Archive for the ‘Bone Marrow Stem Cells’ Category

Brave Nathaniel Nabena smiles from his hospital bed moments before a life-saving procedure.

The nine-year-old had a vital stem cell transplant at Great Ormond Street Hospital on Wednesday after Sunday People readers helped raised more than 215,000.

Nathaniel, battling acute myeloid leukaemia, was on a drip for 30 minutes as umbilical cord stem cells were fed into his body.

Afterwards, dad Ebi said: Nathaniel is very happy. It was amazing to finally get to this point we have all been waiting for.

The youngster was admitted a fortnight ago and had five doses of chemo over ten days to prepare him for the procedure.

How brave has Nathaniel been? Have your say in comments below

Mum Modupe, 38, was able to spend time with him before his transplant.

Consultants warn he faces weeks of sickness as his body reacts to the new cells with symptoms including vomiting and a fever.

Ebi, 45, said: His doctors hope to see improvements after five weeks. It is so hard to see him so exhausted but I dont have a choice. We are grateful to have this done. Our fingers are crossed to see what happens.

For now, Nathaniel has a compromised immune system and is susceptible to falling ill, so he will be staying on the ward.

Stars including Simon Cowell, David Walliams, Katie Price and JLS singer Aston Merrygold rallied to support him after we told of the desperate race to fund treatment.

Nathaniels left eye was removed in his home country of Nigeria a year ago, due to myeloid sarcoma cancer. He was diagnosed with AML in the UK in November after coming here to have a prosthetic eye fitted.

Nathaniel was told a stem-cell transplant was his only hope for survival but it would cost 201,000 as he is not a British citizen. Ebi and Modupe were initially told it could cost as much as 825,000 but the figure was revised after doctors waived their fees and offered to treat him in their own time.

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The lad was admitted to GOSH on May 24 after generous Brits rushed to help the family raise cash.

Business analyst Ebi, who is staying at the hospitals family quarters, said: Ive been there the whole time. When he is not sleeping he is passing the time playing his games.

We sometimes talk about when he gets better and how exciting that will be. This is a difficult thing for him to go through, but Nathaniel is being brave, he is well in himself.

In acute myeloid leukaemia, unhealthy blood-forming stem cells grow quickly in the bone marrow.

This prevents it from making normal red blood cells, white blood cells and platelets meaning the body cannot fight infections or stop bleeding.

A stem cell transplant, also known as a bone marrow transplant, can help AML patients stimulate new bone marrow growth and restore the immune system.

Before treatment, patients need high doses of chemo and sometimes radiotherapy.

This destroys existing cancer and bone marrow cells and stops the immune system working, to cut the risk of transplant rejection.

In an allogeneic transplant, stem cells are taken from a family member, unrelated donor or umbilical cord blood. In Nathaniels case, it was from a cord.

They are then passed into the patients body through a line inserted in a large, central vein, in a process that takes up to two hours.

You can also remove stem cells from the patients body and transplant them later, after any damaged or diseased cells have been removed this is called an autologous transplant.

The survival rate after a transplant for patients with acute leukaemia in remission and using related donors is 55% to 68%, according to Medicine Net. If the donor is unrelated, it is 26% to 50%.

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Brave Nathaniel Nabena, 9, all smiles as he has life-saving procedure - thanks to you - The Mirror

Global Hematopoietic Stem Cell Transplantation (HSCT) Market Size, Status And Forecast 2021-2028

MarketInsightsReports, a leading global market research firm, is pleased to announce its new report on Hematopoietic Stem Cell Transplantation (HSCT) market, forecast for 2021-2028, covering all aspects of the market and providing up-to-date data on current trends.

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Top Companies in the Global Hematopoietic Stem Cell Transplantation (HSCT) Market: ViaCord Inc, Cryo-Save AG, CBR Systems Inc, Pluristem Therapeutics Inc, China Cord Blood Corp, Lonza Group Ltd, Escape Therapeutics Inc, Regen Biopharma Inc

This report segments the global Hematopoietic Stem Cell Transplantation (HSCT) market on the basis of Types are:

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For comprehensive understanding of market dynamics, the global Hematopoietic Stem Cell Transplantation (HSCT) market is analyzed across key geographies namely: United States, China, Europe, Japan, South-east Asia, India and others. Each of these regions is analyzed on basis of market findings across major countries in these regions for a macro-level understanding of the market.

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Key Takeaways from Hematopoietic Stem Cell Transplantation (HSCT) Report

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Hematopoietic Stem Cell Transplantation (HSCT) Market Competitive Analysis with Global Trends and Demand 2021 to 2028:ViaCord Inc, Cryo-Save AG, CBR...

Abstract

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor B (NF-B) and extracellular signalregulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF- induces proteasomal degradation of TRAF2, noncanonical NF-B, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

Multiple myeloma (MM) is characterized by the infiltration of abnormal plasma cells in the bone marrow (BM) and monoclonal protein in serum and/or urine, associated with hypercalcemia, renal dysfunction, anemia, and bone disease (1). The development of high-dose therapy and autologous stem cell transplantation (2, 3) and, more recently, of novel agents including proteasome inhibitors (4), histone deacetylase inhibitor (5, 6), immunomodulatory drugs (IMiDs) (79), and monoclonal antibodies (Abs) (1012), has transformed therapy and markedly improved patient outcome.

The IMiD thalidomide (Thal) was banned because of its teratogenicity when prescribed to treat morning sickness of pregnant women 50 years ago (13). However, Thal and its analogs lenalidomide (Len) and pomalidomide (Pom), initially used empirically predicated upon their antiangiogenic activity (14), have demonstrated remarkable clinical efficacy in MM and other B cell malignancies (15). Our early studies showed that IMiDs trigger direct MM cytotoxicity via activation of caspase-8mediated extrinsic apoptotic pathway, as well as enhancing immune effector antitumor responses while inhibiting T regulatory cells (1619). Multiple groups have subsequently reported that IMiDs directly bind cereblon (CRBN), a substrate adaptor of Cullin4 RING Ligase (CRL4) (20, 21) and activate CRL4CRBN ligase, thereby selectively targeting two B cell transcription factors IKAROS Family Zinc Finger 1 (IKZF1) and IKAROS Family Zinc Finger 3 (IKZF3) for ubiquitination and proteasomal degradation (22, 23). We have also shown that IMiDs directly bind and inhibit TP53-regulating kinase activity in MM cells, followed by MM cell growth inhibition (24). IMiDs trigger additive or synergistic anti-MM activity when combined with proteasome inhibitors and monoclonal Abs in preclinical models (25, 26) and are now used in combinations to treat both newly diagnosed and relapsed MM. However, development of resistance to IMiDs commonly underlies relapse of disease.

To delineate mechanisms of IMiD resistance, the majority of previous studies have focused on CRBN. The expression level of CRBN, CRBN-binding proteins, and CRL4CRBN ligase have been associated with IMiD sensitivity (2730). For example, our prior studies used CRISPR-Cas9 screening to identify signalosome genes regulating expression of CRBN and IMiD sensitivity (31). Although down-regulation or mutations in CRBN have been associated with IMiD resistance (32, 33), MM cells can manifest resistance without CRBN dysfunction (34), indicating potential alternative mechanisms of IMiD resistance. We and others have also shown that MM cell adhesion to extracellular matrix proteins and accessory cells triggers cell adhesionmediated drug resistance to conventional therapeutic agents (35, 36). Moreover, secretion of soluble factors [i.e., tumor necrosis factor (TNF-) and interleukin-6 (IL-6)] from celluar components [i.e., BM stromal cells (BMSCs), osteoclasts, and vascular endothelial cells] activates intracellular signaling pathways including nuclear factor B (NF-B), Rafmitogen-activated protein kinase (MAPK) kinase (MEK)extracellular signalregulated kinase (ERK), Janus kinasesignal transducer and activator of transcription, and phosphatidylinositol 3-kinaseAkt, thereby promoting migration, proliferation, survival, and drug resistance of MM cells (37). Resistance to dexamethasone-induced MM cell apoptosis, for example, is completely abrogated by coculture with BMSCs, IL-6, or insulin-like growth factor 1 (IGF-1). To date, however, the molecular mechanisms mediating IMiD resistance have not been fully delineated.

In this study, we used our in vitro and in vivo preclinical model systems of MM in the BM milieu to delineate molecular mechanisms underlying sensitivity to IMiDs. Genome-wide CRISPR-Cas9 knockout (KO) screening identified TRAF2, a member of TNF receptorassociated factor (TRAF) protein family, to regulate IMiD sensitivity. We show that TRAF2 KO-induced IMiD resistance is mediated via activation of noncanonical NF-B and downstream MEK-ERK signaling, independent of CRBN-IKZF1/3 axis. Within MM BMSC supernatants (SC-sup), TNF- induces proteasomal degradation of TRAF2, followed by noncanonical NF-B and downstream ERK signaling, whereas IL-6 directly triggers ERK activation. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells with high phosphorylated ERK (p-ERK) both in vitro in the presence of SC-sup and in vivo in an inducible TRAF2 knockdown (KD) MM xenograft model. These data, coupled with RNA sequencing (RNA-seq) showing enrichment of ERK signaling in patients with MM at the time of relapse while on single-agent Len maintenance therapy, provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance and improve patient outcome in MM.

We first carried out genome-wide CRISPR-Cas9 KO screening to identify genes and/or pathways mediating IMiD sensitivity (Fig. 1A and fig. S1, A and B). As expected, most of the positively selected genes are associated with activity of CRL4CRBN E3 ligase, the main target of IMiDs mediating their anti-MM activity. Among these genes, we have previously validated that COP9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression (31). TRAF2 was identified in our top 10 genes list (Fig. 1A and fig. S1A), and we demonstrated that three different single-guide RNAs (sgRNAs) targeting TRAF2 were enriched after IMiD treatment (Fig. 1, B and C). To confirm that TRAF2 modulates IMiD sensitivity, we individually cloned the TRAF2 sgRNAs into the LentiCRISPRv2 vector (38) and reintroduced them into MM cells. As expected, TRAF2-KO MM cells acquired notable resistance to Pom and Len treatment (Fig. 1, D and E, and fig. S2, A to C). Conversely, IMiD-resistant RPMI 8226 MM cell line showed increased sensitivity to Pom when TRAF2 was overexpressed (fig. S2D). In patient samples, TRAF2 mRNA was expressed in samples from patients relapsing on Len [Dana-Farber Cancer Institute (DFCI)/Intergroupe Francophone du Myelome (IFM)] and on other therapies (CoMMpass database) (fig. S2E). However, TRAF2 immunohistochemical analysis of BM biopsies from six patients at the time of diagnosis with disease sensistive to Len compared to the time of relapse with disease resistant to single-agent Len maintenance demonstrated lower expression of TRAF2 protein in five of six samples at the time of relapse (Fig. 1F), suggesting that posttranslational modification of TRAF2 may account for clinical resistance. These data demonstrate that TRAF2 expression modulates sensitivity of MM cells to IMiDs.

(A) Volcano plot showing both positively and negatively selected genes in the CRISPR-Cas9 screen at day 21 after Pom treatment. Genes shown in red and blue represent positively and negatively selected genes, respectively. NS, not significant. (B) Normalized reads of sgTRAF2 from cells treated with either dimethyl sulfoxide (DMSO) control or Pom at the indicated time points. Veh, DMSO control. (C) Enrichment of TRAF2 and CRBN sgRNAs after Pom treatment. Each dot specifies one sgRNA. (D and E) Dose-dependent survival of Pom-treated (D) and Len-treated (E) MM.1S cells infected with individually cloned lentiCRISPR viruses targeting the selected gene candidates. Controls were null-targeting lentiCRISPR viruses. Error bars represent SEM (n = 3). IC50, half maximal inhibitory concentration. (F) Representative images of TRAF2 protein expression assessed by immunohistochemical staining of BM biopsies from six patients at time of diagnosis with disease sensitive to Len and at time of relapse with disease resistant to single-agent Len maintenance therapy. Scale bar, 20 M. (G) Representative Western blot analysis of control and TRAF2 KO MM.1S cells treated with DMSO, 0.5 M Pom, or 1 M Len for 72 hours. Whole-cell lysates (WCLs) were collected and probed with indicated Abs. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NT, non-targeting.

Because previous studies showed that CRBN-IKZF1/3 axis plays a crucial role in IMiD-induced MM cell growth inhibition, we next examined whether TRAF2 KO-induced IMiD resistance was CRL4CRBN ligase activity dependent. TRAF2 KO showed no effect on CRBN expression or IMiD-induced degradation of IKZF1/IKZF3 and down-regulation of interferon regulatory factor 4 (IRF4), the main effector of MM cell survival (Fig. 1G). Together, these data suggest that TRAF2 KOmediated IMiD resistance is independent of CRBN-IKZF1/3 axis.

We next investigated the molecular mechanism underlying IMiD resistance in TRAF2 KO cells. TRAF2 KO inhibited cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) triggered by Pom and Len (Fig. 2, A and B, and fig. S3, A and B), indicating that TRAF2 KO inhibits apoptotic cell death triggered by IMiDs. We further confirmed that TRAF2 was required for IMiD-induced cytotoxicity using CellTiter-Glo Luminescent Cell Viability Assay (Fig. 2C and fig. S3C) and flow cytometric analysis with annexin V staining (fig. S3D). Notably, TRAF2 KO has no effect on MM cell growth and cell cycle (fig. S3, E and F). We also examined cross-resistance of TRAF2 KO cells to other therapeutic agents. Viability assays showed that TRAF2 KO cells were also resistant to dexamethasome and melphalan treatment (fig. S3G) but remained sensitive to bortezomib (BTZ) (fig. S3H). These data indicate that TRAF2 KOinduced drug resistance is not specific to IMiDs and independent of ubiquitin-proteasome pathway.

(A and B) Representative Western blot analyses of control and TRAF2 KO MM.1S cells treated with DMSO or 1 M Pom (A) or 1 M Len (B) for 72 hours. WCLs were collected and probed with indicated Abs. (C) Percentage cell viability of control and TRAF2 KO MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CellTiter-Glo (CTG) cell viability assay. CRBN KO cells were analyzed as a positive control. Data are shown as means SEM. ***P < 0.001 by two-sided Students t test. (D) Gene set enrichment analysis plots of datasets identified comparing TRAF2 KO and wild-type signatures. NES, normalized enrichment score. FDR, false discovery rate. (E) Nuclear and cytoplasmic protein were extracted from MM.1S TRAF2 KO cells and immunoblotted with indicated Abs. Cyto, cytoplasmic; nuc, nuclear. (F) WCLs from control and TRAF2 KO MM.1S cells were probed for p-ERK, ERK, and TRAF2 by immunoblotting. The numbers under the bands of blots indicate band intensity normalized to control.

We next performed RNA-seq to delineate signaling cascades mediating IMiD resistance induced by TRAF2 KO. Both noncanonical NF-B (Fig. 2D, left) and ERK (Fig. 2D, right) pathways were enriched in TRAF2 KO cells, consistent with previous reports that TRAF2 regulates NF-B and ERK signaling pathways (39). TRAF2 KO cells showed significantly increased processing of precursor p100 to p52 (NFB2) (Fig. 2E and fig. S4A) and up-regulation of NF-Binducing kinase (NIK) (fig. S4B), as well as activation of noncanonical NF-B pathway (fig. S4C), with minimal impact on p105 or p50 (NFB1) protein expression (fig. S4D). These results suggest that TRAF2 KO predominantly activated noncanonical NF-B pathway. Consistent with RNA-seq analysis, we also confirmed that phosphorylation of ERK and upstream MEK were significantly up-regulated in TRAF2 KO MM cells (Fig. 2F and fig. S4, E to G).

Because both noncanonical NF-B and MEK-ERK pathways were activated in TRAF2 KO cells, we next examined interaction of these signaling pathways mediating IMiD resistance. p52 (NFB2) KO significantly reduced phosphorylation of MEK and ERK in TRAF2 KO cells (Fig. 3A), suggesting that noncanonical NF-B pathway may regulate MEK-ERK activity in TRAF2 KO cells. Moreover, p52 KO in TRAF2 KO cells resensitized them to IMiD treatment (Fig. 3, B and C, and fig. S4H). To further confirm the role of up-regulation of phosphorylated MEK-ERK in resistance to IMiDs, we overexpressed p-ERK2 in IMiD-sensitive MM.1S cells, which conferred resistance to IMiDs (Fig. 3D and fig. S4I). Together, these results indicate that TRAF2 KO activates noncanonical NF-B and downstream MEK-ERK signaling mediating IMiD resistance in MM cells.

(A) Representative Western blot analysis of control and KO MM.1S cells. WCLs were collected and probed with indicated Abs. (B) Percentage cell viability of sgTRAF2 and/or sgp52 MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CTG assay. (C) KO efficiency of p100, p52, and TRAF2 in MM.1S cells was assessed by immunoblot analysis. (D) MM.1S cells were infected with lentivirus to constitutively express activated ERK2 and then treated with Pom (0 to 180 nM) for 72 hours. Cell viability was determined using CTG assay. Data in (B) and (D) are shown as means SEM. ***P < 0.001 by two-sided Students t test. OE, over-expressed; GFP, green fluorescent protein. (E and F) RNA-seq data from MM patient samples of 69 patients at first relapse on Len maintenance therapy. Enrichment scores for ERK pathway activation (E) and correlation between ERK and noncanonical NF-B pathway activation (F) were analyzed.

We next evaluated the clinical significance of ERK activation in relapsed MM patient samples. RNA-seq data from 69 MM patient samples demonstrated activated ERK pathway in 97% cases at the time of first relapse while receiving Len maintenance therapy (Fig. 3E). There was also a significant positive correlation between ERK and noncanonical NF-B signaling in relapsed MM patient samples (Fig. 3F and fig. S4J). These data suggest a pivotal role of ERK activity in mediating IMiD resistance in the clinical setting.

Because we confirmed that ERK activity mediates IMiD resistance, we next sought to determine whether blockade of ERK pathway can overcome IMiD resistance induced by TRAF2 KO. AZD6244 is a potent and highly selective MEK inhibitor (40), and we examined whether AZD6244 abrogated IMiD resistance in TRAF2 KO cells. We first showed that AZD6244 in combination with IMiDs triggered synergistic cytotoxicity in MM.1S wild-type (WT) cells, evidenced by inhibition of cell proliferation (fig. S5, A and B). Addition of AZD6244 overcame resistance and mediated synergistic cytotoxicity with IMiDs in TRAF2 KO MM cells, evidenced by decreased proliferation and p-ERK1/2, as well as by increased induction of PARP cleavage (Fig. 4, A and B, and fig. S5, C to E). To assess the efficacy of combination treatment in vivo, we first generated inducible TRAF2 KD MM.1S cells and confirmed that TRAF2 KD triggered activation of noncanonical NF-B and ERK pathways (fig. S5F) and Pom resistance (fig. S5G) in vitro. These cells were then subcutaneously injected into severe combined immunodeficient (SCID) mice, allowing for induction of TRAF2 KD by intraperitoneal injection of doxycycline. MM.1S WT cells were sensitive to Pom treatment, whereas MM.1S TRAF2 KD cells demonstrated resistance. The combination of AZD6244 and Pom significantly reduced in vivo tumor growth of TRAF2 KD cells, without associated host weight loss (Fig. 4, C to F). These data indicate that MEK inhibitor can abrogate activation of ERK1/2 and overcome IMiD resistance in vivo. Together, our results show that activation ERK signaling plays a crucial role modulating IMiD sensitivity and that MEK inhibitor can overcome ERK-mediated resistance and restore IMiD-induced MM cytotoxicity.

(A) Percentage cell growth of TRAF2 KO MM.1S cells after 3 days of treatment with Len (0 to 1 M) and ERK inhibitor AZD6244 (0 to 1 M). Cell growth was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. (B) Representative Western blot analysis of TRAF2 KO MM.1S cells treated for 48 hours with AZD6244 (0 to 3 M), Len (0 to 3 M), or both. WCLs were collected and probed with PARP Ab. (C to F) MM.1S cells expressing doxycycline-induced shTRAF2 were injected subcutaneously into CB-17 SCID mice (n = 5 for each group). When tumors reached 100 mm3, mice were randomized and treated with vehicle, Pom (2.5 mg/kg), AZD6244 (12.5 mg/kg), or both drugs for 3 weeks. (C) Macroscopic photographs after 21 days of therapy. (Photo credit: Jiye Liu, DFCI). Tumor volume (D) and body weight (E) were monitored over the indicated time period. Data in (D) and (E) are shown as means SEM. **P < 0.01 by two-sided Students t test. (F) Representative images of TRAF2 and p-ERK1/2 immunohistochemistry stain in tumor tissue sections from each group. Scale bars, 40 M.

We and others have shown that the BM microenvironment plays an important role in promoting proliferation, survival, and drug resistance in MM cells (41). Specifically, we showed that either BMSCs or SC-sup activate NF-B and MEK-ERK pathways (37). We therefore next examined the relevance of TRAF2 KO-induced ERK activation-mediated IMiD resistance in the context of the BM microenvironment. As expected, coculture of MM cells with BMSCs (Fig. 5, A and B, and fig. S6, A and B) conferred resistance to IMiDs. Moreover, BMSC supernatants (SC-sup) similarly enhanced MM cell growth and conferred resistance to IMiDs (Fig. 5, C and D, and fig. S6C) associated with down-regulation of TRAF2 (Fig. 5E) and up-regulation of p-ERK (Fig. 5F). These data suggest that IMiD resistance in the BM microenvironment can be mediated, at least in part, by TRAF2 down-regulationinduced ERK activation.

(A and B) MM.1S cells were treated with indicated concentrations of Pom (A) or Len (B) in the presence or absence of BMSC. Cell growth was determined using MTT assay. (C) Percentage cell growth of MM.1S cells after 3 days culture with stromal cell supernatants (SC-sup). Cell growth (means SEM) was determined using MTT assay and normalized to medium control. SCs were from five patients with MM. (D) Percentage cell growth of MM.1S cells after 3 days of treatment with Pom (1 M), SC-sup, or both. Cell growth was determined using MTT assay and normalized to the DMSO control group. (E) Immunoblot analysis of TRAF2 protein level in MM.1S cells cultured with SC-sup for 48 hours. SCs were from five patients with MM. (F) MM.1S cells were cultured for 0 to 24 hours in the presence or absence of SC-sup. WCLs were collected and probed with p-ERK1/2 and ERK1/2 Abs. The numbers under the bands of blots indicate band intensity normalized to control. Data in (A) to (D) are shown as means SEM. ****P < 0.0001 and **P < 0.01 by two-sided Students t test.

To further delineate the mechanism whereby SC-sup confers IMiD resistance, we next performed cytokine array analysis and identified that TNF- and IL-6 were highly secreted by BMSCs (Fig. 6A). TNF-, but not IL-6, treatment induced TRAF2 down-regulation in MM cell lines (Fig. 6, B and C) and patient MM cells (Fig. 6D). TNF- significantly inhibited IMiD-induced MM cytotoxicity in a dose-dependent manner (Fig. 6E and fig. S7, A to C), and similar to TRAF2 KO, TNF- induced IMiD resistance by activating ERK and noncanonical NF-B pathways (fig. S7, D and E), without altering CRBN expression (fig. S7F).

(A) Representative image of cytokine Ab array screening of SC-sup. Supernatant was collected after 24-hour culture with BMSCs and filtered by a 0.22 M low-protein binding membrane. (B) Representative Western blot analysis of MM.1S cells treated with TNF- or IL-6 for 24 hours. WCLs were collected and probed with TRAF2 Ab. (C) MM cell lines were treated with TNF- (5 ng/ml) for 48 hours. Cell lysates were collected and blotted with TRAF2 Ab. (D) Immunoblot analysis of patient MM cells treated with TNF- (5 ng/ml) for 48 hours. WCL was collected and probed with TRAF2 Ab. (E) Percentage cell growth of MM.1S cells after 5 days of treatment with Pom (0 to 3 M) and/or TNF- (0 to 3 ng/ml). Cell growth (means SEM) was determined using MTT assay. (F) MM.1S cells were treated with TNF- (5 ng/ml) for 0 to 10 hours. WCLs were collected and probed with TRAF2 Ab. (G) MM.1S cells were treated with 0.5 nM BTZ or 2.5 nM CFZ for 2 hours, followed by treatment with TNF- (10 ng/ml) for 24 hours. WCLs were collected and probed with TRAF2 Ab. (H) MM.1S cells were cultured with TNF- (5 ng/ml) for 18 hours and then treated with MG132 (10 M) for 6 hours. WCLs were collected and immunoprecipitated by anti-TRAF2 Ab and probed for polyubiquitinated protein and TRAF2. IP, immunoprecipitated. The numbers under the bands of blots indicate band intensity normalized to control.

To further define the mechanism of TNF-mediated TRAF2 down-regulation, we next showed that TNF- promoted TRAF2 protein degradation in a time- and dose-dependent manner (Fig. 6F and fig. S8A) and that the half-life of TRAF2 was markedly shortened by TNF- treatment (fig. S8B). Because previous studies identified TRAF2 as a substrate of the proteasome (42), we also treated MM cells with TNF- in the presence or absence of proteasome inhibitor BTZ or carfilzomib (CFZ). Notably, TRAF2 down-regulation triggered by TNF- was inhibited by these proteasome inhibitors (Fig. 6G), associated with accumulation of ubiquitinated TRAF2 (Fig. 6H). These data confirm that TNF-induced TRAF2 down-regulation is due, at least in part, to its proteasomal degradation in MM cells. As described above, TRAF2 KO induced MEK-ERK phosphorylation via noncanonical NF-B activation, resulting in IMiD resistance. Consistent with a previous study (43), we also show that TNF- also triggered ERK phosphorylation (fig. S7D). Last, we and others have shown that IL-6 activates ERK signaling and resistance to dexamethasone-induced MM cell apoptosis (44). Here, we show that IL-6 also directly induces IMiD resistance (Fig. 7A). In contrast, IGF-1 does not trigger ERK activation or IMiD resistance (fig. S9). These data therefore indicate that soluble factors which induce MEK-ERK activation can protect MM cells from IMiD-induced cytotoxicity in the BM microenvironment.

(A) Percentage cell growth of MM.1S cells after 5 days of treatment with Len (0 to 3 M) and/or IL-6 (0 to 10 ng/ml). Cell growth (means SEM) was determined using MTT assay. (B) Representative Western blot analysis of MM.1S cells cultured for 72 hours in the presence of BMCS with AZD6244 (1 M), Len (1 M), or both. WCLs were collected and probed with anti-cleaved PARP, IKZF1, p-ERK, and ERK Abs. (C) Percentage MM.1S cell growth in cultures with or without SC-sup after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using MTT assay. (D) Percentage MM.1S cell growth in cultures with IL-6 (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay. (E) Percentage MM.1S cell growth in cultures with TNF- (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay.

Because SC-sup (Fig. 5F), TNF- (fig. S7D), and IL-6 (Fig. 7A) induced ERK phosphorylation and IMiD resistance in MM cells, we next determined whether MEK inhibitor was able to inhibit ERK1/2 phosphorylation and overcome IMiD resistance in the context of the BM microenvironment. We first showed that SC-supinduced phosphorylation of ERK was completely blocked by a MEK inhibitor, AZD6244 (Fig. 7B). Moreover, PARP cleavage was markedly enhanced by combination treatment of Pom with AZD6244, without affecting IKZF1 degradation (Fig. 7B). Addition of AZD6244 overcame resistance to Pom and Len in SC-suptreated MM cells (Fig. 7C and fig. S10, A and B). We also observed that IMiD resistance triggered by IL-6 or TNF- was similarly abrogated by AZD6244 (Fig. 7, D and E). These data indicate that MEK-ERK inhibitor can overcome IMiD resistance triggered by TNF- and IL-6 in SC-sup and restore MM cell sensitivity to IMiD treatment in the BM millieu.

During the past two decades, IMiDs have demonstrated remarkable anti-MM activity when used alone or combined with proteasome inhibitors and/or monoclonal Abs as initial, salvage, and maintenance therapies (7, 25, 26, 45, 46). More potent IMiDs with enhanced affinity to CRBN have recently been developed to even further increase their clinical efficacy (4749). Moreover, we and others (24) have also identified novel binding protein of IMiDs, such as TP53-regulating kinase, which may broaden their clinical utility. However, most MM cells eventually acquire resistance to IMiDs, which has, to date, been attributed to decreased expression of CRBN and rarely CRBN mutations (50, 51). Defining mechanisms underlying clinical resistance to IMiDs is therefore essential to inform the design of novel strategies to restore and/or enhance IMiD sensistivity and improve patient outcome.

Targeted genome editing technologies have transformed our abilities to discover basic biological mechanisms underlying specific phenotypes (52, 53). Specifically, the development of the CRISPR-Cas9 system and Cas9-based functional genetic screening tools has facilitated the identification of genes essential for drug resistance (54, 55), and we have used genome-wide CRISPR-Cas9 KO screening to delineate mechanisms of IMiD resistance in MM. We found that many CRL4CRBN E3 ubiquitin ligaseassociated genes are enriched in positively selected genes, confirming that CRBN pathway genes mediate sensitivity of MM to IMiDs. Conversely, many genes essential for MM survival and proliferation (31, 5658) are depleted in negatively selected genes. From this screening, we previously identified the signalosome (CSN) family genes to be positively enriched, and validated that CSN genes regulate CRBN expression, suggesting that strategies to up-regulate CSN may restore CRBN levels and IMiD sensitivity (31). In the current study, we identified TRAF2 as one of the top 10 genes positively selected in our genome-wide CRISPR-Cas9 KO screening. TRAF2 is a member of the TRAF protein family functions as a component of TNF receptor complex and mediates activation of NF-B and/or ERK pathways (59, 60). It also functions as a RING domain E3 ligase that is activated by sphingosine-1-phosphate and catalyzes the lysine-63linked polyuniquitination of receptor interacting serine/threonine kinase 1 (RIP1), thereby leading to NF-B activation (61).

An integrated analysis from 155 MM samples identified that inactive mutations of TRAF2 result in constitutive activation of noncanonical NF-B pathway (62). Here, we show that TRAF2 KO significantly induces IMiD resistance, thereby identifying TRAF2 as an essential mediator of IMiD sensitivity in MM cells. However, TRAF2 KO does not alter CRBN expression or IMiD-induced degradation of IKZF1/3 and its downstream targets IRF4 and c-Myc. Our data therefore identify a novel mechanism underlying IMiD resistance, independent of the CRBN-IZKF1/3 axis. We show that IMiD resistance in TRAF2 KO cells is mediated by noncanonical NF-B and its downstream ERK signaling and that MEK inhibitor AZD6244 can restore sensitivity to IMiDs in vitro and in vivo using our inducible TRAF2 KD MM model. This is of great potential clinical interest, because our analyses of RNA-seq data show nearly universal activation of ERK signaling in MM patient samples at the time of first relapse while on Len maintenance therapy, suggesting that ERK inhibitor may restore IMiD sensitivity in the clinic.

We and others have shown that BMSCs and accessory cells (plasmacytoid dendritic cells, myeloid-derived suppressor cells, osteoclasts, and T regulatory cells) in the MM BM microenvironment play a crucial role in MM pathogenesis by promoting tumor cell growth, survival, and immunosuppression, as well as conferring drug resistance. These biologic sequelae are due to direct tumor cellBMSC/accessory cell interaction (35) and/or secretion of soluble factors including IL-6, TNF-, IGF-1, and vascular endothelial growth factor (63, 64) in the BM milieu. Moreover, our early studies showed that TNF- can directly stimulate the production of IL-6 and up-regulate adhesion molecules (65), thereby further promoting tumor/accessory cell interactions. Here, we show that SC-sup, IL-6, and TNF- induce IMiD resistance in MM cells mediated via ERK signaling. Although IL-6 directly activates ERK signaling, we show that TNF- triggers proteasomal degradation of TRAF2 and activation of noncanonical NF-B, with downstream ERK pathway activation. In contrast, IGF-1 neither activates ERK signaling nor triggers IMiD resistance. Therefore, ERK pathway signaling is implicated in mediating IMiD resistance triggered by multiple stimuli in the BM milieu. Combination MEK inhibitor AZD6244 with IMiDs overcomes resistance to Pom and Len conferred by the BM milieu.

In summary, we have identified and validated that activation of MEK-ERK pathway directly by soluble factors (i.e., IL-6) or indirectly by activation of TRAF2 degradationinduced noncanonical NF-B activation mediates IMiD resistance in the BM microenvironment. These studies not only delineate a novel CRBN-independent mechanism of IMiD resistance in the BM milieu but also provide the preclinical rationale for combining inhibitors of MEK/ERK signaling with Len or Pom to overcome IMiD resistance and improve patient outcome in MM.

MM.1S, RPMI 8226, H929, U266, and human embryonic kidney (HEK) 293T cells were purchased from the American Type Culture Collection. AMO-1, JJN-3, OPM2, and KMS-12BM cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ). All cell lines were verified by short tandem repeat (STR) DNA fingerprinting analysis (Molecular Diagnostic Laboratory, DFCI) and tested for mycoplasma using the MycoAlert Mycoplasma Detection Kit (Lonza). All cells were grown at 37C in 5% CO2 condition: MM.1S, RPMI 8226, H929, U266, AMO-1, JJN-3, OPM2, and KMS-12BM cells were maintained in RPMI 1640 medium; HEK293T cells were maintained in Dulbeccos modified Eagles medium. All media were supplemented with 10% fetal bovine serum (FBS), 1 antibiotic-antimycotic, 1 GlutaMAX, and 1 Hepes.

BM samples were obtained from patients with MM after informed consent and approval by the Institutional Review Board of the DFCI. Mononuclear cells were separated by Ficoll-Paque PLUS (GE Healthcare Life Sciences). MM cells were purified by CD138-positive selection with human CD138 MicroBeads (Miltenyi). Long-term BMSCs were established by culturing CD138-negative BM mononuclear cells for 4 to 6 weeks in RPMI 1640 medium supplemented with 10% FBS and 1 antibiotic-antimycotic.

The culture medium of established BMSCs was replaced with fresh complete medium. Supernatant was collected 24 hours later, followed by centrifugation at 2000 rpm for 10 min to clear cells and debris. Filtration was then performed with a 0.22 M low-protein binding membrane (Millipore Sigma).

Len, Pom, BTZ, CFZ, and MG132 were purchased from Selleck Chemicals; AZD6244 was purchased from Cayman Chemical. All were dissolved in dimethyl sulfoxide (DMSO) and stored at 20C for up to 6 months. For all cell-based experiments, drugs were diluted at least by 1:1000 to ensure that the final DMSO concentration was lower than 0.1%. Cycloheximide solution was purchased from Millipore Sigma. Human recombinant TNF- and IL-6 were purchased from STEMCELL Technologies. Doxycycline was purchased from Boston Bioproducts. Abs were obtained as follows: IKZF1 (no. 5443, Cell Signaling Technology), IKZF3 (no. 15103, Cell Signaling Technology), IRF4 (no. 4299, Cell Signaling Technology), CRBN (no. SAB045910, Sigma-Aldrich), TRAF2 (no. 4724, Cell Signaling Technology and no. ab126758, Abcam), glyceraldehyde-3-phosphate dehydrogenase (no. 5174, Cell Signaling Technology), cleaved PARP (no. 5625, Cell Signaling Technology), caspase-3 (no. 14220, Cell Signaling Technology), NF-B2 p100/p52 (no. 4882, Cell Signaling Technology), histone H3 (no. 4499, Cell Signaling Technology), phosphoNF-B2 p100 (Ser866/870) (no. 4810, Cell Signaling Technology), ubiquitin (no. 3936, Cell Signaling Technology), p44/42 MAPK (Erk1/2) (no. 4695, Cell Signaling Technology), phosphor-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (no. 4370, Cell Signaling Technology), pan-actin (no. 8456, Cell Signaling Technology), NF-B1 p105/p50 (no. 3035, Cell Signaling Technology), lamin A/C (no. 4777, Cell Signaling Technology), anti-rabbit immunoglobulin G (IgG), horseradish peroxidase (HRP)linked Ab (no. 7074, Cell Signaling Technology), and anti-mouse IgG, HRP-linked Ab (no. 7076, Cell Signaling Technology). Protein G Sepharose was purchased from Millipore Sigma.

For RNA-seq, total RNA of WT and TRAF2 KO cells was extracted using the RNeasy Mini Kit (Qiagen). Library was prepared, and samples were sequenced on NovaSeq 6000 PE150. RNA-seq datasets were aligned to human reference genome hg38 using Homo sapiens steroidogenic acute regulatory protein (STAR). RNA-seq by expectation-maximization was used to do the transcript quantification, and differential expression analysis was performed with DESeq2. Gene set enrichment analysis (GSEA) was performed to identify significantly enriched pathways. The biologically defined gene sets were obtained from the Molecular Signatures Database (http://software.broadinstitute.org/gsea/msigdb/index.jsp). Genes used for GSEA analysis were preranked on the basis of log2 fold change of TPM (transcripts per kilobase million) between WT and TRAF2 KO cells.

Cells were plated in medium (8000 cells per well, 100-l final volume) in white, 96-well opaque plates (no. 3917, Corning). Cells were incubated for indicated intervals at 37C in a 5% CO2 incubator. Assay plates were removed from the incubator and equilibrated to room temperature before addition of 50 l of CellTiter-Glo reagent (Promega), according to the manufacturers instructions. Plates were shaken on an orbital shaker for 2 min at 500 rpm and then incubated at room temperature on the bench top for at least 10 min. Luminescence was detected using a spectrophotometer (SpectraMax M3, Molecular Devices).

The growth-inhibitory effect was assessed by measuring 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) (Sigma-Aldrich) dye absorbance, as previously described (56). Cells were cultured in 96-well plates (100 l) with or without drug treatment; for the last 4 hours, cells were pulsed with 10 l of MTT, followed by addition of 100 l of isopropanol containing 0.04 N HCl. Absorbance was measured at 570 nm, with 630 nm as a reference wavelength, using a spectrophotometer (SpectraMax M3, Molecular Devices).

Cells were treated, harvested, washed with phosphate-buffered saline, and lysed in radioimmunoprecipitation assay buffer (no. R0278, Millipore Sigma) containing protease inhibitor and phosphatase inhibitor (no. 78440, Thermo Fisher Scientific). The suspension was incubated for 15 min on ice and vortexed for 5 min. Then, samples were centrifuged at 13,000 rpm at 4C for 10 min. The supernatant was used as whole-cell lysates. Protein concentrations were quantified with a BCA protein assay kit (no. 23227, Thermo Fisher Scientific). Samples were mixed with 4 LDS sample buffer (no. NP0007, Thermo Fisher Scientific), and boiled at 95C for 8 min. Equal amounts of protein were run on NuPAGE Bis-Tris gels (Thermo Fisher Scientific) at a constant voltage. Proteins were transferred onto nitrocellulose membrane by iBlot Gel Transfer Device (Thermo Fisher Scientific). Then, the membranes were blocked in 5% nonfat dry milk for 1 hour at room temperature and incubated with primary Abs in 5% bovine serum albumin at 4C overnight. Blots were then washed three times with 1 Tris Buffered Saline with Tween (TBS-T), before incubation with secondary Abs for 1 hour. SuperSignal chemiluminescent substrate (Thermo Fisher Scientific) was used for signal detection. For reblotting the membranes, blots were stripped in stripping buffer (no. 46428, Thermo Fisher Scientific) according to the manufacturers instruction and reblocked. The intensity of band was quantified by ImageStudio (LI-COR).

On day 0, HEK293T cells were plated in a T150 flask. On day 1, for each flask, 20 g of lentiviral vector, 15 g of psPAX2 (no. 12260, Addgene), and 10 g of pMD2.G (no. 12259, Addgene) diluted in 3 ml of Opti-MEM were combined with 150 l of Lipofectamine 2000 diluted in 3 ml of Opti-MEM. The mixture was left for 20 min and then added to the cells. Twelve hours after transfection, the medium was replaced by fresh complete medium. The supernatant containing virus was collected 72 hours after transfection, followed by centrifugation at 2000 rpm for 10 min to pellet cell debris. Filtration was then performed with a 0.45-m low-protein binding membrane (no. SE1M003M00, Millipore). Then, the virus was concentrated by the Lenti-X Concentrator (no. 631231, Takara).

For generation of CRISPR KO cell lines, oligonucleotides (table S1) targeting different genes were annealed and subcloned into LentiCRISPRv2 vectors (38). Constructs were packaged into lentivirus in HEK293T cells. Target cells were seeded in 12-well plates and spinfected with virus for 1.5 hours at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). Medium was then aspirated, and fresh complete medium was added to exclude Polybrene. After 1 day, cells were selected for stable KO using puromycin (0.5 g/ml). After 7 days, cells were collected for immunoblotting or other experiments. To generate inducible TRAF2 KD cells for in vivo study, the SMARTvector inducible human TRAF2 lentivirus plasmid (Horizon Dharmacon) was transfected into HEK293T cells with packaging vectors. Cells were spinfected for 1 hour with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days. For the constitutive expression of ERK2-MEK1 fusion protein, the sequence of full length of ERK2-MEK1 was cloned from pCMV-myc-ERK2-L4A-MEK1_fusion vector (no. 39197, Addgene) into plenti-CMV-Puro-DEST (no. 17452, Addgene). The expression plasmid was transfected into HEK293T cells with the packaging vectors. Cells were spinfected for 1.5 hours with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days.

The cytokine array assay was performed using a Human Cytokine Array C5 kit (no. AAH-CYT-5-2, RayBiotech), according to the manufacturers instruction.

MM cells were treated with TNF- (5 ng/ml) for 24 hours and then 10 M MG132 for 6 hours. Cells were lysed in IP lysis buffer (no. 87787, Thermo Fisher Scientific). TRAF2 protein was pulled down by Protein G Agarose with TRAF2 Ab overnight at 4C and washed with IP lysis buffer. Protein was eluted by incubation with LDS loading buffer at 100C for 5 min, separated by SDSpolyacrylamide gel electrophoresis, transferred to nitrocellulose membrane, and probed with indicated Abs.

Cells were cultured in 12-well plates with or without TNF- and treated with cycloheximide (100 g/ml) for the indicated time periods before harvest. Cell lysates were analyzed by Western blotting.

A total of 6 106 Tet-inducible TRAF2 KD MM.1S cells were suspended in 100 l of RPMI 1640 medium and injected into the flanks of 200 cGyirradiated female SCID mice. Tumor size was measured every 2 days with an electrical caliper. The tumor volume was determined with the formula: (length width2) 0.5, where length is the longest diameter and width is the shortest diameter. When the tumor volume reached 100 to 150 mm3, xenografted mice were randomized to treatment and control cohorts. In the TRAF2 KD group, mice received doxycycline (2.5 mg/kg) via intraperitoneal injection to induce TRAF2 KD. AZD6244 (12.5 mg/kg per day) and Pom (2.5 mg/kg for 5 days/week) administrated by oral gavage. All care and treatment of experimental animals was conducted under a protocol approved by DFCI Institutional Animal Care and Use Committee guidelines. All mice were housed in a pathogen-free environment at a DFCI animal facility and were handled in strict accordance with Good Animal Practice, as defined by the Office of Laboratory Animal Welfare.

Cells were harvested and concentrations adjusted to 1 106 cells/ml. After washing, cells were suspended in 50 l of Hanks balanced salt solution (HBSS) containing 2% FBS; 1 ml of ice-cold 70% ethanol was then added in a dropwise manner while mixing gently on a vortex, with storage on ice for no less than 2 hours. Pelleted cells were washed with HBSS containing 2% FBS twice, and then 1 ml of 4,6-diamidino-2-phenylindole (DAPI) working solution was added, followed by incubation in the dark for 15 to 30 min at room temperature. Cells were filtered through a 40-m mesh filter and then analyzed by flow cytometry.

MM cells (1 106) were treated with Pom for 5 days and then stained with the LIVE/DEAD Fixable Aqua Dead Cell Staining Kit (no. L34957, Thermo Fisher Scientific) and annexin Vphycoerythrin conjugate (no. 640908, BioLegend), according to the manufacturers instruction. Cells were analyzed in BD FACSCanto II (BD Biosciences) using the FACSDiva software (BD Biosciences).

Tissue specimen sections of formalin-fixed, paraffin-embedded BM biopsies from six patients at diagnosis with MM sensitive to Len and at the time of relapse with disease resistant to single-agent Len were prepared and precessed for immunohistochemistry to detect TRAF2 protein expression by using TRAF2 Ab (no. ab126758, Abcam). Tumor samples from mice were harvested and fixed in formalin and then embedded in paraffin and cut in 4 M sections. Sections were stained with TRAF2, p-ERK1/2, and DAPI. Tissues were imaged using a microscope.

RNA-seq data from 69 patients with MM at the time of first relapse while on single-agent Len maintenance (DFCI/IFM) were collected after study participants provided written informed consent. After RNA extraction, RNA quantity was evaluated, and only samples with 100 ng of RNA with RNA integrity number (RIN) value 7 were sequenced with stranded 50base pair paired-end sequencing. After quality control, raw samples were quantified using Salmon and Gencode transcripts. Single-sample GSEA (ssGSEA), an extension of GSEA, was used to calculate separate enrichment scores for ERK pathway. R and ggpubr were used for statistical test and visualization. Pearson correlation analysis and Fishers exact test were used for association analysis and enrichment in relapse samples. The DFCI/IFM and CoMMpass patient sample RNA-seq databases were used to analyze correlation between noncanonical NF-B and ERK pathway activation in relapsed patient samples. TPM-level gene expression data were used only for patients who had CD138+ BM samples profiled at the time of relapse. We downloaded the Biocarta ERK pathway and Gene Ontology NIK NF-B signaling pathways from the Molecular Signatures Database website, and with ssGSEA, we quantified the enrichment score for each patient. Spearman correlation between the two pathways were evaluated using R and ggpubr.

Students t test or analysis of variance followed by Dunnetts test was used to compare differences between the treated group and the relevant control group. A value of P < 0.05 was considered significant.

Acknowledgments: We thank E. Campeau, M. Robinson, and F. Zhang for expression vectors. We also thank D. Chauhan and E. Morelli for helpful comments. We thank the staff from the hematologic neoplasia core facilities at DFCI for technical assistance. We also thank the Genome Center of WuXi AppTec Inc. for the initial data analysis of the CRISPR screening. Funding: This work was supported by the National Institutes of Health grants SPORE-P50100707 (to K.C.A.), R01-CA050947 (to K.C.A.), R01-CA178264 (to T.H. and K.C.A.), and P01-155258 (K.C.A. and N.M.). K.C.A. is an American Cancer Society Clinical Research Professor. This study was also supported, in part, by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Riney Family Myeloma Initiative, and the National Natural Science Foundation of China (NSFC grant no. 81800204). Author contributions: K.C.A. conceived the project, designed the research, analyzed the data, wrote the manuscript, and supervised the project. J.L. and T.H. designed and performed the research, analyzed data, and wrote the manuscript. J.L. and L.X. performed xenograft experiments. S.W. and W.Z. performed CRISPR-Cas9 screening data analysis. M.K.S. analyzed RNA-seq data from patients with MM. T.S. performed immunohistochemistry. D.O. provided assistance in some cell-based assays. G.A. and G.B. provided BM sections. S.G. and L.Y. performed immunohistochemistry. T.J. performed some Western blot experiments. K.W. helped process the human samples. R.C. provided biological materials and performed immunohistochemistry. Y.-T.T. provided biological material and analyzed data. N.M. and P.R. helped collect patient samples and analyzed data. Y.C. helped analyze data and revised the manuscript. Competing interests: K.C.A. serves on advisory boards to Millennium, Janssen, Sanofi, Bristol Myers Squibb, Gilead, Precision Biosciences, and Tolero and is a scientific founder of OncoPep and C4 Therapeutics. The authors declare that they have no other 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. All sequencing data were uploaded to Gene Expression Omnibus with accession no. GSE171341.

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ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment - Science Advances

Lymph nodes are small, bean-shaped glands that play a crucial role in the immune system. They filter lymphatic fluid, which helps rid the body of germs and remove waste products.

The body contains hundreds of lymph nodes. They form clusters around the body and are particularly prominent in areas such as the neck, armpit and groin and behind the ears.

The bodys cells and tissues dispose of waste products in lymphatic fluid, which lymph nodes then filter. During this process, they catch bacteria and viruses that could harm the rest of the body.

Lymph nodes are an essential part of the bodys immune system. Due to their function, they come into contact with toxins, which can cause them to swell. Although swollen lymph nodes are common, they may occasionally indicate lymph node cancer, or lymphoma.

Keep on reading to learn more about lymph nodes and their function within the immune system.

Lymph nodes are part of the lymphatic system, which is a complex network of nodes and vessels.

In certain areas of the body, such as the neck, armpit, and groin, lymph nodes sit close to the skin. This means a person may feel them swell when an infection develops.

Lymph nodes are also present in the stomach and between the lungs. However, there are no lymph nodes in the brain or spinal cord.

The name of a lymph node depends on its location in the body.

Lymph nodes form clusters throughout the body. Their main function is to filter out potentially harmful substances.

All tissues and cells in the body excrete lymphatic fluid, or lymph, in order to eliminate waste products. The lymph then travels through vessels in the lymphatic system and passes through lymph nodes for filtering.

Lymph nodes contain lymphocytes. These are a type of white blood cells that help destroy pathogens, such as bacteria, viruses, and fungi. When lymph nodes detect a pathogen in the lymph, they produce more lymphocytes, which causes them to swell.

Upon encountering bacteria or damaged cells, lymph nodes destroy them and turn them into a waste product.

When the lymph reenters the bloodstream, waste products travel to the kidneys and liver. The body then excretes waste products in the urine and feces.

Learn more about how the lymphatic system works here.

Swollen lymph nodes do not always indicate cancer. Below, we list some of many conditions that can cause lymph node swelling.

Lymphadenitis occurs when bacteria, viruses, or fungi in the lymph infect lymph nodes. When this happens, lymph nodes swell and are painful to the touch.

If multiple clusters of nodes become infected, a person may feel pain and swelling in both their neck and groin.

The most common type of lymphadenitis is localized lymphadenitis. This means the condition only affects a few nodes. If the infection occurs in several node clusters, a doctor will likely diagnose generalized lymphadenitis.

The condition usually results from an infection elsewhere in the body.

Symptoms of lymphadenitis include:

Lymphadenitis treatments include:

The type of treatment necessary will depend on a variety of factors, such as the severity of the disease and a persons underlying conditions and allergies. A doctor will help a person choose the most suitable treatment based on these factors.

Learn more about swollen lymph nodes in the neck here.

Swollen lymph nodes in the neck may be due to a viral or bacterial throat infection, such as strep throat.

Viral throat infections, such as colds, can present with swollen lymph nodes, a runny nose, and pinkeye.

These infections usually resolve on their own. However, a person can take over-the-counter pain relievers to alleviate pain they may experience when swallowing.

Strep throat is a bacterial infection that develops in the throat and tonsils due to group A streptococcus. People may contract strep throat if they come into contact with droplets containing the strep bacteria.

A person with strep throat may experience swollen lymph nodes on the neck, a sore throat, a fever, and red spots on the roof of the mouth.

Doctors treat strep throat with antibiotics.

Impetigo is an infection that develops due to group A streptococcus and may cause lymph nodes in the armpits and groin to swell.

A person can contract impetigo when the bacteria enter the body through a break in the skin. This can happen through sharing a towel, razor, or yoga mat.

Symptoms of impetigo include:

If a person has impetigo, they should seek medical attention to address their symptoms and prevent the condition from spreading to others.

Treatment will usually involve antibiotics.

Ringworm, or jock itch, is a fungal infection that can affect many areas of the body. If the fungus develops in the groin, a person may experience lymph node swelling in that area.

Typically, ringworm starts as a fungal lesion. The fungus often transmits when people share towels or razors.

Ringworm thrives in moist environments, and therefore a person should take care to dry thoroughly after a wash and try not to stay in damp clothes.

Common ringworm symptoms include:

A doctor will prescribe an antifungal treatment to address ringworm.

The best way to prevent ringworm is to wear breathable fabrics, avoid sharing towels and razors, and dry thoroughly after bathing.

Learn more about swollen lymph nodes in the groin here.

Lymphoma is a type of cancer that affects the lymphatic system. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma.

Hodgkin lymphoma occurs when cancer cells spread from one cluster of lymph nodes to another. By contrast, in non-Hodgkin lymphoma, there is no order in how cancer cells spread throughout the lymphatic system.

Typical symptoms of lymphoma include:

These are also common symptoms of viral infections, which can make lymphoma hard to diagnose. However, in people with lymphoma, symptoms tend to persist for longer periods of time.

It is of note that these symptoms do not clearly indicate cancer. If a person experiences any of these, they should contact a doctor to identify the cause of their symptoms.

Treatment options for lymphoma include:

A person should contact a healthcare professional if they are experiencing persistent swelling of lymph nodes.

Swelling usually indicates an infection, and therefore a person should not immediately worry about lymphoma.

After reaching a diagnosis, a doctor will recommend the appropriate course of treatment.

Lymph nodes are a part of the lymphatic system. They filter lymph, which contains pathogens and damaged cells, and send the dead cells to the kidneys and liver.

Lymph node swelling usually results from an infection. In rare cases, however, it may be due to lymphoma.

If a person is concerned about swelling and other symptoms they have, they should contact a doctor.

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Lymph nodes: Purpose, location, and disease warning signs - Medical News Today

DUBLIN--(BUSINESS WIRE)--The "Global Stem Cell Therapy Market by Type (Allogeneic, Autologous), Therapeutic Application (Musculoskeletal, Wound & Injury, CVD, Autoimmune & Inflammatory), Cell Source (Adipose tissue, Bone Marrow, Placenta/Umbilical Cord) - Forecasts to 2026" report has been added to ResearchAndMarkets.com's offering.

The global stem cell therapy market is projected to reach USD 401 million by 2026 from USD 187 million in 2021, at a CAGR of 16.5% during the forecast period.

Growth in this market is majorly driven by the increasing investment in stem cell research and the rising number of GMP-certified stem cell manufacturing plants. However, factors such as ethical concerns and the high cost of stem cell research and manufacturing process likely to hinder the growth of this market.

The allogeneic stem cell therapy segment accounted for the highest growth rate in the stem cell therapy market, by type, during the forecast period

The stem cell therapy market is segmented into allogeneic and autologous stem cell therapy. Allogeneic stem therapy segment accounted for the largest share of the stem cell therapy market. The large share of this segment can be attributed to the lesser complexities involved in manufacturing allogeneic-based therapies.

This segment is also expected to grow at the highest growth rate due to the increasing number of clinical trials in manufacturing allogeneic-based products.

Bone Marrow-derived MSCs segment accounted for the highest CAGR

Based on the cell source from which stem cells are obtained, the global stem cell therapy market is segmented into four sources. These include adipose tissue-derived MSCs (mesenchymal stem cells), bone marrow-derived MSCs, placenta/umbilical cord-derived MSCs, and other cell sources (which include human corneal epithelium stem cells, peripheral arterial-derived stem cells, and induced pluripotent stem cell lines).

The bone marrow-derived MSCs segment is expected to witness the highest growth rate during the forecast period, owing to an increasing number of clinical trials focused on bone marrow-derived cell therapies and the rising demand for these cells in blood-related disorders.

Asia Pacific: The fastest-growing country in the stem cell therapy market

The stem cell therapy market is segmented into North America, Europe, Asia Pacific, RoW. The stem cell therapy market in the Asia Pacific region is expected to grow at the highest CAGR during the forecast period.

Factors such as the growing adoption of stem cell-based treatment in the region and the growing approval & commercialization of stem cell-based products for degenerative disorders drive the growth of the stem cell therapy market in the region.

Market Dynamics

Drivers

Restraints

Opportunities

Challenges

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/qiagh1

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Stem Cell Therapy Market by Type, Therapeutic Application and Cell Source - Global Forecasts to 2026 - ResearchAndMarkets.com - Business Wire

When he called the Olivia Hospital and Clinic to postpone his physical, he was urged to keep it. Physicals are important, he was reminded.

Keeping that date proved to be a lifesaving decision.

The physical went well, and shortly after he told his daughter that he was as fit as a horse.

But Dr. Jon Kemp, his primary physician who had urged him to keep the date for the physical, noticed a slight abnormality in a standard blood test. He recommended further testing.

On Dec. 20 Kramer was diagnosed with multiple myeloma.

Thanks to the early diagnosis, Kramer, age 62, has the means of keeping this disease at bay. Its a cancer of the plasma cells in bone marrow, and is the second most common blood cancer.

He is about to undergo a stem cell transplant this week as part of his treatment.

He learned that hes not alone on the journey ahead.

At Tuesdays meeting of the Renville County Board of Commissioners, fellow board members came wearing T-shirts proclaiming: In this county, nobody fights alone.

Organizers of the surprise sold 76 of the T-shirts to show support for Kramer and raise funds for the Renville County Walk in the Park campaign. More than 40 T-shirt wearing supporters joined the meeting via Zoom. Staff in the health department sang a song to express their support, and staff members told him they would keep him in their thoughts and prayers.

Thank you, said Kramer. He told the West Central Tribune that he was totally surprised by the display of support.

He has lots of support from family and friends, and its all-important. Kramer farms in eastern Renville County. He has lined up plenty of helping hands while he undergoes the stem cell transplant, which will sideline him for at least six weeks.

He said doctors are confident the stem cell transplant can knock the cancer into remission. They will be harvesting bone marrow cells and freezing a portion of them to make it possible to perform at least two more transplants in future years as well.

The decision to keep the date of that routine physical made all the difference. Absolutely, said Kramer.

Health providers told him that in too many cases, multiple myeloma is not diagnosed until a patient comes in with a broken leg or other bone, and wondering why. The cancer carves holes and weakens bones as it progresses unbeknownst to the person.

Thanks to the early diagnosis, Kramer said they found only pinholes in his bones, having caught the disease in the first of its three stages. He began chemotherapy in early January, and it has proven effective, he added.

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Keeping the physical appointment was critical, the show of support appreciated by Renville County Commissioner - West Central Tribune

Multiple myeloma is a type of cancer that originates from white blood cells called plasma cells. Many factors affect the outlook for a person with this disease, including their age, overall health, and kidney function, as well as the stage of cancer at diagnosis.

Multiple myeloma is a cancer of the plasma cells, which are a type of white blood cell. Over time, myeloma cells multiply and accumulate in the bone marrow and solid parts of the bones.

Multiple myeloma can lead to organ damage that affects the kidneys, the bones, and the overall immune system.

In this article, we look at the outlook for people with different stages of multiple myeloma. We also look at the symptoms and treatment of multiple myeloma and what can affect a persons outlook.

The American Cancer Society (ACS) estimates that doctors will diagnose 34,920 new cases of multiple myeloma in 2021 and that there may be 12,410 deaths from the disease.

When a person receives a multiple myeloma diagnosis, the doctor will use the Revised International Staging System (RISS) to determine the stage of the cancer. This staging system is based on:

A person will receive a diagnosis of either stage 1, 2, or 3 multiple myeloma. There is also a stage 0, a slow-growing type of multiple myeloma that is called smoldering myeloma.

However, survival rates are based on summary staging, which the Surveillance, Epidemiology and End Results (SEER) program developed. This staging system groups cancers into:

As multiple myeloma does not spread to the lymph nodes, the regionalized stage is not relevant to this cancer.

The 5-year relative survival rate for multiple myeloma is as follows:

These statistics mean that a person with localized multiple myeloma is 75% as likely as someone without multiple myeloma to live for 5 years after receiving the diagnosis.

People who receive a smoldering myeloma diagnosis can live for years without any treatment. Additionally, beginning treatment early does not appear to affect the outlook.

The stage of multiple myeloma is among the factors that can affect a persons outlook.

Other factors include:

A small 2014 study involving 82 people with an average age of 61 years found that those with damaged kidneys had a median survival rate of 13 months, whereas those without kidney damage lived for an average of 41 months.

Additionally, changes in chromosomes and genetic abnormalities can affect a persons outlook. The specific chromosomal abnormalities that doctors consider high risk affect chromosomes 4, 14, 16, and 17.

The treatment for smoldering myeloma typically consists of watchful waiting, as this stage is slow growing.

Drug therapy for multiple myeloma consists of:

Other treatment options include:

Multiple myeloma can cause:

A doctor may recommend supportive therapies to help manage these side effects. These may include surgery to help support weakened bones and prevent fractures.

Learn more about the treatment options and how to manage the symptoms.

A person should contact a healthcare professional if they notice any symptoms of multiple myeloma.

After receiving a multiple myeloma diagnosis, a person may want to ask the following questions:

Multiple myeloma is a type of cancer that affects the blood. The outlook for people with multiple myeloma depends on the stage of the cancer at the time of diagnosis. It also depends on how well a persons kidneys are functioning and their age and overall health.

However, different treatment options are available. A person should talk with a healthcare professional about which treatment options would best suit them.

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Outlook for multiple myeloma: Figures and factors that affect it - Medical News Today

On the day of his Year 10 school prom, as other students excitedly prepared for the big occasion, then 15-year-old Rian Harvey was sat in a ward of Royal Marsden Hospital, awaiting the stem cell transplant that would save his life after a leukaemia relapse.

Despite the hot weather on that day back in July 2015, his hospital room windows had to remain sealed shut, as even the smallest bug bite could have killed him due to his compromised immune system.

Six years on, he finds himself grateful that he relapsed when he did, with five years to build his immunity before the Covid-19 pandemic hit.

Blood cancer patients are one of the most vulnerable groups of people at risk of Covid-19, according to research, being 57 per cent more likely to suffer severe disease compared to other cancer patients.

Recalling his own experience, Rian, now 22, says: Its scary, you look at everything that person has gone through, they had blood cancer and then had a stem cell transplant, they have gone through all the stress of only to be taken by a pandemic that came out of nowhere.

I know the vulnerability that you are in for stem cell transplants, Ive been there myself. Your immune system cant take anything.

Despite the high risk these patients face, charities such as Anthony Nolan, which assist blood cancer patients with finding a stem cell match, were left out of the allocated government budget that was announced in March.

The cancellation of face-to-face fundraising and events, despite the increase in demand for services, have led their gross income to be down by an estimated 5.5m for 2021.

Henny Braund, chief executive of the charity, said people with blood cancer and blood disorders were heavily impacted by the pandemic and everyone who needs treatment and support must be able to access it without delay.

This budget does not address the pressure currently facing cancer services across the UK, he adds.

Stem cell transplants are carried out to treat conditions such as blood cancer. The process involves removing the healthy stem cells of one person and transferring them to another, provided they have a similar or identical special genetic marker called the HLA.

While this match is sometimes present between family members, it is not always the case, leaving patients in the UK reliant on the British Bone Marrow Registry to find a suitable match. The odds of a match are one in 1000.

One of Anthony Nolans primary roles is to encourage more people to put themselves on the registry so patients have an increased chance to find a match. This can be done via a simple cheek swap, which provides sufficient HLA data for the initial matching process.

Will Briant, 24, from London, donated stem cells in 2015 after signing up to be on the registry at university. I think it ultimately is a huge part of who I am now, he says. Its something that I look to in my darker moments and find great inner strength from.

The identities of donors and recipients remain anonymous to one another, but they are allowed to exchange letters after the transplant.

I was incredibly emotional when I got the letter, he adds. He made it clear that not only was I giving him the chance of time for himself, but it was also for all of his family and friends, he told me he had a very big family. Looking back now, at a time where we cant all be with our families, it just highlights just how important and valuable that must have been for him.

Apart from encouraging people to sign up to the registry, the money Anthony Nolan raises go towards funding research, offering support and information to patients and families as well as providing post-transplant-care. They have helped 18,000 people find a match.

Unfortunately, they are part of the 35 per cent of charities who used the furlough scheme offered by the government to curb the loss of income. To ensure their survival, 24 per cent of surveyed charities said they were letting furloughed employees return as volunteers.

Terence Lovell, chief engagement and marketing officer at Anthony Nolan, says: We still desperately need funds to continue our life-saving work through providing stem cells transplants and co-ordinating efforts across the NHS to ensure patients receive the care and support they need.

Despite the circumstances, Rian has decided to make the most of his time in lockdown. He regularly shares his experience fighting cancer on his social media platforms and is currently in the process of writing a book and producing a podcast to further share his message.

The cancer mill is still very much open for business and I am trying to push people, that have not necessarily been through what Ive been through, to be more positive and see the world the way that I do, he says, I wake up in the morning, open my front door, take a deep breath of fresh air and I think this is amazing because five years ago I couldnt even open a window in the hospital.

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How Covid-19 has disrupted efforts to care for blood cancer patients - The Independent

Gene therapy has shown promise in recent years for treating a range of diseases, including sickle-cell anemia, hemophilia, various forms of inherited blindness, mesothelioma, and Duchenne muscular dystrophy. A new success story may soon be added to this list, with the publication yesterday of the outcomes of a clinical trial that used gene therapy to cure a rare immune system disorder in infants.

The study, described in the New England Journal of Medicine, was carried out by researchers from UCLA and Great Ormond Street Hospital in London over the course of five years, beginning in 2012.

Adenosine deaminase (ADA) is an enzyme found in a type of white blood cell called lymphocytes, which are primarily active in the brain, GI tract, and thymus gland. Lymphocytes make antibodies and attack infected cells, so theyre pretty crucial to the immune system.

ADAs job is to convert a molecule thats harmful to lymphocytes into a non-harmful version of itself. If ADA cant work its magic, that molecule starts to build up in lymphocytes, becoming toxic and ultimately killing the cellsand leaving the immune system virtually defenseless, highly vulnerable to invaders like viruses and bacteria.

Mutations in the ADA gene mean the body doesnt make enough of the enzyme to successfully do its job. This deficiency of ADA leads to a condition called severe combined immunodeficiency (SCID). Those suffering from SCID can not only get sick very easily, but conditions that would be neutralized by a normal immune system quickly become deadly for them.

SCID was more commonly known as bubble boy disease after David Vetter, a boy born in Texas in 1971, spent 12 of his 13 years of life enclosed in a plastic bubble to protect him from germs.

About 20 different genetic mutations can cause SCID; ADA-SCID refers to immunodeficiency caused by lack of the ADA enzyme: severe combined immunodeficiency due to adenosine deaminase deficiencya bit of a mouthful. The worst part of ADA-SCID is that it occurs in babies; most are diagnosed with the condition before theyre even six months old, and without treatment they typically dont live past age two.

ADA is rare, estimated to occur in about 1 in 200,000 to 1,000,000 newborns worldwide; both the mothers and the fathers ADA gene must have mutations for the child to end up with this condition.

The first step in the gene therapy treatment was to collect hematopoietic stem cells, which are those that manufacture blood cells, from the patients. The researchers then inserted an intact copy of the ADA gene into the stem cells using an RNA virus called a lentivirus (the most well-known lentivirus is HIV).

The altered cells were re-injected into the patients, where they started producing ADA normally, yielding healthy immune cells.

Out of 50 total patients30 in the US and 20 in the UKwith ADA-SCID, 48 appear to have been rid of their condition thanks to the gene therapy, with no complications reported. The two patients who didnt have success with the therapy went back to traditional treatment methods, and didnt experience any adverse effects as a result of having tried the therapy.

If, or hopefully when, gene therapy becomes the go-to treatment for ADA-SCID, it will be a welcome reprieve from traditional options, which are neither pleasant nor cheap: patients need weekly injections of ADA until a bone marrow transplant can be done, and absent a donor, they must consistently receive injections, take antibiotics, and undergo antibody infusions for life.

If approved in the future, this treatment could be standard for ADA-SCID, and potentially many other genetic conditions, removing the need to find a matched donor for a bone marrow transplant and the toxic side effects often associated with that treatment, said Dr. Claire Booth, co-author of the study and a consultant in pediatric immunology and gene therapy at Londons Great Ormond Street Hospital.

Theres no mention of the cost of the therapy, nor whether this could be a prohibitive factor to making it a viable option. Nonetheless, the study is encouraging not just for its potential to revolutionize treatment of ADA-SCID, but as a harbinger for the promise of gene therapy for a multitude of genetic conditions.

People ask us, is it a cure? Who knows long term, but at least up to three years, these children are doing well, said Dr. Stephen Gottschalk, who was not involved in this study but performed a similar gene therapy on kids with SCID at St. Jude Childrens Research Hospital in Memphis. The immune function seems stable over time so I think it looks very, very encouraging.

Image Credit: liyuanalison from Pixabay

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How One Round of Gene Therapy Fixed 48 Kids' Immune Systems - Singularity Hub

Dr Pria Suchak, 31, initially registered with blood cancer charity DKMS last July, when she was inspired by a message on social media.

Every 20 minutes someone in the UK is diagnosed with a blood cancer those that affect the body's bone marrow, blood or lymphatic system - such as leukaemia, myeloma or lymphoma.

Yet, only two per cent of the UK population are registered as potential blood stem cell donors.

Pria said: My friends nephew had leukaemia, so she was using her Facebook page to encourage strangers to sign up him.

"Her nephew is of mixed heritage - half Chinese and half Caucasian. So she was trying to encourage more people for minority ethnic communities to sign up.

"I wanted to help give someone a second chance of life, so I signed up with DKMS, and my husband registered at the same time.

Patients from black, Asian or other minority backgrounds have a 20 per cent chance of finding the best possible blood stem cell match from an unrelated donor, compared to 69 per cent for northern European backgrounds.

Pria ordered a home swab kit in July 2020 and was contacted by DKMS just five months later, informing her that she was a potential match for a stranger in need of a lifesaving blood stem cell transplant.

The mum-of-two said: I received a call from a lady at DKMS. She said I was extremely close to being a match, but there were also eight other people who were identified as possible matches too.

"A few weeks later, I received another call from DKMS saying that I was the best match out of the nine potential donors.

"I didnt expect that. As it was nine of us in total, you never expect you'll be chosen.

Following further tests and a medical examination, a date was set for Pria to donate her blood stem cells by peripheral blood stem cell collection (PBSC).

In the run-up to the procedure, donors are given a drug with the growth factor G-CSF to increase the number of stem cells in the blood.

Pria said: At the time I had so many things going on. We had just gotten past Christmas, both of my children had birthdays in January, and I was about to sit a final GP exam.

"DKMS were excellent and did their best to schedule my G-CSF injections the day after I sat the exam. Of course, they checked that this wouldnt impact the patient.

My actual donation was really nice, especially as there were other donors in the room at the same time donating for other patients.

"We all got on really well and chatted loads. The clinicians told us that we were the chattiest group they had ever had. Ive remained terrific friends with one of my fellow donors.

Because of the minimum two-year anonymity period in the UK, donors can only contact the patient anonymously, by letter or email.

Pria said: I dont know anything about my patient other than she is a woman. She really is a stranger, but I hope my blood stem cells help her to live a long life.

I strongly encourage people in Crawley to register with DKMS. By donating their blood stem cells, not only will you potentially help a stranger in desperate need, but you'll also help their family and friends by giving them more time together.

Crawley has a population of around 114,000 with 14 neighbourhoods, the largest inland town in West Sussex. Yet, just 865 residents have registered with DKMS.

On May 28, DKMS celebrates their day of awareness - World Blood Cancer Day. This May, the charity aims to register 2,000 new registrations (roughly one for every donor in the UK waiting) by the end of May 28.

If you are called upon to donate your blood stem cells it is because you are likely the patients best match.

There are two donation methods. Around 90 per cent of all donations are made through a method called peripheral blood stem cell (PBSC) collection.

This method is very similar to giving blood. It involves being connected to an apheresis machine. Apheresis means 'to separate'.

This machine separates blood being taken from one of the donor's arms, and separates the blood stem cells from it. The donor's blood is then returned to them through their other arm. This is an outpatient procedure that is usually completed in four-to-six hours.

In just ten per cent of cases, donations are made through bone marrow collection. Bone marrow is taken from the pelvic bone under general anaesthetic, and this lasts around an hour.

DKMS need blood stem cell donors from all backgrounds. If you are aged between 17-55 and in good general health, you can support Gareth and the other 2,000 people in need of a lifesaving blood stem cell transplant by registering online at http://www.dkms.org.uk/register-now for your home swab kit.

By registering, you'll join a group of over 840,000 other DKMS lifesavers-in-waiting, ready to make a difference by giving someone a much-needed second chance of life.

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Crawley GP urges residents to save the life of a stranger - Crawley Observer

CLEVELAND When 61-year-old Ken Anderson was diagnosed with Multiple Myeloma 3 years ago, he didnt know what to expect.

It kind of hits you. It hits you hard, he said. Its a blood cancer, and its in your bone marrow, and it degenerates your bones is what it does.

The cancer is incurable, but treatable.

You live with it and you have to have many rounds of chemotherapy to keep the myeloma at bay, said Dr. Ted Teknos, the president of University Hospitals Seidman Cancer Center.

With so many unknowns, the dad of 4 girls and grandfather of 2 knew one thing, he was going to fight.

You just have to look to the road ahead, he said.

For the past 3 years, that road has been filled with ups and downs and countless rounds of chemotherapy treatments and even a bone marrow transplant.

They give you your stem cells back and those regenerate and lasted for about 6 months, and then there was a relapse, said Anderson.

Through it all, he remained hopeful for a medical breakthrough. He read about the research and followed up on the results of clinical trials in something called CAR T therapy.

I didn't know how far out that would be. It didn't say how far out it was. It sounded, to me, something like 10 or 20 years.

But it wasnt 20 years, the FDA approved CAR T therapy for Multiple Myeloma patients, and University Hospitals is the first in Ohio to treat patients with it. Anderson, who is from Kirtland, is the first patient in Ohio to receive it.

These treatments, now, are available for those that have run out of options, said Dr. Teknos.

Dr. Teknos compared the treatment to something straight out of a science fiction movie.

In essence, its like a heat-seeking missile for the cells to go find the cancer and eradicate it, he said.

It works by taking a patients own white blood cells, genetically modifying them in a lab and then infusing them back into their body so the patients cells can fight off the cancer cells.

They will engineer them to attack my cancer cells, said Anderson.

Dr. Teknos calls it living therapy.

You're taking living cells out of a patient, you're modifying them, and then you're growing them up in the lab and then re-infusing them back into the patient, he said. It's their own cells that have been modified and fight the cancer.

Dr. Teknos said in clinical trials, about 75% of Multiple Myeloma patients had a response to therapy, and in 1/3 of patients, their cancer went away.

Its really a game changer, said Dr. Teknos. There are patients who literally had weeks to live and then a year and a half later, have no cancer at all.

Andersons cells are currently in the lab. He will receive his infusion next month. He is cautiously optimistic that the next stop on his journey will have him feeling better.

I won't have to be on the chemo anymore, so I'm just back to feeling like myself would be would be really exciting, he said. People who are out there and diagnosed with this, with this disease, know that we are on the cusp of some big things here in the treatment of it, and this is a huge advance.

While Anderson is currently fighting Multiple Myeloma, University Hospitals is also offering a new CAR T cell therapy treatment for patients diagnosed with Diffuse Large B-Cell Lymphoma.

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University Hospitals treats first cancer patient in Ohio with "game changing" CAR T therapy - News 5 Cleveland

First-term GOP Reps. Marjorie Taylor GreeneMarjorie Taylor GreeneRep. Marjorie Taylor Greene says she's meeting with Trump 'soon' in Florida QAnon site shutters after reports identifying developer Republicans head to runoff in GA-14 MORE (Ga.) and Lauren BoebertLauren BoebertJuan Williams: The GOP is now the party of grifters and kooks The Memo: Boehner's blasts don't move today's GOP Overnight Energy: Progressives fear infrastructure's climate plans won't survive Senate | EPA to propose vehicle emissions standards by July's end | Poll shows growing partisan divide on climate change MORE (Colo.) were the only lawmakers to vote against a bill to reauthorize a bone marrow transplant program on Thursday evening.

The measure passed the House 415-2.It reauthorizes the C.W. Bill Young Cell Transplantation Program and National Cord Blood Inventory, which facilitate bone marrow and umbilical cord blood donations and transplants for people with leukemia or other blood diseases.

The bill also directs the Department of Health and Human Services to conduct a review of the state of the science on using adult stem cells and birthing tissues to develop new therapies that could potentially be included in the program.

The bipartisan measure was sponsored by Reps. Doris MatsuiDoris Okada MatsuiThe Hill's Morning Report - Presented by Tax March - CDC in limbo on J&J vax verdict; Rep. Brady retiring Hillicon Valley: Grid security funding not included in Biden's infrastructure plan | Russia fines Twitter | Lawmakers call for increased school cybersecurity Lawmakers urge Education Department to take action to defend schools from cyber threats MORE (D-Calif.), Gus Bilirakis (R-Fla.) and Chellie PingreeRochelle (Chellie) PingreeDemocrats condemn 'lawlessness' amid Capitol chaos Five House Democrats who could join Biden Cabinet Biden leads Trump by 11 points in Maine: survey MORE (D-Maine).

Greene and Boebert, bothvocal supporters of former President TrumpDonald TrumpBiden administration still seizing land near border despite plans to stop building wall: report Illinois House passes bill that would mandate Asian-American history lessons in schools Overnight Defense: Administration says 'low to moderate confidence' Russia behind Afghanistan troop bounties | 'Low to medium risk' of Russia invading Ukraine in next few weeks | Intelligence leaders face sharp questions during House worldwide threats he MORE, have quickly established reputations as controversial figures.

Greene wrote on Twitter that the bill did not have sufficient protections against the use of fetal tissue.

The Fake News Media is attacking me for being TOO PRO-LIFE (100%), she tweeted. Last night, Congress passed a bill which is not clear about preventing buying of body parts of babies murdered in the womb. I voted NO.

In a separate statement on Friday, Greene also said the bill was rushed.

The whole reason we are nearly $30 trillion in debt, have murdered over 62 million people in the womb, and have ZERO transparency on our spending is because Congress does not take the time to fully read and understand the bills it passes, she said.

"Im not voting for bills that dont go through committee and add hundreds of millions of dollars to the national debt," Boebert tweeted on Friday. The bill authorizes about $50 million per year for the transplant programs, though it will take an appropriations bill passing to actually spend that money.

Greene has been surrounded by controversy ever since coming to Congress. In February, she apologized to GOP colleagues for her past embrace of QAnon and other conspiracy theories, and the House voted to remove her from her committee assignments over previous endorsements ofracist dogma and violence against Democratic politicians.

Matsui released a statement Thursday praising the bill's passage and calling on the Senate to act.

Every three minutes, someone is diagnosed with a blood cancer, she said. For patients and families facing these fatal diseases, a bone marrow or cord blood transplant may be the best treatment or only potential for a cure.

Updated: 9 p.m.

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Greene, Boebert only lawmakers to vote against bone marrow transplant bill | TheHill - The Hill

Newswise A Phase II clinical trial to assess mesenchymal adult stem cells as a disease-modifying therapy for Parkinson's disease has been launched at The University of Texas Health Science Center at Houston (UTHealth).

"Studies have shown mesenchymal stem cells can migrate to the sites of injury and respond to the environment by secreting several anti-inflammatory and growth factor molecules that can restore tissue equilibrium and disrupt neuronal death," said Mya C. Schiess, MD, professor in the Department of Neurology and director and founder of the movement disorder subspeciality clinic and fellowship program at McGovern Medical School at UTHealth. "The stem cells interact directly with the immune cells, leading to an anti-inlammatory state that allows a restorative process to take place."

Safety and tolerability results, assessed on a previous trial, were recently published in the journal Movement Disorders. The Phase I study showed that there were no serious adverse reactions related to the stem cell influsion and no immunological reactions to the cells, which come from the bone marrow of a healthy adult donor. The study enrolled 20 patients with mild to moderate disease, who were infused with one of four different dosages and monitored for a year. Additionally, researchers reported a reduction in preripheral inflammatory markers and a reduction in motor symptoms.

Parkinson's diease is the second most common neurodegenerative disease, affecting more than a million Americans. It is also the fastest-growning of the neurodegenerative diseases, with more than 60,000 new cases identified every year. It is predicted that by 2040, Parkinson's disease will affect 17.5 million people worldwide.

Research has shown that one of the forces playing a critical role in the diease's development and progression is a chronic neuroinflammatory process that damages the brain's microenvironment and alters its healthy equilibrium. Inflammatiion perpetuates the neurodegenration in the brain areas that control movement, causing the tremors, imbalance, loss of speech, slowness, and other motor impairments.

The randomized, double-blind, placebo-controlled Phase II trial will investigate the safest and most effective number of repeat doses of stem cells to slow the progression of Parkinson's disease. The study will enroll 45 patients, ages 50 to 79, who will receive three infusions of either placebo or stem cell therapy at three-month intervals and will be followed for a year after the last infusion.

"Currently, there is no approved therapy that can delay the degenerative process in Parkinson's disease," Schiess said. "By investigating a treatment that can slow or stop the progression, we hope to improve the quality of life of those suffering from the disease. The ultimate goal is to use this treatment in individuals with a prodromal condition, meaning they are showing early signs of Parkinson's disease but are not yet clinically symptomatic. We hope to be able to potentially stop the diease's conversion or clinical manifestation in patients who are high-risk."

The Phase II trial, approved by the U.S. Food and Drug Administration, is supported with funding from the Michael J. Fox Foundation, John S. Dunn Foundation, and John and Kyle Kirksey.

Other McGovern Medical School faculty co-authors on the paper included Jessika Suescun, MD, Christopher Adams, MD, and Sean Savitz, MD, in the Department of Neurology. Marie-Francoise Doursout, PhD, Department of Anesthesiology; Charles Green, PhD, Department of Pediatrics; and Jerome G. Saltarrelli, PhD, Department of Surgery. Timothy M. Ellmore, PhD, Department of Psychology at the City College of New York, N.Y., was senior author.

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First in the nation, FDA-approved Phase II mesenchymal stem cell therapy for Parkinson's disease begins - Newswise

Newswise A clinical trial to assess the safety and efficacy of stem cell therapy for treatment-resistant bipolar depression launched recently at The University of Texas Health Science Center at Houston (UTHealth).

"Since mesenchymal stem cells are known to counteract inflammation and promote neurogenesis, we are hopeful that they provide an innovative therapy for patients with treatment-resistant biopolar depression," said Jair Soares, MD, PhD, chair of Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences in McGovern Medical School at UTHealth. "Depending on the results, these stem cells could reduce morbidity and mortality associated with the disease."

Bipolar disorder is characterized by dramatic shifts in mood, energy, and activity levels that can affect a person's ability to carryout daily tasks, according to the National Institute of Mental Health. People with the disorder can swing from depression to mania. An estimated 2.8% of U.S. adults had bipolar disorder in 2016, and a large portion of them do not have a satisfactory response to available treatments.

This double-blind, randomized, placebo-controlled trial will use allogenic mesenchymal stem cells, which are multipotent stem cells taken from a bone marrow donor. The mesenchymal stem cells are manufactured in the Judith R. Hoffberger Cellular Theraputics Labratory at UTHealth, a state-of-the-art Food and DRug Administration-registered facility designed to comply with current Good Manufacturing Practice.

In a 2010 study published in Translational Research, scientists reported that stem cells showed efficacy in neurodegenerative illnesses that share several biological underpinnings of bipolar disorder, such as Parkinson's disease, with no adverse effects.

In previously published studies by researchers at UTHealth, stem cells have shown a dampening effect on inflammation, which has been linked to bipolar disease. Inflammatory markers have also been associated with a decreased likelihood of response to treatment in people with bipolar disease.

The trial will enroll 30 patients, who will recieve a single injection of either the stem cell product or placebo and continue to receive their usual care for bipolar depression for the eight weeks of the study.

UTHealth has been studying stem cells for traumatic brain injury and stroke for more than two decades.

Soares sees patients at UT Physicians, the clinical practice of McGovern Medical School.

McGovern Medical School co-investigators are Charles S. Cox Jr., MD; Fabio Triolo, PhD; Marsal Sanches, MD, PhD;Joo de Quevedo, MD, PhD; Sudhakar Selvaraj, MD, PhD; Antonio Teixeira Jr., MD, PhD; and Benson M. Irungu, PhD. Cox is a professor and George and Cynthia Mitchell Distinguished Chair in Neurosciences in the Department of Pediatric Surgery. Triolo is an associate professor and the Clare A. Glassell Distingued Chair in the Department of Pediatric Surgery. De Quevedo and Teixeira are professors; Sanches and Selvaraj are associate professors; and Irungu is an assistant professor in the Faillace Department of Psychiatry and Behavioral Sciences.

Soares, Cox, Triolo, and de Quevedo are also members of The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences

More here:
Researchers investigate whether stem cell therapy is safe and effective for treatment-resistant bipolar disease - Newswise

Cell and gene therapies are overlapping fields of research and treatments. While both aim to treat and potentially cure diseases, they have slightly differing approaches and have different historical backgrounds. Due to growing interest surrounding this field, the general public still has much to learn and understand about each of these potentially life-saving therapies.

Below, we provide a general overview and brief historical context for each type of therapy.

Cell therapyis the process of replacing damaged or dysfunctional cells with new, healthy ones by transferring live cells into a patient. These can be autologous (also known as self-to-self, using cells from the patient receiving the treatment) or allogeneic (using cells from a donor for the treatment). While this field of treatment has recently begun to expand, some forms of cell therapy like the cancer-treating hematopoietic stem cell transplantation(HSCT) have been in practice for decades.

While many people have heard of bone marrow transplants, few realize that this procedure is a stem cell therapy. While stem cells can be derived from many sources, such as umbilical cord blood and mobilized peripheral blood, bone marrow derived stem cell therapy is the most commonly used today and has been for more than 50 years.

The first transfusion of human bone marrow was given to a patient with aplastic anemia in 1939. After World War II researchers diligently worked to restore bone marrow function in aplasia patients caused by exposure to radiation produced by the atomic bomb. After a decade of work they were able to show, in a mouse model, that aplasia could be overcome by bone marrow treatment.

The first allogeneic HSCT, which led the way to current protocols, was pioneered by E. Donnall Thomas and his team at the Fred Hutchinson Cancer Research Center and reported in the New England Journal of Medicine in 1957. In this study six patients were treated with radiation and chemotherapy and then received intravenous infusion of bone marrow rich stem cells from a normal donor to reestablish the damaged or defective cells. Since then the field has evolved and expanded worldwide. While almost half of HSCT are allogeneic, the majority of HSCT are autologous, the patient's own stem cells are used for treatment, which carries less risk to the patient.

In 1988, scientists discovered that they could derive stem cells from human embryos and grow the cells in a laboratory. These newly derived stem cells, referred to as embryonic stem cells (hESCs), were found to be pluripotent, meaning they can give rise to virtually any other type of cell in the body. This versatility allows hESCs cells to potentially regenerate or repair diseased tissue and organs. Two decades after they were discovered, treatments based on hESCs have been slow in coming because of controversy over their source and concerns that they could turn into tumours once implanted. Only recently, testing has begun as a treatment for two major diseases: heart failure and type 1 diabetes.

In 2006, researchers made a groundbreaking discovery by identifying conditions that would allow some cells to be 'reprogrammed' genetically. This new type of stem cell became known as induced pluripotent stem cells (iPSCs). Since this discovery, the field has expanded tremendously in the past two decades. Stem cell therapies have expanded in use and have been used to treat diseases such as type 1 diabetes, Parkinson's and even spinal cord injuries.

There has also been a growing focus on using other immune cells to treat cancer. Therapies such as CAR T-cellare dependent upon a patient's T-cells, which play a critical role in managing the immune response and killing cells affected by harmful pathogens. These cells are then reengineered to target and kill certain cancerous cells. Several CAR T-cell therapies have been FDA approved, with the first approval being given in 2017 for Yescarta and Kymriah, to be used for the treatment of B-cell leukemia in children and young adults.

Gene therapyis a process that modifies the expression of a gene or alters the biological process of living cells for therapeutic use. This process can take the form of replacing a disease-causing gene with a new, healthy one, inactivating the mutated gene, or introducing a new gene to help the patient's body fight a disease.

While the use of gene therapy to treat humans is fairly new, the science behind it has been used in science for decades. Farmers and geneticists have collaborated for years on crop improvement using cross pollination, genetic engineering and microinjection techniques to create stronger, more resilient crops.

The first human patient to be treated with gene therapy was a four-year old girlsuffering from severe combined immunodeficiencyin 1990. She received treatment for a congenital disease called adenosine deaminase (ADA). Since then, gene therapies have been used to treat diseases such as cancer, cystic fibrosis and hemophilia.In 2017, the FDA gave its first approval of a gene therapy called Luxturna, which is used to treat patients with established genetic vision loss that may result in blindness. Gene therapies are still being studied and developed, with over 1,000 clinical trialscurrently underway.

ThermoGenesis Holdings Inc., is a pioneer and market leader in the development and commercialization of automated cell processing technologies for the cell and gene therapy fields. We market a full suite of solutions for automated clinical biobanking, point-of-care applications and large-scale cell processing and manufacturing with a special emphasis on the emerging CAR-T immunotherapy market. We are committed to making the world a healthier place by creating innovative solutions for those in need.

For more information on the CAR-TXpress multi-system platform, please contact our Sales team.

Disclaimer

Thermogenesis Holdings Inc. published this content on 13 April 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 13 April 2021 07:10:03 UTC.

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ThermoGenesis : The History of Cell and Gene Therapy - marketscreener.com

Treatment options for chronic myeloid leukemia often include targeted therapies. Treatment plans and their effectiveness may depend on the phase of the condition.

Chronic myeloid leukemia (CML) is a slow-growing type of blood cancer that can affect white and red blood cells and platelets. It occurs in about 15% of adults who receive a leukemia diagnosis.

CML has three phases: chronic, accelerated, and blast.

The different phases can have an impact on a persons overall prognosis and how a doctor and the person approach the treatment plan.

This article discusses common treatments for CML and the differences between the phases of the condition.

The chronic phase is the earliest stage of CML.

In this phase, the cancer grows and spreads most slowly, and people typically experience few or no symptoms.

Moreover, during this stage of CML, people have less than 10% blast cells, which are cancerous immature white blood cells.

Most people receive a diagnosis of CML in the chronic phase.

During the chronic phase, the first line of treatment is tyrosine kinase inhibitors (TKIs). A doctor may try one or more TKIs, such as:

If a specific TKI is ineffective, a doctor may change a persons dose or use a different medication. On rare occasions, a doctor may recommend a bone marrow transplant.

During treatment, a doctor will need to check the progress regularly. To do this, they will need to draw blood and check for levels of BCR-ABL, a cancer-causing gene, every 36 months. A persons doctor should review the results of the tests with the person.

A 2017 long-term study found that the 10-year survival rate of people who received a diagnosis of chronic phase CML was about 83% when they took imatinib.

The American Cancer Society states that about 70% of people have a complete response to TKI treatments within the first year.

If the first treatment does not prove effective, a doctor may consider the following:

Treatment following a stem cell transplant can vary based on the response a persons body has to the transplant.

If the persons body does not reject the transplant, a doctor may try to have the immune system attack the cancer cells by either reducing the amount of immunosuppressors or introducing donor cells.

The second phase of CML is the accelerated phase, during which blast counts are higher, and symptoms are likely to develop.

In addition, during this stage, a person has increased cancer activity.

According to the American Cancer Society, a doctor will often diagnose the accelerated phase if one or more of the following occur:

A person with accelerated phase CML is also more likely to experience symptoms such as:

The American Cancer Society states treatment for the accelerated phase will be similar to that for the chronic phase. The main difference is that in the second phase of CML, long-term success with treatment is less likely.

Treatment options, which will depend on what doctors have already used, may include:

It is difficult to determine the life expectancy of a person who receives a diagnosis of CML in the accelerated phase.

The American Cancer Society indicates a person is less likely to have a long-term response to the treatment.

However, researchers are studying new therapies, which may help prolong the life expectancy of people with a diagnosis of accelerated CML.

The blast phase is the most advanced stage of CML.

People with a blast phase CML diagnosis have at least 20% blast cells in their blood. At this stage, the cancer has also spread beyond the blood into organs or other tissues.

Additionally, a person will likely experience fever, small appetite, and weight loss.

Treatment will vary between people depending on the cancer and the type of treatment a person has already undergone.

A cure for CML in the blast phase is unlikely. That is why doctors will possibly recommend medication and therapy to help a person feel better and relieve their symptoms.

According to the American Cancer Society, a doctor may recommend newer TKIs, such as bosutinib, dasatinib, or nilotinib. Chemotherapy drugs may be effective.

If treatment is successful, a doctor may recommend a stem cell transplant.

With newer therapies, the exact survival rate of people with a blast phase CML diagnosis is not clear.

People with blast phase CML are less likely to respond well to treatment and to recover from their condition than people with a chronic phase CML.

A 2018 study reports that people with CML whose cancer cells have the T315I mutation are less likely to respond to both older and newer TKIs.

As a result, doctors will likely recommend a different strategy, such as:

CML is a type of cancer. There are several potential therapies a doctor may recommend a person undergo to treat the cancer, slow its growth, or improve a persons quality of life.

Below, we describe some of the most common approaches.

Targeted therapies are medications that identify and attack cancer cells based on certain markers.

CML contains BCR-ABL, a gene that is not present in healthy cells. The gene causes the production of BCR-ABL protein, which is a type of tyrosine kinase. Targeted therapies for CML contain TKIs that stop the growth and reproduction of cancer cells with the protein.

According to the American Cancer Society, TKIs are a frequently used treatment option in the chronic phase of CML. However, doctors may also use them in later phases of the condition.

Interferon therapy is the most common treatment for CML.

It recreates interferons, a substance the immune system produces naturally. The therapy helps prevent the growth and division of cancer cells.

Chemotherapy, or chemo, which doctors use to treat many different types of cancer, slows or stops the growth and division of cancer cells.

It may cure the cancer, reduce the likelihood of it returning, or slow or stop its growth. It may also improve symptoms.

Chemotherapy used to be the primary treatment for CML. However, TKIs are now the first line of treatment.

Doctors will typically only recommend chemotherapy if a person does not respond well to TKIs or is undergoing a stem cell transplant.

Radiation therapy uses high doses of waves of energy to destroy cancer cells. The damaged cancer cells can no longer reproduce, and die as a result.

The National Cancer Institute states that it can take several weeks of treatment to damage cancer cells enough for them to start dying off. It could then take a few weeks or months for the cells to die off completely.

However, according to the American Cancer Society, radiation is not a common treatment for CML.

Doctors may use it to reduce the size of the spleen if the cancer has spread there, to treat bone pain resulting from bone damage. They may also use it during stem cell transplant throughout the body.

Surgery is not a typical treatment option for CML. That is because the cancer can spread throughout a persons bone marrow and other organs.

Doctors will typically only recommend surgery to remove the spleen if the cancer has affected it.

A stem cell transplant involves destroying cancer cells and some healthy cells in the bone marrow, where the leukemia starts.

Once the cancer is destroyed, a doctor replaces the cells with healthy bone marrow cells that a donor provided. Usually, doctors offer this treatment option to younger people who have a matched tissue donor.

While this is the only treatment that can cure CML, it has several associated risks, including infection and graft-versus-host disease.

A person with a diagnosed CML may wish to try alternative or complementary therapies to help alleviate symptoms. They should seek guidance from a doctor to find the most suitable therapies.

According to a 2016 study, traditional Chinese herbal medicine may be effective in managing CML when people use it in conjunction with Gleevec.

However, a person should speak with their doctor about this type of treatment before finding a licensed practitioner of traditional Chinese medicine.

Another study looked at several different herbs and fruits for the treatment of leukemia. Although the study indicates more research is necessary, it reports positive results when using herbs such as ginger, garlic, and carrots.

CML is a slow-growing type of leukemia that develops in the bone marrow.

Experts distinguish three phases of the condition: chronic, accelerated, and blast. Treatments across the three phases are often similar and involve using TKIs.

A person can work with their doctor to create the best treatment options for them. If the treatment is ineffective, a doctor may recommend other therapies to achieve remission or improve a persons quality of life.

View post:
Treating chronic myeloid leukemia (CML): By phase and more - Medical News Today

LCol Laura Laycock on deployment.

LCol Laura Laycock

It was Oct. 7, 2019, and life was not just good, it was amazing.

My career in the Royal Canadian Air Force was going great. I loved my job and was getting promoted. Throughout my Canadian Armed Forces career of over 20years, I had represented Canada around the world with NORAD, NATO and the UN. I had married the most incredible man. We relocated to Ottawa, started to travel the world together, and were ready to start a family.

Then, on Oct. 8, 2019, everything changed.

I was diagnosed with Chronic Myeloid Leukemia(CML) after blood work for vertigo showed extremely elevated white blood cell counts. CML is a blood cancer where the bone marrow overproduces white blood cells, which eventually impairs the development of white and red blood cells and platelets. Its usually caused by a spontaneous mutation in DNA, which contains our genetic code.

LCol Laycock

Twenty years ago, researchers developed a new line of drugs that combat this overproduction of white blood cells. These targeted oral chemotherapy pills have been revolutionary in the fight against CML. Most people who take them do so for the rest of their lives and have good survival rates; however, a stem cell transplant remains the only actual cure. But its risky and not needed for most people.

Its now been about 17months since my diagnosis and my body has not tolerated this targeted chemotherapy. I fall into that small fraction of people who get debilitating or life-threatening side effects from this medication. My doctors are discussing other treatment options, one of which is a stem cell transplant, but my mixed ethnicity (European/Middle Eastern) has made it difficult to find a donor match.

My journey since my diagnosis has been to slow down and educate myself so that I can heal and advocate for my care; to appreciate every little moment of joy; and to do my best to overcome each challenge that arises. I have found strength in the extraordinary support Ive received from my family, my friends and my community, both old and new.

With the help of family and friends, I recently began a social media campaign to increase stem cell donor education and registration in Canada and around the world. Many people are unaware of the potentially lifesaving role they can play by registering to become stem cell donors. Stem cell transplants are vital treatment options for people with a range of medical conditions including spinal cord injuries, heart disease, diabetes, and some cancers.

The process to donate is simple. First, you register online with Canadian Blood Services or Hma-Qubec and do a mail-in cheek swab., and then you wait. It could be months or years before you are identified as a match. During this waiting period, you should update your contact information with the registry if it changes.

When you are matched, you will be contacted to continue with the donation process. This process is similar to giving blood, but it has its differences. The cells are usually collected intravenously from peripheral blood in a non-surgical procedure but, in rare cases, they are collected directly from the bone marrow in a surgical procedure. In either case, the risks associated with donating are minor.

In Canada, individuals aged17 to 35 can register to become stem cell donors (ages18 to 35 in Quebec). Both CBS and Hma-Qubec are part of an international network of donor registries from over 50countries. This network has a pool of over 38million donors but, unfortunately, matches are rare.

Your stem cells could potentially help others around the world, and throughout this process donor privacy is assured at all times.

LCol Laycock on her wedding day.

Stem cell matching relies on Human Leukocyte Antigen typing, which is highly influenced by ethnicity. This means that a patients best chance of finding a matching donor is from those who share similar ethnic backgrounds. Research conducted by Gragert et al.(2014) has shown that the likelihood of finding a match for certain ethnic groups can be as low as 16 percent and as high as 75 percent for others. This disparity highlights the need for more ethnically diverse stem cell donors in our registries.

Today, I am calling on my DND and CAF families to register as stem cell donors to help people, like me, who are fighting for our lives. If you arent able to register, please share this call with those who can. You, or someone you know, could be the match that saves a life a simple swab is all it takes to be a hero.

Read this article:
Stem cell treatment needed to fight the good fight - Victoria Lookout

Its important to be able to control the timing and spacing of the gene knockouts so the researchers can look at the same mice over time, and test for different situations.

VHL helps control cells response to different oxygen levels, especially low levels. Our current data indicates that VHL gene deletion accelerates the production of red blood cells and helps create blood vessels in the bone and bone marrow, Spencer said. This, in turn, impacts how B-cells develop.

The researchers will be able to peer inside the bone marrow and see how the microenvironment has changed when VHL is deleted in the mesenchymal cells and pre-osteoblasts. Several diseases are linked to the marrow microenvironment, so the research has the potential to inform the work of many other research teams as could the development of the new mouse model. Manilay said many researchers have tried to build models with the same specifications she and Spencer need, but those models have not worked.

Were trying something different, so this could really help researchers all over the world if it works, she said. This is high-risk, high-reward research. The risk is this could completely fail, but even then, wed be able to provide information to other researchers.

This $400,000, two-year R21 grant builds on an NIH R15 award the team received last year to examine the effects of the VHL gene defect that makes the bones grow extremely dense, with little room for marrow. Because marrow is where both immune system and blood cells develop, less marrow than normal could have a wide range of negative consequences, and the team wanted to know whether immune cells were responding to altered oxygen conditions, which are also a hallmark of the defect. B-cells can sense when they are in low-oxygen conditions, Spencer said, and they can turn on genes to help them adapt.

Spencer, whose research focuses on biomedical imaging, became the first scientist to capture an image of native adult hematopoietic stem cells (HSC) within the bone marrow of a living organism. Manilay is interested in the relationship between bone and bone marrows HSCs on immune cells fates.

Spencer, with the Department of Bioengineering in the School of Engineering, and Manilay, with the Department of Molecular and Cell Biology in the School of Natural Sciences, are both members of the Health Sciences Research Institute.They worked on the foundation of this research for more than a year before the first grant started. Manilays lab had gathered preliminary data, including some work done by graduate student Betsabel Chicana, who recently won an NIH fellowship for her immunology work. The graduate students collaborated throughout, analyzing data and cross-training in each others disciplines.

Now that weve been doing this for more than a year, Im really seeing the benefits among my students, Spencer said. Exposing them to other research methods and other ways to ask questions and design experiments gives them a broader training, which will benefit their futures as researchers.

View post:
Collaboration Furthers Understanding of Immune Cell Development | Newsroom - UC Merced University News

Leukemia cutis can happen when leukemia cells enter your skin. This rare condition causes patches of discolored skin to appear on the body.

In some cases, the appearance of leukemia cutis lesions on the skin is the first sign of leukemia a cancer of the blood and bone marrow.

Along with standard leukemia therapies, this complication can usually be addressed with topical treatments to help heal the damaged skin. If you have leukemia cutis, your outlook will usually depend on your age and the type of leukemia you have.

Leukemia cutis is an uncommon complication, affecting only about 3 percent of people with leukemia. However, it is often a sign that the cancer is at an advanced stage.

With leukemia, malignant leukocytes (white blood cells) are usually only present in the bloodstream. In the case of leukemia cutis, the leukocytes have entered the skin tissue, causing lesions to appear on the outer layer of your skin. The word cutis refers to the skin, or dermis.

Generally, leukemia cutis results in one or more lesions or patches forming on the outer layer of skin. This condition can mean that the leukemia is more advanced and may have spread to your bone marrow and other organs.

Because there are fewer healthy white cells to combat infections caused by other diseases, rashes and sores may be more common among people with leukemia. Low blood platelets from leukemia can cause damage to blood vessels that appear as red spots or lesions on the skin.

These may include:

However, these skin changes are different than those brought on by leukemia cutis.

While the legs are the most common area for leukemia cutis lesions to appear, they can also form on the arms, face, trunk, and scalp. These skin changes can include:

The lesions usually dont hurt. However, with certain types of leukemia particularly acute myeloid leukemia (AML) the lesions may bleed.

A dermatologist may initially diagnose leukemia cutis based on a physical examination of the skin and a review of your medical history. A skin biopsy is needed to confirm the diagnosis.

Leukemia cutis is a sign of leukemia. It wont develop if the body isnt already dealing with this type of blood cancer.

But leukemia isnt just one disease. There are multiple types of leukemia, each one classified by the kind of cell affected by the disease.

You can also have an acute or a chronic form of leukemia. Acute means it comes on suddenly and usually with more severe symptoms. Chronic leukemia develops more slowly and often with milder symptoms.

The types of leukemia that most commonly trigger leukemia cutis are AML and chronic lymphocytic leukemia (CLL).

Scientists arent sure why cancerous leukocytes migrate to skin tissue in some people with leukemia. It may be that the skin is an optimal environment for healthy leukocytes to transform into cancerous cells.

One possible risk factor that has emerged is an abnormality in chromosome 8, which has been found more often in individuals with leukemia cutis than in those without it.

Treating leukemia cutis usually includes treatment for leukemia as the underlying condition.

The standard leukemia treatment is chemotherapy, but other options may be considered depending on your overall health, your age, and the type of leukemia you have.

Other leukemia treatment options include:

For blood cancers, external beam radiation is a typical form of treatment. With this therapy, a focused beam of radiation is delivered outside the body from various angles. The goal is to injure the DNA in cancer cells to stop them from reproducing.

Immunotherapy, a type of biological therapy, uses the bodys own immune system to fight cancer. It is typically given by an injection that either stimulates immune system cells activity or blocks the signals cancer cells send to suppress the immune response.

Immunotherapy may also be given orally, topically, or intravesically (into the bladder).

Stem cell transplantation is more commonly known as a bone marrow transplant. Bone marrow is where blood stem cells develop. Stem cells can become any type of cell.

Through stem cell transplantation, healthy blood stem cells replace stem cells damaged by the cancer or by chemotherapy or radiation therapy. However, not everyone is a good candidate for this treatment.

Only treating the leukemia cutis lesions will not address the underlying disease of leukemia. That means treatments designed to remove or reduce lesions should be done in combination with systemic treatment for leukemia itself.

Treatments for leukemia cutis symptoms can include:

Again, these treatments will only treat the leukemia cutis lesions, but systemic treatment of the leukemia itself will be needed as well.

The length of time leukemia cutis lesions may last depends on many factors, including how well the leukemia itself is responding to treatment. If the leukemia goes into remission, its unlikely more lesions will appear.

With effective treatment, existing lesions could fade. However, other factors, including your age and overall health, can affect how widespread the lesions are and how long they may last.

There are encouraging trends in the treatment of leukemia, but it remains a challenging disease to treat and live with.

For people with AML who dont have leukemia cutis, research suggests that the survival rate at 2 years is about 30 percent. However, the survival rate drops to 6 percent among people with the skin lesions.

A separate study of 1,683 people with AML found that leukemia cutis was associated with a poor prognosis, and that those with AML and leukemia cutis may benefit from more aggressive treatment.

The outlook for people with CLL is better, with about an 83 percent survival rate at 5 years. The presence of leukemia cutis doesnt seem to change that outlook very much, according to a 2019 study.

Leukemia cutis is a rare complication of leukemia. It happens when malignant leukocytes invade the skin and cause lesions on the skins outer surface.

AML and CLL are more often associated with leukemia cutis than other types of leukemia.

While leukemia cutis usually means the leukemia is in an advanced stage, there are treatments for both the cancer and this uncommon side effect that may help extend life and improve its quality.

Go here to see the original:
Leukemia Cutis: Symptoms and Treatment - Healthline

A lack of ethnic diversity among donors, coupled with cultural myths, have led to a paucity of bone marrow donors, resulting in hundreds of avoidable deaths caused by leukaemia and other blood-related diseases.

According to Jane Ward, the deputy director of the South African Bone Marrow Registry (SABMR), the lack of sufficient education to counter cultural beliefs, especially among black South Africans, contributes to donor resistance. A common myth is that regenerative stem cells are somehow body parts and cannot be parted with.

She said a major education and destigmatisation campaign is needed to help people donate and to realise that help is available.

Also, by the time many black patients go to a doctor or clinic to be referred upwards for treatment, its often too late. We can only transplant bone marrow when a patient is in remission, and that requires extensive treatment.

If you dont catch it quickly enough, you cant treat it. That and the lack of facilities, plus the costs which we cover for matching, donor collection and stem cell transport have proved the biggest hurdles, Ward said.

Youre more likely to find a match within your own ethnic group and its been shown that there are more white donors on registries worldwide. Theres simply not enough ethnic diversity among donors.

Two other societal phenomena have contributed to shrinking the local bone marrow registry base from 74000 to 73000 donors over the past five years: emigration and ageing.

Last year, of those donors removed from the local donor base, more than 6% were lost because of emigration, Ward revealed.

And because stem cells age with their hosts, donors are retired from the database at 60 years old.

Emigration is not a train smash because we contact them and transfer them to the registry of the destination country but that ups the cost in getting the donor cells transported back here, she explained.

A new partnership between the SABMR and Netcells, South Africas largest private cord blood bank, is set to improve access to more cost-effective, life-saving treatment for leukaemia and some 79 other blood related diseases.

While 550 patients have received matched unrelated transplants since the SABMR was established in 1991 an outflow of critical tissue matching capability required for Dr Chris Barnards historic 1967 heart transplant the chances of finding a bone marrow match remain slim.

This new partnership includes the establishment of a public community cord blood stem cell bank Africas first and marks another milestone in reducing the one-in-100000 odds of finding a bone marrow match for patients in South Africa.

While South Africa has been part of the world registry for bone marrow transplants for 20 years, giving it access to some 39-million registered donors, there are only 73000 South African donors in an ageing local registry.

This puts South Africans at a major cost and access disadvantage. One of the biggest stumbling blocks remains the few black (global and local) donors and the gap between South Africas funded private transplant funding and unfunded state sector transplants which the community cord blood stem cell bank aims to address.

There are other reasons why donor recruitment remains so low.

The SABMR only began recruiting donors in 2018, meaning it had to develop a recruitment division from scratch after the well-known Sunflower Fund relinquished this task as part of its cancer treatment funding efforts.

Ward said that recent advances in medical technology have brought umbilical cord blood stem cells to the table as an effective treatment. Besides infant cord blood stems cells, blood from young healthy males aged 18 to 25 is the preferred transplant choice. Although that age bracket is the preferred choice, any one who is healthy and younger than 60 can donate.

According to Ward, a consequence of this reality is that South Africa recently became only the second country globally to drop the donor recruitment age from 18 to 16 in its attempt to swell the registry.

Education is vital to counter myths and create a younger, informed donor base. We want everybody in the next generation to know about this life-saving treatment and how they can help.

One way to achieve this is to use new channels such as TikTok and Instagram for the younger generation being targeted.

Shelley Bredin, the managing director of Netcells, outlined how her company works and will partner with the SABMR.

Netcells receives umbilical cord blood stem cells from infants at birth, freezing them for future use. The parents opting to do this do so as an insurance against future blood-based diseases.

The umbilical stem cells are also a 25% match for a sibling, widening the insurance safeguard. Parents can, at the outset, choose whether to opt for community stem cell banking or private stem cell banking, the former costing half the price (R15000). This is in return for the stem cells being allocated on a priority needs basis to either their family or an outside matched recipient on a first-come-first-served basis via the SABMR registry.

If the community banked stem cells are used for an outside recipient, the parents are reimbursed fully. Once the initial selected storage period ends, when privately banking the stem cells, Netcells contacts the parents and asks them if they want to continue storage or to donate them to the SABMR as a philanthropic gesture.

If parents opt for private stem cell banking, the frozen cells are kept exclusively for their use, but the up-front price increases to R29000 for 10 years storage.

Its a very personal decision, she said. Our intention is to make the stem cells more attainable for more people and at the same time serving to expand the donor pool in South Africa. Some who have the money would still prefer to bank privately as they dont want to take the gamble.

Cost remains an ever-present reality, with Covid-19 dramatically reducing the global pool of available and usable donor blood cells.

Its no longer just an issue of an adult donor having to be medically fit. The question becomes, will the donor get Covid? You have to test [the donor], for that. Yet [umbilical] cord blood remains readily available, and you dont need a whole bunch of tests on the donor, Bredin said

This was yet another current contextual advantage of the new partnership, she emphasised.

Bredin said cord blood is a much simpler source of stem cells than an adults blood. By establishing a community cord blood bank, they hope to reduce the need for expensive global sourcing.

An adult blood cell donation can cost between R250000 and R270000 from a foreign country (just over half that locally) while foreign-sourced umbilical cord blood can cost up to R1-million. Only a very few local medical aids fund all sourced donations and transplants.

Leukaemia is the most common cancer among children and teens worldwide, accounting for 30% of all cancers diagnosed in children.

The miraculous, life-saving bone marrow transplant addressing end-stage haematological disorders happens just 12500 times a year globally, according to the SABMR.

Anyone wanting to find out more about stem cell harvesting and donation or who would like to contribute to the SABMR donor fund to help save lives should visitnextbio.co.za/netcells/ or sabmr.co.za/become-a-donor/. Alternatively they can email: [emailprotected]

Here is the original post:
More ethnically diverse bone marrow donors needed to save lives - Mail and Guardian

TEHRAN For the first time, MAHAK Charity Foundation has started using the Total Body Irradiation (TBI) cancer treatment method for children in the country.

Launched by the MAHAK Pediatric Cancer Treatment and Research Center (MPCTRC), TBI delivers radiation to the whole body from head to toe. It destroys remaining malignant cells, creates space in bone marrow for donors bone marrow stem cells, and prevents rejection by suppressing the patients immune system. TBI increases the survival rate in children with high-risk leukemia.

It is a part of the preparation procedure for hematopoietic (or bone marrow) stem cell transplantation. In this method, the immune system of the individual who needs transplantation gets suppressed allowing the recipient to accept foreign bone marrow stem cells.

Moreover, it can eradicate the remaining cancer cells and thereby increase survival rates of high-risk leukemia patients.

TBI is a method that has been used across the world for decades and is now mostly reserved for high-risk leukemia in need of transplantation. Using this type of irradiation in Iran would increase the survival rate of children with high-risk leukemia.

MAHAK is an NGO that supports services for cancer-stricken children and their families in accordance with international standards, as a result, over 35000 children with cancer have benefited from it during the past 29 years.

FB/MG

Original post:
New pediatric cancer treatment method being used in Iran - Tehran Times

Adipose-derived stem cells are mesenchymal stem cells obtained from adult fat tissues during various surgical interventions such as breast reduction, liposuction, or abdominoplasty. Adipose-derived stem cells (ADSCs) possess the ability to proliferate into numerous cell lineages such as chondrocytes, adipocytes, and others. Owing to this property, these multipotent stem cells can substitute bone marrow as a rich source of stem cells.

The report performs an insightful analysis of various fundamental market aspects, including SWOT analysis, CAGR during the projected period, recent developments, new product launches, technology upgradation, product offerings, application landscape, end-users, and geographical footprint of the leading companies. The market estimations carried out by our team of industry experts are based on various research methodologies and validated information on the present market scenario.

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Global Adipose-derived Stem Cell Market Research Scope:

The global market can be broadly segmented on the basis of product type, application spectrum, competitive landscape, geography, and end-use industries. Each of the market segments has been elaborately represented in the table of contents (ToC) included in the report, as well as in the format of graphs, tables, charts, etc. The report, additionally, expounds on the intensely competitive terrain of the global Adipose-derived Stem Cell market, taking into account some major factors like strategic business growth initiatives, product development, key market players, revenue share, and a wide range of research &development activities.

Some of the prominent players of the industry include Allocure, Inc., Celgene Corporation, Pluristem Therapeutics, Inc., Intrexon, Inc., Celleris SA, Tissue Genesis, Inc., Mesoblast Ltd., Cytori Therapeutics, Antria, Inc., ThermoFisher Scientific, American CrysoStem, Merck KGaA, Others

Market Segmentation:

The market is broadly categorized on the basis of product types offered in the market, region, broad application spectrum, and the leading manufacturers/companies.

Cell Type

Product Type

Disease Indication

End-user Industries

Application

Regional Segmentation:

The latest Adipose-derived Stem Cell market report highlights the ongoing market demands and trends, more importantly, in the market that is spread across the major regions of the country. The report entails an insightful analysis of the current growth opportunities for various regions of the Adipose-derived Stem Cell market. It further mentions the year-on-year growth rate of these regions over the forecast duration. The leading regional segments encompassed in the report include:

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Some Fundamental Market Parameters Elucidated in the Report:

Market dynamics: The Adipose-derived Stem Cell market report explains the scope of various commercial possibilities over the next few years and further estimates revenue build-up over the forecast years. It analyzes the key market segments and sub-segments and provides deep insights into the market to assist readers in developing vital strategies for profitable business expansion.

Competitive Outlook: The established market players operating in the Adipose-derived Stem Cell industry have been listed in this report, with a major focus on their geographical reach and production facilities. To gain a competitive advantage over the other players in the Adipose-derived Stem Cell industry, the leading players are focusing more on offering products at rational prices.

Objectives of the Report: The chief aim of the research report is to provide the manufacturers, distributors, suppliers, and buyers engaged in this sector with access to a deeper and improved understanding of the global Adipose-derived Stem Cell market.

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Adipose-derived Stem Cell OverviewMarket Key Companies, Business Opportunities, Competitive Landscape and Industry Analysis Research Report by 2027 ...

12 April 2021

A clinical trial for a new gene therapy approach to treat sickle cell disease has been approved to proceed by the US Food and Drug Administration.

Patients with sickle cell disease have a mutation in the beta-haemoglobin gene, causing them to produce misshapen red blood cells that can block blood vessels leading to severe pain, anaemia and potentially life-threatening complications, such as organ damage and strokes.Currently, the only cureis a stem cell transplant from a healthy donor, but in the newly-approved trial, scientists from the University of California will use CRISPR/Cas9 genome editing to replace the faulty gene with a functional version.

'Gene therapy and genome editing allow each patient to serve as their own stem cell donor,' said Professor Donald Kohn, from the Broad Stem Cell Research Centre at the University of California Los Angeles, one of the clinical trial leaders. 'In theory, these approaches should be much safer than a transplant from another person and could become universally available because they eliminate the need to find the needle in a haystack that is a matched stem cell donor.'

In the trial, blood stem cells will be harvested from the patients and grown in the lab. CRISPR/Cas9 will be used to 'cut and replace' a sequence of DNA containing the mutation with a healthy copy. The edited cells will then be returned to the patient's body in the same way they would be if the patient was receiving donor stem cells.

'The goal of this form of genome editing therapy is to correct the mutation in enough stem cells so the resulting blood in circulation has corrected red blood cells,' said Dr Mark Walters, from the University of California San Francisco Benioff Children's Hospital, another of the clinical trial leaders.

The study will take place over four years, and include six adults and three adolescents with severe sickle cell disease, testing both safety and efficacy.

The treatment does have risks: the patientswill need to have high dose chemotherapy, to kill allremaining bloodstem cells before the modified stem cells are put back. This is also necessary before receiving donor stem cells and can cause severe side effects as the patient's immune system is temporarily disabled.

A similar trial, using CRISPR/Cas9 to activate bone marrow stem cells to produce an alternative version of haemoglobin, rather than correcting the faulty version, has recently shown promising results in a patient with sickle cell disease (see BioNews 1052).

Here is the original post:
CRISPR gene therapy for sickle cell disease approved by the FDA - BioNews

Apr 15th 2021

THE ANCIENT GREEKS were good at inventing fantastical animals. The chimera, for instance, was a thing of immortal make, not human, lion-fronted and snake behind, a goat in the middle. It was eventually slain by Bellerophon, with help from his flying horse.

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Not all chimeras are mythological. To biologists, the term describes organisms whose bodies consist of cells from two distinct lineages. In twin pregnancies, for example, one twin can occasionally absorb the other. The resulting individual is built from cells with separate genomes. A 2019 forensic-science conference discussed the case of a man who had received a bone-marrow transplant. Since bone marrow produces blood cells, subsequent DNA tests on the mans blood matched his donors genome, not his own. (More unexpectedly, the donors DNA also turned out to be present in swabs taken from the mans cheeks, and in his semen.)

For several decades scientists have been experimenting with cross-species chimeras, organisms which, as in the Greek myths, are composites of different animals. They have created mouse-rats, sheep-goats and chicken-quails. Now, in a paper published in Cell, Tao Tan, a biologist at Kunming University of Science and Technology, and a team of American, Chinese and Spanish researchers, report efforts to extend the principle to humans. They have managed to create embryos that are part-monkey and part-human.

The work builds on earlier endeavours by many of the same researchers. In 2017 Juan Carlos Izpisa Belmonte, a biologist at the Salk Institute in San Diego, announced the creation of chimeric human-pig embryos. But quite how successful those efforts were is uncertain. Only about one cell in 100,000 in the embryos were human, and it was unclear whether they contributed to the organisms growth. This time things are different. The human cells seem happy to co-operate, at least some of the time, with the monkey ones.

The researchers began with 132 embryos of the crab-eating macaque. Six days after fertilisation these were injected with human extended pluripotent stem cells, which can develop into any other cell type found in the body. Tagging the human cells with fluorescent markers allowed the researchers to track where in the developing embryo they, and their descendants, went.

In the early stages of development, mammal embryos develop into four distinct cell types. Epiblasts go on to form the organism itself; hypoblasts develop into the yolk sac; trophectoderms become the placenta and extra-embryonic mesenchyme cells make a membrane that surrounds the embryo. The chimeras human cells made their way into all four types of tissue, though they were outnumbered in every case. No more than 7% of the epiblast was made up of human cells, and just 5% of the hypoblast (in other areas the numbers were lower still).

The cells location seemed to influence which proteins they produced. Human cells in the chimeras epiblast behaved more like those found in human embryos than those found in monkey embryos. But that was not true of human hypoblast or extra-embryonic mesenchyme cells, both of which behaved more like monkey cells.

The monkey cells, in turn, were affected by the presence of the human ones. The researchers found 126 different sorts of cell-to-cell interactions among monkey cells in the chimeric embryos, compared with just 19 in non-chimeric ones, as well as differences in the activity levels of many genes.

The cells were grown in a lab, which imposed limitations. The number of surviving embryos began falling by day 15. By day 20 none was left. But that was enough time for a process called gastrulation to take place. Gastrulation is a vital development stage in which embryonic cells become primed to form different organs and tissues. The human cells took longer to reach this point than the monkey ones did. But they managed nevertheless, providing more evidence that the human cells were not merely passive passengers, but were mucking in to help with the process of embryonic development.

The researchers hope this biotechnological wizardry will help with two goals. One is to shed light on the complicated process of embryological development, which might eventually lead to treatments for some congenital diseases. Chimeras may offer a way around some of the ethical difficulties involved in experimenting on human embryos.

The other is the hope that chimeric animals might one day provide a source of organs to be transplanted into sick humans. In 2017 Japanese researchers demonstrated the principle by transplanting parts of a pancreas that had grown inside a mouse-rat chimera into a diabetic mouse, curing it. Whether that can work in people is, for now, unclear. And research into human chimeras is ethically fraught. America, for instance, forbids federal funding of such work. Most of the work reported in this latest paper happened in China.

But if chimeric human organs do become a reality, macaques are unlikely to be the animal of choice, says Dr Izpisa Belmonte. The most likely donor would probably be pigs (this is why his 2017 experiment focused on the animals). Their organs are roughly the size of their human equivalents, and, fairly or unfairly, they seem to provoke fewer moral qualms. (Pigs already provide thousands of people with replacement heart valves, for instance.)

The advantage of working with monkeys, at least for now, is that they are much closer, in evolutionary terms, to humans. That may have helped smooth out any compatibility issues between the two sets of cells. The hope is that lessons from experiments with humanitys close cousins might allow the researchers to revisit their work with its more distant, porcine relativesand get better results.

This article appeared in the Science & technology section of the print edition under the headline "Fantastic beasts and how to make them"

See the original post here:
Researchers have created embryos that are part-human and part-monkey - The Economist

The coronavirus pandemic has dominated the headlines and our daily lives for over a year. Medical News Today has covered this fast-moving, complex story with live updates about the latest news, interviews with experts, and an ongoing investigation into the deep racial disparities that COVID-19 has helped unmask.

However, this has not stopped us from publishing hundreds of fascinating stories on a myriad of other topics.

We begin this weeks Recovery Room with new findings of research into Parkinsons disease that may also have wider implications for the treatment of other neurodegenerative diseases and cancer.

Next comes a detailed exploration of the role that carbohydrates play in the development of diabetes. Its a complex picture, and a low carb diet may not be the panacea that some claim it to be.

We also have two reports about the influence of artificial intelligence (AI) on medical research, as well as articles covering breakthroughs in HIV prevention, sickle cell disease reversal, and heart tissue regeneration.

Finally, we look at research confirming that a steady income is good for self-confidence but may have a minimal effect on feelings about other people.

We highlight this research below, along with several other recent stories that you may have missed amid all the COVID-19 fervor.

We begin with the most-read article of the past week, with more than 124,000 page views: our report on new insights into a biochemical pathway that drives Parkinsons disease. The discovery may help scientists develop treatments for this disease, as well as type 2 diabetes and cancer.

Parkin is a protein that plays a key role in maintaining cellular energy by removing damaged mitochondria, a process known as mitophagy. The new research indicates that the biochemical pathway that activates Parkin is shorter than previously thought, which helps explain how Parkin triggers mitophagy within minutes of cellular distress occurring.

Type 2 diabetes, cancer, and some neurodegenerative diseases stem from metabolic dysregulation in damaged mitochondria, so the Parkin pathway is likely to have a role in their progression, too.

Click below to learn more about how drugs developed to treat diabetes may also be used to treat Parkinsons, or click here to visit our new Parkinsons disease resource page.

Learn more here.

Our new article exploring the role that carbohydrates play in diabetes was also very popular, with over 117,000 page views so far this week.

First, our editors looked at the relationship between carb consumption, insulin, and blood sugar. They also explored how many carbs a person with diabetes should consume, good carbs, foods to include in the diet and foods to avoid, and the effects of specific diets, including a low carb diet.

The takeaway is that not all carbs are bad for a person with diabetes, but the focus should be on healthy, whole foods rather than processed foods and those high in refined sugars.

Learn more here.

Good nutrition is important at every stage of life. This week, we published a new article on the critical role of nutrition in a childs brain development, especially in the first 3 years.

Our editors first list a variety of healthy brain foods. They then share ideas for breakfasts that may help a child stay focused at school and snacks for children to try while studying. Click the link below to see the variety of foods and nutrients that should be part of every childs diet.

Learn more here.

A reliable HIV vaccine has been difficult to develop because there are so many strains of the virus, around 50 million, according to one researcher involved in a new phase 1 clinical trial.

The new course of vaccines is designed to activatebroadly neutralizing antibodies (bnAbs) that target a wide variety of HIV strains. Only one very rare type of immune cell is able to produce bnAbs, and the vaccine activated these naive B cells in 97% of participants who received it, according to the researchers.

This novel technique could also be used to make vaccines for other diseases that have proven challenging for vaccine developers, including malaria, influenza, and hepatitis C.

Learn more here.

Two of this weeks articles highlighted how AI is being deployed to aid medical research.

First, we described ways that researchers are using powerful learning algorithms to model and predict how proteins behave in human cells. Existing AI technology used to process natural language was adapted to see if it could also predict protein language and expression.

The researchers made the technique available on a new web application, linked to in our article, that allows scientists to submit a protein sequence and view its predicted behavior.

Learn more here.

We also reported on how AI is being used to analyse the brain scans of thousands of people with multiple sclerosis (MS) in an effort to learn more about the disease.

The AI program, called SuStaIn, performed an unsupervised analysis of the brain scans and detected patterns that might otherwise have been missed. As a result, three new subtypes of the disease were identified, each presenting as different types of abnormalities in the brain.

These subtypes could be used to predict a persons response to different treatments. If this finding is supported by more clinical research, it could help ensure that the correct therapy is given at the correct time.

Learn more here.

This week, we reported on a new study that concludes that a drug that appears to reverse sickle cell disease in mice is safe for humans. The drug candidate, called FTX-6058, restored the ability to produce fetal hemoglobin.

Around 1 in 365 Black people in the U.S. are born with sickle cell disease, which is relatively rare in white people. Currently, the only cure is a stem cell or bone marrow transplant, but these are very risky. FTX-6058 will now be used in a phase 2 clinical trial that includes people with sickle cell disease, for the first time, by the end of this year.

Learn more here.

Unlike humans, adult zebra fish regenerate their hearts and other organs after injury. Until recently, the way that they do this has been unclear, but researchers are now looking more closely at the role that a protein called KLF1 plays in this remarkable ability.

Inhibiting the gene for KLF1 severely limited the ability of zebra fish to regenerate heart tissue. Investigating the role of KLF1 in human hearts will require much more work, but if the protein can help regenerate heart tissue after an injury in humans, it could be a game-changer in the treatment of heart disease.

Learn more here.

April is National Autism Awareness Month, and last weeks Recovery Room featured the experience of a parent who established a school following the diagnosis of her sons autism.

This week, MNT reported on a new approach to assessing autism spectrum disorder that focuses more on proficiency and growth than deficits in a childs development. Changing the narrative in this way could help develop a more constructive and holistic way to understand each childs unique requirements and help with the selection of therapies and interventions.

This approach is also better able to account for factors such as household income and other elements of social context, compared with measuring a childs progress against a rigid set of outcomes.

Learn more here.

Finally, this week, we reported on what claims to be the first study into the emotional benefits of living with a secure income. This large study tracked the emotional responses of 1.6 million people in 162 countries.

Its key findings are that people with a steady income are more likely to feel confident and proud of themselves and that these feelings can persist for decades. However, making more money did not appear to strengthen positive feelings about others, and nor did it affect feelings such as anger.

According to this research, earnings are only linked to some inward-facing emotions, so a societys affluence may not have as strong an influence on community harmony as policymakers might expect.

Learn more here.

We hope that this weeks Recovery Room has provided a taste of the stories that we cover atMNT. We will be back with a new selection next week.

We publish hundreds of new stories and features every month. Here are some upcoming articles that may pique our readers interests:

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The Recovery Room: News beyond the pandemic April 16 - Medical News Today