapons and sensors, this improved logistics support and reduced life-cycle costs. Lockheed Martin provided a total of 163 CCIP kits for Turkeys surviving F-16C/D Block 40/50s. After modernization, the aircraft featured APG-68(V)9 multi-mode radar, color cockpit displays and recorders, JHMCS, Link 16 data link, Sniper targeting pods, and new weapons, including the AGM-84K Joint Standoff Land Attack Missile Expanded Response (SLAM-ER), AGM-154A/C JSOW, AIM-9X, and CBU-103/105 Wind Corrected Munitions Dispensers (WCMD). Other weapons available to Turkish Vipers include the AIM-120 AMRAAM as well as the AGM-65 Maverick TV-guided air-to-ground missile.

The most recent Peace Onyx IV program provided another 14 F-16C and 16 F-16D Block 50+ jets, which are known to be compatible with the 1,300-pound Roketsan Stand-Off Missile (SOM) for standoff precision strike, as well as other indigenous weapons. These aircraft were delivered between June 2011 and December 2012.

More recently, TAI has set about upgrading 35 of its oldest Block 30 Vipers. This is based around a service-life extension using kits supplied by Lockheed Martin. The status of this program is currently uncertain, with reports that the U.S. Congress may have blocked the contract in response to Ankaras purchase of the S-400 air defense system.

Today, the THKs F-16C/D fleet is operated by two squadrons at Balikesir, two squadrons at Bandirma, two squadrons at Diyarbakir, one squadron at Eskiehir, one squadron at Konya, and two squadrons at Merzifon. Units are assigned particular roles, among them air defense, SEAD/DEAD, tactical air support for maritime operations, close air support, reconnaissance, and aggressor.

Eskiehir is home to 113 Filo, a former RF-4E operator, which is assigned the DB-110 reconnaissance pod that is used with the F-16, four of these pods having been acquired.

F-16 inventory (this and subsequent similar data is provided by Flight InternationalsWorld Air Forces 2020 publication):

Greece: 153

Turkey: 245

The Hellenic Air Force also operates the Mirage 2000 multi-role fighter, having acquired two distinct versions of the delta-wing jet. The first order was placed for 36 single-seat Mirage 2000EGs and four two-seat Mirage 2000DGs and deliveries began in 1988. Although being used primarily for air defense, these aircraft can be armed with the AM.39 Exocet anti-ship missile.

HELLENIC AIR FORCE

Afterburner take-off for a Hellenic Air Force Mirage 2000-5EG.

The HAF subsequently obtained a further 15 new-build Mirage 2000-5BG/EG (Mirage 2000-5 Mk 2) jets and brought 10 of its earlier aircraft to the same standard. One reason for adding the more capable Mirage 2000-5 Mk 2 may have been to match the beyond-visual-range capabilities of Turkeys F-16s armed with AIM-120 AMRAAM missiles. The French-made jets are armed with the MBDA MICA missile, available in both radar-guided and infrared-guided variants.

The Greek Mirage 2000-5 Mk 2 jets also have an important long-range conventional strike role with the MBDA SCALP-EG cruise missile. A first airframe upgraded by HAI took to the air in 2005 and the first new-built fighters from Dassault began to arrive in Greece in 2007.

The HAFs Mirage fleet is divided between two squadrons based at Tangra, and the jets also conduct rotational detachments to islands in the Aegean.

Mirage 2000 inventory:

Greece: 42

As well as both flying the F-16, Greece and Turkey are among the last operators of the F-4 Phantom II. However, both countries have now retired their reconnaissance-configured RF-4 fleets.

The Hellenic Air Force has a single unit operating F-4E fighters that were upgraded to Peace Icarus 2000 standard under the Avionics Upgrade Program (AUP) between 1997 and 2001. Stationed at Andravida near the west coast of the Peloponnese peninsula, these jets are multi-role-capable, but its thought they now focus on air-to-ground missions.

HELLENIC AIR FORCE

A Hellenic Air Force F-4E in its hardened aircraft shelter, armed with the Vietnam War-era HOBOS TV-guided bomb.

Among others, the AUP added AN/APG-65Y radar, inertial navigation system/GPS, AN/ALR-68(V)2 radar warning receiver, color multifunctional displays, a new head-up display, and hands on throttle and stick (HOTAS) controls. The Rafael Litening II laser targeting pod provides day/night precision targeting and weapons include laser-guided bombs, AGM-65 Maverick air-to-ground missiles, AIM-120 AMRAAM, and AIM-9 Sidewinder.

While 33 of the 36 Greek F-4Es that underwent the AUP remain operational, its thought that around 20 are actually available for operations at any given time.

Turkeys Phantoms also underwent a significant mid-life upgrade, emerging as the F-4E Terminator 2020. The modernization involved Israel Aircraft Industries (IAI) and covered 54 airframes, including structural and avionics work. The upgraded avionics include an Elta EL/M-2032 multi-mode radar, digital glass cockpit, wide-angle HUD, and HOTAS controls. The jets can be armed with the Israeli-made Popeye standoff missile, as well as the indigenous Roketsan SOM for use against land and sea targets. Other stores include the HGK 500-pound INS/GPS-guided bomb, KGK 500-pound or 1,000-pound glide bomb, and the LGK-82 an indigenous version of the 500-pound GBU-12 laser-guided bomb.

TURKISH MINISTRY OF NATIONAL DEFENSE

A pair of Turkish Air Force F-4E Terminator 2020s.

While both countries have made efforts to acquire new-generation fighters to modernize their fighter arms, Turkey was ejected from the F-35 stealth fighter program in response to its purchase of Russian-made S-400 air defense systems. Greece, meanwhile, has been identified as a possible F-35 customer too, and more recently unconfirmed reports have emerged in the Greek press that the country is examining a potential purchase of 18 Rafale multi-role fighters.

It was expected that the Turkish Phantoms would be retired with the arrival of the F-35, but with Ankaras expulsion from the Joint Strike Fighter program, its possible the THK F-4s will continue in service until around 2030, by which time the next-generation TF-X fighter may be available. Today, the F-4Es serve with a single squadron at Eskiehir.

F-4E inventory:

Greece: 33

Turkey: 48

Airborne early warning (AEW) is a critical function for modern complex air operations and both Greece and Turkey contribute to NATOs E-3A Sentry Component, which maintains a pooled fleet of the Airborne Warning and Control System (AWACS) aircraft at Geilenkirchen Air Base in Germany. The component also has forward operating bases at Aktion in Greece and Konya in Turkey. However, both countries have also established independent airborne early warning and control (AEW&C) capabilities.

HELLENIC AIR FORCE

The EMB-145H combines the Ericsson Erieye AESA radar with the Embraer EMB-145 bizjet airframe.

Greece opted for its own AEW&C solution in 1999 when it ordered four Embraer EMB-145H aircraft from an Embraer, Ericsson, and Thales consortium. The aircraft are equipped with Ericsson Erieye AESA radar. These aircraft also have a signals intelligence (SIGINT) capability using Elettronica ALR-733(V)5 electronic support measures (ESM). The Greek aircraft has five workstations and the mission crew typically comprises a radar operator, mission commander, SIGINT specialist, and two weapons controllers.

Prior to the delivery of the EMB-145H aircraft, the HAF leased a pair of S 100B Argus AEW&C aircraft from the Swedish Air Force for a two-year period as an interim solution. The EMB-145H aircraft have been operational at Elefsis, west of Athens, since 2009. Using the Link 11 and Link 16 networks, the Embraers can exchange data with airborne, naval, and ground-based assets.

BOEING

A pre-delivery shot of the fourth and final 737 AEW&C for Turkey.

Turkeys airborne early warning and control fleet is based around the Boeing 737 AEW&C that was acquired under the Peace Eagle program and is sometimes referred to by the local designation E-7T. The aircrafts primary sensor is the Northrop Grumman Multi-Role Electronically Scanned Array (MESA) surveillance radar. The impetus to acquire the aircraft seems to have been to fill the gaps in airspace coverage over Turkeys mountainous territory, where ground-based radars wouldnt necessarily detect high-speed, low-flying targets.

The Boeing 737 AEW&C was selected in 2000 and four examples were eventually ordered, the first provided by Boeing, while the remaining three were outfitted by TAI. The project experienced a number of delays, including as a result of a breakdown in relations between Ankara and Israel, the latter which was to provide the Elta ESM system. The first aircraft was finally delivered to the air force in 2014, six years late. Today, the four aircraft are stationed at Konya and as well as working with fighters and monitoring airspace over the Aegean, the fleet has been used to monitor movements along the Syrian border including reportedly tracking Wing Loong II drones operating over Libya. Unlike the HAFs EMB-145H, the 737 AEW&C can use inflight refueling to extend the duration of its missions.

AEW&C inventory

Greece: EMB-145H (4)

Turkey: 737 AEW&C (4)

With most combat operations anticipated to take place regionally, the Hellenic Air Force has a fairly modest tactical transport fleet. It also lacks an organic air-to-air refueling capability, meaning fighters would have to be refueled on the ground, perhaps at forward-located island airstrips. The air force operates around seven older C-130B/H Hercules airlifters, plus two more H-models modified for electronic intelligence (ELINT) missions. Surviving Hercules underwent an Avionics Upgrade Program (AUP) between 2005 and 2010, including modifications to the INS/GPS, autopilot, weather radar, and digital engine controls. A partially glass cockpit and revised electronic warfare system were also included.

HELLENIC AIR FORCE

A Hellenic Air Force C-27J Spartan tactical airlifter.

The HAF also flies eight more modern twin-turboprop C-27J Spartan tactical transports, delivered from 2005, although these have experienced limited availability in recent years. Mainly employed for airlift, the Spartans can also be used for medical evacuation and maritime patrol.

TURKISH MINISTRY OF NATIONAL DEFENSE

Three different Turkish Air Force tactical transports on the runway. From front to back: A400M, C-130, and C-160.

In contrast to the HAF, the Turkish Air Force has an aerial refueling capacity using seven KC-135R Stratotankers, which can deliver fuel via their boom or a boom-to-drogue adapter. For its transport needs, the THK relies upon around 16 C-130B/Es (airframes that are even older than those operated by Greece) and a diminishing number of Transall C-160Ds, as well as smaller CN235s, 42 of which were ordered and two of which have been adapted for ELINT duties.

The Turkish airlift fleet is also in the process of modernization through the induction of the A400M, and the last of 10 examples are scheduled to be handed over in 2022. Two C-160Ds have been adapted for communications jamming and can reportedly also undertake communications intelligence (COMINT) missions.

Tactical transport and tankers inventory

Greece: C-27J (8), C-130B/H (9)

Turkey: A400M (9), C-130B/E (16), C-160D (13), CN235 (42), KC-135R (7)

Both nations include fixed-wing maritime patrol aircraft (MPA) with anti-submarine warfare (ASW) capabilities and, although these are assigned to their respective naval air arms, there is some crossover as Greeces P-3 Orion aircraft are operated by Hellenic Air Force flight crews working alongside naval mission crews.

The Hellenic Navy ceased operations with its five P-3Bs in September 2009 before a mid-life upgrade and modernization program was launched, Lockheed Martin being awarded a $142-million, seven-year contract covering reactivation of one aircraft plus hardware and software for the other four. The first refurbished P-3B was handed over by HAI in Tanagra in May 2019.

LOCKHEED MARTIN

Official handover of the first refurbished P-3B to Hellenic Navy officials in May 2019.

The aircraft are initially undergoing an interim upgrade, but its planned for them to be brought up to full P-3HN standard that should provide another 20 years of service. This also includes an indigenous tactical mission suite, the Maritime Mission Integration and Management System (M2IMS). The Greek Orion fleet is stationed at Elefsis. Once back to full strength, the P-3 will provide Greece with a long-range maritime patrol capability to monitor the Mediterranean, and especially the Aegean, including the Aphrodite gas field off the coast of Cyprus.

Turkish MPA capability rests not with its air force but with its naval air arm. After the retirement of the veteran S-2 Tracker in the early 1990s, the Turkish Navy was left without a fixed-wing MPA capability until the launch of the Meltem project at the end of that decade. This has provided six MPA-configured CN235M-100 twin turboprops, acquired under Meltem I, and then outfitted with the Thales AMASCOS-300 (Airborne Maritime Situation and Control System) under Meltem II. For ASW missions, the aircraft can be armed with Mk 46 torpedoes.

Finally, the Turkish Meltem III program is now providing a more advanced MPA capability, based on the ATR 72-600 twin-engine turboprop, outfitted by Leonardo. The work has been subject to delays, however, and the first of six aircraft was reportedly still undergoing final tests in April 2020, having made a first post-conversion test flight back in 2014.

Maritime patrol inventory

Greece: P-3B (1, plus 4 to be refurbished)

Turkey: CN235M-100 MPA (6)

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Face-Off In The Aegean: How Greek And Turkish Air Forces Stack Up - The Drive

Recommendation and review posted by Bethany Smith

International pharmaceutical giants GSK and Sanofi have today announced that they have begun clinical trials of their coronavirus vaccine.

The two firms have revealed that 440 adults would be given doses of their vaccine at 11 sites across the US. The results are scheduled to be published in December with more trials scheduled to take place over the next few months.

The Anglo-French partnership uses the same protein-based technology as one of Sanofis influenza vaccines.

Thomas Triomphe, Executive Vice President and Global Head of Sanofi said: The initiation of our clinical study is an important step and brings us closer to a potential vaccine which could help defeat COVID-19. Our dedicated teams and partner continue to work around the clock as we aim to deliver first results in early December. Positive data will enable a prompt start of the pivotal phase three trial by the end of this year.

This follows the news last week the British firm AstraZeneca also began clinical trials in the UK.

The trial, called NCT04507256, will evaluate the safety, tolerability and pharmacokinetics of AZD7442.1 The trial will include up to 48 healthy participants in the UK aged 18 to 55 years and is funded by the Defense Advanced Research Projects Agency (DARPA), part of the US Department of Defense, and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the US Department of Health and Human Services.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: This trial is an important milestone in the development of our monoclonal antibody combination to prevent or treat COVID-19. This combination of antibodies, coupled to our proprietary half-life extension technology, has the potential to improve both the effectiveness and durability of use in addition to reducing the likelihood of viral resistance.

A new 500m funding package will be invested in next generation testing technology and increased testing capacity, the Health and Social Care Secretary announced today.

To date, large-scale COVID-19 testing system has carried out more than 16 million tests and this new funding for quick result test trials and repeat population testing will help take the programme to the next level.

A new, community-wide trial in Salford will launch imminently to assess the benefits of repeat population testing. Existing, promising trials in Southampton and Hampshire, using a saliva test and a rapid 20-minute test, will also be expanded using the new funding.

By using this cutting-edge technology to widely roll out rapid tests, chains of transmission will be broken almost immediately by delivering on-the-spot results. Successful trials will then be expanded and rolled out more widely.

The funding will also be used to further extend capacity for existing polymerase chain reaction (PCR) testing across the country. All positive results will be passed to the NHS Test and Trace system, to trace contacts, prevent further transmission, and save lives.

Health and Social Care Secretary Matt Hancock said: Testing is a vital line of defence in combating this pandemic. Over the past 6 months we have built almost from scratch one of the biggest testing systems in the world. We need to use every new innovation at our disposal to expand the use of testing, and build the mass testing capability that can help suppress the virus and enable more of the things that make life worth living. We are backing innovative new tests that are fast, accurate and easier to use and will maximise the impact and scale of testing, helping us to get back to a more normal way of life.

I am hugely grateful for the work being done on this national effort to strengthen our ability to tackle this virus. While we work on a vaccine we must innovate our way out of this crisis.

Trials across the country will now be launched or extended, with the latest starting in Salford today.

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GSK and Sanofi begin coronavirus vaccine trials in the UK and US - Business Leader

Recommendation and review posted by Bethany Smith

FCC Environment runs the Bletchley Landfill Site, near Newton Leys, and it applied to Milton Keynes Council to add another 15 years to its operational life.

The tip is due to close in 2022 under permission granted in 2002, but the application would see it taking commercial and council waste until 2037 with another two years to finish off restoration work.

One of the objectors, resident Ethan Kelly-Wilson told Thursdays development control committee that he would be nearing retirement, and his child would be grown up before the site would be returned to nature.

Other objectors also made the case that residents, especially in Newton Leys, had brought their new homes on the understanding that they would only have to put up with the site for a few more years.

Adding 15 years would have a devastating impact, said Bletchley and Fenny Town councillor Ed Hume.

Mat Nicholson, the estates manager for owner FCC Environment, said he had concerns over the manner which some of the information was presented to the committee.

He claimed that it was in a manner not to give the full picture.

He said that the site, which employs 15 people, is regionally important, making up one quarter of the landfill space that is left in the whole of the south east of England.

Mr Nicholson said none of the statutory consultees had objected but that was not highlighted to the committee.

He claimed that consultees like the Environment Agency and the councils own environmental health officers were not given equal weight to other issues.

He admitted there had been a large number of recent complaints but claimed there is a disparity between complaints and reality.

Mr Nicholson added that if the life of the site was not extended then it would not be possible to restore the site as agreed. And he said it would cause issues with site gases and water.

But Tracy Darke, the councils director of economy, growth and culture, said councillors had to make a judgement on where the planning balance lies by taking everything into account.

Residents expected to have a country park in 2023 but in 2035 we could be in exactly the same position.

There is no clarity around when we get to the end date anyway.

Ward councillor Emily Darlington (Lab, Bletchley East) said having a landfill site in Milton Keynes until 2037 would go against the citys aim to be the greenest city.

And other speakers said they did not want Milton Keynes to be an exporter of other peoples rubbish when the council is aiming to send nothing at all to landfill.

Cllr Paul Trendall (Lib Dem, Campbell Park & Old Woughton) said: MK isnt everyones dumping ground.

Councillors voted unanimously to reject the application. FCC Environment will have the opportunity to appeal to the Government to get an inspector to overturn the committees decision.

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Committee rejects owners case to throw out 15 year Milton Keynes landfill site's life extension plan - Milton Keynes Citizen

Recommendation and review posted by Bethany Smith

MarketResearch.Bizhas added the most recent research reportWorldwide Gene Therapy Market, this report assists with breaking down top makers, districts, and in like manner covers Industry deals channel, wholesalers, brokers, vendors, Research Findings, and Conclusion.

Global Gene Therapy Market report goals to convey a 360-degree perspective available as far as front line innovation, drivers, limitations, and up and coming patterns with sway examination of these patterns available during the estimate time frame. Further, the Gene Therapy Market report additionally shields vital Chaptericipants profiling with SWOT examination, key advancements of items/administrations from the previous five years.

>Company Profiles <

Novartis, Kite Pharma Inc, GlaxoSmithKline PLC, Spark Therapeutics Inc, Bluebird bio Inc, Genethon, Transgene SA, Applied Genetic Technologies Corporation, Oxford BioMedica PLC, NewLink Genetics Corp., Amgen Inc

|Click To get SAMPLE PDF of Gene Therapy Market (Including Full TOC, Table & Figures)

Main Points Covered in the Report:

The total market measurements both as far as revenue and volume.

Complete examination about the Gene Therapy market elements, which incorporates the development factors, restrictions, difficulties, and openings.

Detailed data about the key business players, their essential skills, and the Gene Therapy market share.

Strengths of the purchasers and providers which will help customers for improving their decision-making skills.

The most recent 2020 version of this report reserves all provides to give further remarks on the most recent situations, downturn, and effect of COVID-19 on the whole business. It additionally gives subjective data on when the business can reevaluate the objectives the business is taking to address the circumstance and potential activities.

Note In request to give more precise market conjecture, every one of our reports will be refreshed before conveyance by considering the effect of COVID-19.

Connect with our Analyst to understand the CORONA Virus/COVID-19 impact and be smart in redefining Business Strategies @https://marketresearch.biz/report/gene-therapy-market/covid-19-impact

Gene Therapy Market Segmentation Outlook:

By Vector:Viral vectorRetrovirusesLentivirusesAdenovirusesAdeno Associated VirusHerpes Simplex VirusPoxvirusVaccinia VirusNon-viral vectorNaked/Plasmid VectorsGene GunElectroporationLipofection

By Gene Therapy:AntigenCytokineTumor SuppressorSuicideDeficiencyGrowth factorsReceptorsOther

By Application:Oncological DisordersRare DiseasesCardiovascular DiseasesNeurological DisordersInfectious diseaseOther Diseases

Regions Covered in the Global Gene Therapy Market:

The Middle East and Africa (GCC Countries and Egypt)

North America (the United States, Mexico, and Canada)

South America (Brazil etc.)

Europe (Turkey, Germany, Russia UK, Italy, France, etc.)

Asia-Pacific (Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia)

Key Questions Answered

What is the size and CAGR of the worldwide Gene Therapy market?

Which are the main portions of the worldwide Gene Therapy market?

What are the key driving elements of the most productive regional market?

What is the nature of competition in the worldwide Gene Therapy market?

How will the worldwide Gene Therapy market advance in the coming years?

What are the fundamental systems received in the worldwide Gene Therapy market?

The study analyses the accompanying key business aspects:

Analysis on Strategies of Leading Players:Market players can utilize this investigation to increase upper hand over their rivals in the Gene Therapy and Equipment market.

Study on Key Market Trends:This segment of the report offers a more profound investigation of the most recent and future patterns of the Gene Therapy and Equipment market.

Market Forecasts:Buyers of the report will approach exact and approved evaluations of the absolute market size as far as worth and volume. The report likewise gives utilization, creation, deals, and different gauges for the Gene Therapy and Equipment market.

Regional Growth Analysis:All significant areas and nations have been canvassed in the report. The local examination will help market players to take advantage of unexplored local markets, get ready explicit procedures for target districts, and think about the development of every single provincial market.

Segmental Analysis:The report gives exact and solid figures of the piece of the pie of significant sections of the Gene Therapy and Equipment market. Market members can utilize this examination to make key interests in key development pockets of the Gene Therapy and Equipment market.

Major Points From TOC:

Chapter One:Overview of Gene Therapy

Chapter Two:Global Gene Therapy Competition Exploration by Top Players

Chapter Three:Top Players Profiles

Chapter Four:Gene Therapy Market Size by Type and Application

Chapter Five:United States Gene Therapy Development Status and Outlook

Chapter Six:EU Gene Therapy Market Development Status and Outlook

Chapter Seven:Japan Gene Therapy Market Status and Outlook

Chapter Eight:China Gene Therapy Market Development Status and Outlook

Chapter Nine:India Gene Therapy Market Outlook

Chapter Ten:Southeast Asia Gene Therapy Market viewpoint

Chapter Eleven:Market Forecast by Type and Application

Chapter Twelve:Gene Therapy Industry Dynamics

Chapter Thirteen:Market Effect Factors Analysis

Chapter Fourteen:Conclusion

....For Detailed InformationClick Here For Complete TOC

A Brief Of The Market Division:

According to the product type, the Gene Therapy market is ordered into In-house, Outsource, Hotels and Small Caterers. In addition, the market share overall industry of each and every item alongside the anticipated valuation is referenced in the report.

Realities identified with the items business value, development rate over the timespan, just as income is available in the report.

Discussing applications, the Gene Therapy market is partitioned into Economy Class, Business Class and First Class. The market share of each product application in tandem with the revenue that every single application may register is present in the report.

Factors And Difficulties Depicted In The Report:

Data about the drivers influencing the commercialization size of the Gene Therapy market just as their effect on the income chart of this vertical is available in the report.

Most recent patterns driving the Gene Therapy market alongside the difficulties in the industry is included in the report.

Marketing Strategies In The Report:

A few strategies that are actualized by the investors with respect to the item showcasing is given in the report.

According to the report, brief with respect to the business channels picked by the organizations are available in the report.

Sellers of these items couple with the brief of clients for the equivalent is referenced in the report.

Investigation Of The Competitors In The Business:

A diagram of the producers presents in the Gene Therapy market containing with as far as possible just as deals zone is associated with the report.

Subtleties of each competitor comprising of organization profile just as their scope of products depicted is initiated in the report.

Information identified with the product deals, income age, value models just as gross edges is portrayed in the report.

The report also speaks about several other information such as evaluation of the competitive landscape, information identified with the market concentration rate and concentration ratio in the upcoming years.

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Industry Survey [2020]: Gene Therapy Market Lucrative Growth Analysis [PDF] By 2029 (Cover COVID-19 PANDENIC IMPACT by MarketResearch.biz) - News...

Recommendation and review posted by Bethany Smith

SAN DIEGO and BOSTON, Sept. 02, 2020 (GLOBE NEWSWIRE) -- Sorrento Therapeutics, Inc. (Nasdaq: SRNE, Sorrento) and SmartPharm Therapeutics, Inc. (SmartPharm) announced today that Sorrento has completed the acquisition of SmartPharm, a gene-encoded protein therapeutics company developing non-viral DNA and RNA gene delivery platforms for COVID-19 and rare diseases with broad potential application in enhancing any antibody-centric therapeutics.

The platform in synergy with Sorrentos industry-leading fully human G-MAB antibody library has the potential to be the engine for the next-generation, cost-effective in vivo production of antibody therapeutics in patients. By encoding the antibody sequence into a plasmid, a single injection into someones muscle could potentially lead the person to make their own antibodies in vivo for months, instead of relying on repeat administrations of an externally manufactured antibody.

We are very encouraged by the preclinical data generated thus far by our STI-2020dna plasmid candidate against COVID-19, said Henry Ji, Ph.D., CEO of Sorrento Therapeutics. But beyond STI-2020dna the integration of the plasmid DNA technology with our existing antibody products has the potential to make antibody therapy much more accessible and affordable for patients, and is applicable to a multitude of indications ranging from cancer to infectious diseases.

The current SmartPharm R&D and senior management team will remain in place and is expected to integrate into the Sorrento research, development, and corporate infrastructure.

The merger was completed on September 1, 2020 and at such time, SmartPharm became a wholly owned subsidiary of Sorrento. The total value of the consideration payable to the holders of capital stock of SmartPharm in the merger was $19.4 million, subject to certain adjustments for net working capital, indebtedness, transaction expenses and cash. Upon completion of the merger, SmartPharm stockholders became entitled to receive an aggregate of approximately 1.76 million shares of Sorrento common stock based on a price per share equal to $10.60.

About SmartPharm Therapeutics

SmartPharm Therapeutics, Inc. is a privately held, development stage biopharmaceutical company focused on developing next-generation, non-viral gene therapies for the treatment of serious or rare diseases with the vision of creating Biologics from Within. SmartPharm is currently developing a novel pipeline of non-viral, gene-encoded proteins for the treatment of conditions that require biologic therapy such as enzyme replacement and tissue restoration. SmartPharm commenced operations in 2018 and is headquartered in Cambridge, MA, USA. For more information, please visit http://www.smartpharmtx.com.

About Sorrento Therapeutics, Inc.

Sorrento is a clinical stage, antibody-centric, biopharmaceutical company developing new therapies to turn malignant cancers into manageable and possibly curable diseases. Sorrento's multimodal, multipronged approach to fighting cancer is made possible by its extensive immuno-oncology platforms, including key assets such as fully human antibodies ("G-MAB library"), clinical stage immuno-cellular therapies ("CAR-T", "DAR-T"), antibody-drug conjugates ("ADCs"), and clinical stage oncolytic virus ("Seprehvir"). Sorrento is also developing potential coronavirus antiviral therapies and vaccines, including COVIDTRAP, ACE-MAB, COVI-MAB, COVI-GUARD, COVI-SHIELD and T-VIVA-19; and diagnostic test solutions, including COVI-TRACK and COVI-TRACE. Sorrento's commitment to life-enhancing therapies for patients is also demonstrated by our effort to advance a first-in-class (TRPV1 agonist) non-opioid pain management small molecule, resiniferatoxin ("RTX"), and ZTlido (lidocaine topical system) 1.8% for the treatment of post-herpetic neuralgia. RTX is completing a phase IB trial for intractable pain associated with cancer and a phase 1B trial in osteoarthritis patients. ZTlido was approved by the FDA on February 28, 2018.

For more information, visit http://www.sorrentotherapeutics.com

Forward-Looking Statements

This press release and any statements made for and during any presentation or meeting contain forward-looking statements related toSorrento Therapeutics, Inc., under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995 and subject to risks and uncertainties that could cause actual results to differ materially from those projected. Forward-looking statements include statements regarding the potential effects that the acquisition of SmartPharm may have on Sorrentos business and product candidate pipeline; the data read-outs related to ongoing studies for COVID-19 using antibodies and gene-encoded antibodies; the potency and potential therapeutic capabilities of gene-encoded antibodies and STI-2020dna, and their respective impact on SARS-CoV-2; the expected length of any therapeutic benefit or antiviral protection provided by gene-encoded antibodies and STI-2020dna; the potential administration and applications for a range of disease indications of gene-encoded antibodies and STI-2020dna, alone or in combination; the status of preclinical testing for STI-1499 and STI-2020dna; the therapeutic potential of gene-encoded antibodies, and STI-2020dna for SARS-CoV-2 and COVID-19; the potential costs and cost-effectiveness associated with STI-2020dna and other DNA plasmids; Sorrentos ability to produce antibody candidates against pathogens and cancer cells; Sorrentos ability to transition from product development to full scale manufacturing and commercialization; Sorrentos ability to advance SmartPharms non-viral gene therapy technology and its gene-encoded platform technology; Sorrentos ability to combine SmartPharms technology with Sorrentos technology and manufacturing capabilities; and Sorrentos potential position in the biopharmaceutical industry. Risks and uncertainties that could cause our actual results to differ materially and adversely from those expressed in our forward-looking statements, include, but are not limited to: risks related to Sorrento's technologies and prospects with newly acquired technologies, including the acquisition of SmartPharm and the utilization of SmartPharms Gene-Encoded Therapeutics (GET) platforms for the treatment and prevention of coronavirus infections and other pathogens and cancer cells; risks related to seeking regulatory approvals and conducting clinical trials; the clinical and commercial success of the treatment and prevention of coronavirus infections using gene-encoded antibodies; the viability and success of using gene-encoded antibodies for treatments in anti-viral therapeutic areas, including coronavirus; clinical development risks, including risks in the progress, timing, cost and results of clinical trials and product development programs; risk of difficulties or delays in obtaining regulatory approvals; risks that prior study and trial results may not be replicated in future studies and trials; risks that clinical study results may not meet any or all endpoints of a clinical study and that any data generated from such studies may not support a regulatory submission or approval; risks related to seeking regulatory approvals and conducting clinical trials; risks of manufacturing drug product; risks related to leveraging the expertise of its employees, subsidiaries, affiliates and partners to assist the company in the execution of its strategies; risks related to the global impact of COVID-19 and other risks that are described in Sorrento's most recent periodic reports filed with theSecurities and Exchange Commission, including Sorrento's Annual Report on Form 10-K for the year endedDecember 31, 2019, and subsequent Quarterly Reports on Form 10-Q filed with theSecurities and Exchange Commission, including the risk factors set forth in those filings. Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release and we undertake no obligation to update any forward-looking statement in this press release except as required by law.

Media and Investor Relations

Alexis Nahama, DVM (SVP Corporate Development)Telephone: 1.858.203.4120Email: mediarelations@sorrentotherapeutics.com

Sorrento and the Sorrento logo are registered trademarks of Sorrento Therapeutics, Inc.G-MAB, COVI-GUARD, COVI-SHIELD, COVIDTRAP, T-VIVA-19, COVI-MAB, ACE-MAB, COVI-TRACK, and COVI-TRACE are trademarks of Sorrento Therapeutics, Inc.

ZTlido is a trademark owned by Scilex Pharmaceuticals Inc.All other trademarks are the property of their respective owners. 2020 Sorrento Therapeutics, Inc. All Rights Reserved.

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Sorrento Announces the Closing of Its Acquisition of SmartPharm to Build Next Generation G-MAB-Encoded Plasmid DNA For Cost-Efficient and In Vivo...

Recommendation and review posted by Bethany Smith