NORGES BANK INVESTMENT MANAGEMEN bought a fresh place in Boston Properties Inc. (NYSE:BXP). The institutional investor bought 2.4 million shares of the stock in a transaction took place on 12/31/2019. In another most recent transaction, which held on 12/31/2019, SECURITY CAPITAL RESEARCH & MANA bought approximately 832.5 thousand shares of Boston Properties Inc. In a separate transaction which took place on 12/31/2019, the institutional investor, WELLINGTON MANAGEMENT CO. LLP bought 425.7 thousand shares of the companys stock. The total Institutional investors and hedge funds own 99.00% of the companys stock.

In the most recent purchasing and selling session, Boston Properties Inc. (BXP)s share price decreased by -7.75 percent to ratify at $111.89. A sum of 1868448 shares traded at recent session and its average exchanging volume remained at 760.61K shares. The 52-week price high and low points are important variables to concentrate on when assessing the current and prospective worth of a stock. Boston Properties Inc. (BXP) shares are taking a pay cut of -24.31% from the high point of 52 weeks and flying high of -6.89% from the low figure of 52 weeks.

Boston Properties Inc. (BXP) shares reached a high of $117.45 and dropped to a low of $108.11 until finishing in the latest session at $112.69. Traders and investors may also choose to study the ATR or Average True Range when concentrating on technical inventory assessment. Currently at 5.60 is the 14-day ATR for Boston Properties Inc. (BXP). The highest level of 52-weeks price has $147.83 and $120.17 for 52 weeks lowest level. After the recent changes in the price, the firm captured the enterprise value of $32.94B, with the price to earnings ratio of 33.92 and price to earnings growth ratio of 4.85. The liquidity ratios which the firm has won as a debt-to-equity ratio of 2.19.

Having a look at past record, were going to look at various forwards or backwards shifting developments regarding BXP. The firms shares fell -18.17 percent in the past five business days and shrunk -22.42 percent in the past thirty business days. In the previous quarter, the stock fell -19.86 percent at some point. The output of the stock decreased -15.25 percent within the six-month closing period, while general annual output lost -17.14 percent. The companys performance is now negative at -18.84% from the beginning of the calendar year.

According to WSJ, Boston Properties Inc. (BXP) obtained an estimated Overweight proposal from the 21 brokerage firms currently keeping a deep eye on the stock performance as compares to its rivals. 0 equity research analysts rated the shares with a selling strategy, 8 gave a hold approach, 12 gave a purchase tip, 1 gave the firm a overweight advice and 0 put the stock under the underweight category. The average price goal of one year between several banks and credit unions that last year discussed the stock is $151.00.

CRISPR Therapeutics AG (CRSP) shares on Thursdays trading session, dropped -11.92 percent to see the stock exchange hands at $38.12 per unit. Lets a quick look at companys past reported and future predictions of growth using the EPS Growth. EPS growth is a percentage change in standardized earnings per share over the trailing-twelve-month period to the current year-end. The company posted a value of $0.97 as earning-per-share over the last full year, while a chance, will post -$4.99 for the coming year. The current EPS Growth rate for the company during the year is 134.10% and predicted to reach at -10.40% for the coming year. In-depth, if we analyze for the long-term EPS Growth, the out-come was 54.00% for the past five years.

The last trading period has seen CRISPR Therapeutics AG (CRSP) move -48.49% and 13.62% from the stocks 52-week high and 52-week low prices respectively. The daily trading volume for CRISPR Therapeutics AG (NASDAQ:CRSP) over the last session is 1.48 million shares. CRSP has attracted considerable attention from traders and investors, a scenario that has seen its volume jump 37.35% compared to the previous one.

Investors focus on the profitability proportions of the company that how the company performs at profitability side. Return on equity ratio or ROE is a significant indicator for prospective investors as they would like to see just how effectively a business is using their cash to produce net earnings. As a return on equity, CRISPR Therapeutics AG (NASDAQ:CRSP) produces 11.70%. Because it would be easy and highly flexible, ROI measurement is among the most popular investment ratios. Executives could use it to evaluate the levels of performance on acquisitions of capital equipment whereas investors can determine that how the stock investment is better. The ROI entry for CRSPs scenario is at 4.90%. Another main metric of a profitability ratio is the return on assets ratio or ROA that analyses how effectively a business can handle its assets to generate earnings over a duration of time. CRISPR Therapeutics AG (CRSP) generated 9.60% ROA for the trading twelve-month.

Volatility is just a proportion of the anticipated day by day value extendthe range where an informal investor works. Greater instability implies more noteworthy benefit or misfortune. After an ongoing check, CRISPR Therapeutics AG (CRSP) stock is found to be 8.52% volatile for the week, while 7.29% volatility is recorded for the month. The outstanding shares have been calculated 63.90M. Based on a recent bid, its distance from 20 days simple moving average is -27.05%, and its distance from 50 days simple moving average is -31.04% while it has a distance of -25.29% from the 200 days simple moving average.

The Williams Percent Range or Williams %R is a well-known specialized pointer made by Larry Williams to help recognize overbought and oversold circumstances. CRISPR Therapeutics AG (NASDAQ:CRSP)s Williams Percent Range or Williams %R at the time of writing to be seated at 99.28% for 9-Day. It is also calculated for different time spans. Currently for this organization, Williams %R is stood at 99.28% for 14-Day, 99.48% for 20-Day, 99.54% for 50-Day and to be seated 99.67% for 100-Day. Relative Strength Index, or RSI(14), which is a technical analysis gauge, also used to measure momentum on a scale of zero to 100 for overbought and oversold. In the case of CRISPR Therapeutics AG, the RSI reading has hit 24.91 for 14-Day.

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Stocks Expected To Recuperate: Boston Properties Inc. (BXP) and CRISPR Therapeutics AG (CRSP) - BOV News

Recommendation and review posted by Bethany Smith

Warren Buffett once said: "Opportunities come infrequently. When it rains gold, put out the bucket, not the thimble." Many investors don't realize it, but it's raining gold right now.

The stock market sell-off caused by worries about the coronavirus outbreak (and, more recently, plunging oil prices) has made a lot of really good stocks cheaper than they've been in quite a while. Long-term investors with available cash should be getting their buckets ready to put out. Here are three stocks where you could invest $10,000 right now and likely reap significant returns over the long run.

Image source: Getty Images.

Vertex Pharmaceuticals (NASDAQ:VRTX) haven't fallen as much as most other stocks during the coronavirus correction. That makes sense. Biotech stocks shouldn't be negatively affected by COVID-19, generally speaking. The companies' drugs will still be needed. Their clinical studies of drug candidates will still move forward.

You can add an exclamation point to those statements when it comes to Vertex. The biotech dominates the worldwide cystic fibrosis (CF) market. Over the last few months, it's picked up important reimbursement deals in Europe and elsewhere that should boost sales for several of its CF drugs. Vertex already won U.S. approval for Trikafta, its newest CF drug on the market, and awaits approval in Europe. The drug should expand the addressable patient population for its CF therapies by more than 50%.

Vertex's pipeline is focused on several other rare genetic diseases. It's partnering with CRISPR Therapeuticsto test gene-editing therapies for treating beta-thalassemia and sickle cell disease. It's evaluating VX-814 in a phase 2 clinical study targeting alpha-1 antitrypsin deficiency. Vertex also has preclinical and early stage clinical programs targeting other rare genetic diseases.

But the biotech doesn't have its eyes only on rare diseases. Vertex is developing drugs that manage pain. Thanks to its acquisition of Semma Therapeutics last year, it's also now on a path to advance an experimental drug to clinical testing that could potentially cure type 1 diabetes.

The traditional way of buying advertising is for agencies to negotiate over a period of time with media companies.The Trade Desk (NASDAQ:TTD) operates a software platform that allows advertisers to buy digital ads immediately and cost-effectively through what's called programmatic ad buying.

Shares of The Trade Desk have dropped more than 25% from the highs set earlier this year. Have the business prospects for the company dwindled because of the coronavirus epidemic? No.

It's possible that some companies could be impacted by COVID-19 and cut back on their advertising budgets. However, it's also likely that more people will stay home, watch streaming TV, and browse the internet more instead of getting out and exposing themselves to infection by the novel coronavirus.

The Trade Desk beat Wall Street estimates in its Q4 results, delivering year-over-year revenue growth of 35% and adjusted earnings growth of 37%. The company also provided an optimistic outlook for 2020 despite its management being fully aware of the COVID-19 threat. With the programmatic ad market still only in its early stages and The Trade Desk standing atop the industry, the current market correction presents a tremendous buying opportunity.

Enterprise Products Partners (NYSE:EPD) stock has plunged nearly 40% since early January. The entire oil and gas industry has been hit by a double-whammy. The coronavirus outbreak is causing people to travel less, reducing demand for oil. More importantly, an oil price war triggered by Russia is hammering North American oil and gas companies especially hard.

I don't expect that Enterprise Products Partners stock will recover until oil prices rebound somewhat. But I think that's going to happen sooner or later. Russia (and Saudi Arabia) won't be able to flood the market with cheap oil indefinitely.

Keep in mind that Enterprise Products Partners' natural gas pipelines, storage, transportation, and processing businesses make most of their money from fees and not commodity-based pricing. That will help the company move past the current challenges. It's also beneficial that Enterprise Products Partners ranks as one of the bellwethers in the midstream market and has a solid credit profile.

Buying shares of Enterprise Products Partners right now might seem a little scary, but there's a nice bonus -- the company's dividend. Thanks to the shellacking its stock has taken, Enterprise Products Partners' dividend yield stands at close to 9.8%.

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Coronavirus Market Correction: Where to Invest $10000 Right Now - Motley Fool

Recommendation and review posted by Bethany Smith

The U.S. Navys plan for a bigger fleet is collapsing before our eyes.

To save money, the Navy is canceling an effort to add 10 years to the service lives of its 27 oldest Arleigh Burke-class destroyers. The fleet announced the extension back in 2018.

Decommissioning the old Burkes after 35 years of use instead of 45 years means the fleet will lose a large proportion of its surface combatants starting in 2026 or 2027. First-in-class USS Arleigh Burke, DDG-51, commissioned in 1991.

A Burke is around 500 feet long, displaces around 9,000 tons of water and packs around 90 missiles in vertical launchers.

Defense News was among the first news outlets to report on the cancellation of the service-life extension. The change is the latest decision to weigh on the Navys plan to expand the fleet, which in early 2020 operates 295 front-line ships.

The Navy since late 2016 has wanted to grow to 350 or 355 ships, including 12 aircraft carriers, 156 surface combatants and 66 attack submarines.

"To continue to protect America and defend our strategic interests around the world, all while continuing the counter terrorism fight and appropriately competing with a growing China and resurgent Russia, our Navy must continue to grow," Ray Mabus, Pres. Barack Obamas long-serving Navy secretary, explained while announcing the expansion plan in December 2016.

The plan began to collapse in late 2019 as the Navy came to terms with flattening budgets, the rising cost of ship-construction and maintenance and the poor performance of several new ship types.

Will we get to 355 ships? Vice Chief of Naval Operations Adm. Robert Burke said in October 2019. I think with todays fiscal situation, where the Navys top line is right now, we can keep around 305 to 310 ships whole, properly manned, properly maintained, properly equipped and properly ready.

In a sudden reversal following years of increasing ship-construction, the Navy in its $207-billion 2021 budget proposal asked for just eight new front-line vessels, down from 12 or 13 in previous years. The Navy also has proposed to decommission early four of its new Littoral Combat Ships as well as several cruisers and amphibious ships.

Amid the uncertainty, the sailing branch has delayed its annual shipbuilding plan and other force-structure projections, drawing rebukes from lawmakers who, in the absence of firm plans, increasingly dictate U.S. naval force-structure by way of annual appropriations.

In written testimony that the Navy submitted to the Senate Armed Services Committee, the services assistant secretary for research, development and acquisition James Geurts said performing service life extensions on Burkes wasnt cost-effective.

Service-life extensions can be targeted, physical changes to specific hulls to gain a few more years, or a class-wide extension based on engineering analysis, Geurtss testimony reads. The Navy has evaluated the most effective balance between costs and capability to be removing the service-life extension on the DDG-51 class.

The earliest Burkes -- 27 Flight I and early Flight II vessels -- have an expected hull life of 35 years, Defense News explained, citing internal Navy documents. USS Arleigh Burkes hull life could expire in 2026 or shortly thereafter. Thereafter, the fleet could lose three or more Burkes annually for around a decade.

Later Flight IIA and Flight III destroyers have 40- or 45-year hull-lives. The Navy is still building new Flight III Burkes at a rate of around two per year. The service so far has ordered 77 Burkes of all flights.

With shipbuilding plans in chaos, the Navy increasingly is counting on small, cheap robotic ships to rescue it from a major contraction.

Acting Secretary of the Navy Thomas Modly in early December 2019 codified this policy in his SECNAV Vector 1 memo, which called for an integrated plan to achieve a 355 (or more) ships, unmanned underwater vehicles and unmanned surface vehicles for greater global naval power, within 10 years.

USNI News was the first to report on Modlys memo.

The Navy in its 2020 budget request asked Congress for the first installment on a $4-billion acquisition of 10 large unmanned surface vessels and nine unmanned submarines. Boeing is developing the robotic submarines, using its 51-feet-long Orca submersible as a starting point.

The sailing branch hasnt yet selected a shipyard to build the unmanned surface vessels. The USVs could be similar to the Sea Hunter robot ship that the Navy has been testing since 2016. Sea Hunter is 132 feet long.

Under the Navys current rules, unmanned vessels do not count as part of the front-line fleet. That policy is likely to change.

David Axe serves as Defense Editor of the National Interest. He is theauthor of the graphic novelsWar Fix,War Is BoringandMachete Squad.

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Kiss These US Navy Destroyers Goodbye - The National Interest

Recommendation and review posted by Bethany Smith

The RNLI has today Tuesday 10 March 2020 announced that it will extend the life of its Severn class lifeboats so they can continue saving lives at sea for another 25 years.

The largest and most powerful class of lifeboat, the Severn entered service back in 1996 and there are currently 44 of these 42 tonne lifesaving vessels in the charitys fleet. With an operational lifespan of 25 years, these amazing lifeboats are now approaching retirement age and are due to come off service soon.

However, the charitys expert in-house engineering team has worked in partnership with academic and industry experts, establishing that the lifeboats hulls can continue operational service for another 25 years. Through a life extension upgrade, the Severns wheelhouse will be completely redesigned and a wide range of upgrades will be made, ensuring the vessels can operate safely and effectively for another 25 years.

As well as fitting the lifeboats out with more modern and sophisticated technology and systems, the upgraded Severns will have significant safety enhancements to ensure the RNLIs volunteer crews are as safe as possible while out saving lives at sea in all weathers.

Nick Fenwick is Project Manager for the RNLIs Severn life extension programme. He said: From shock-mitigating seats for the crew, to new survivor space seating for casualties and a new daughter craft that can be launched quickly for rescuing casualties in shallow waters or close to rocks, the life extension upgrades will ensure our Severn class lifeboats are ready to save lives at sea for another 25 years.

The upgrades will bring the technology and systems onboard the Severn class lifeboats right up to date. A key upgrade will be the installation of the Systems and Information Management System, also known as SIMS.

Similar to the SIMS systems in our Tamar and Shannon class lifeboats, it is an electronic integrated bridge system that allows the crew to monitor, operate and control many of the lifeboats functions directly from their seats. These functions include the navigation and the mechanics of the lifeboat, such as the engines, bilge and electrics. This greatly increases our crews safety, reducing the need for them to walk around the lifeboat in the rough and challenging sea conditions they so often face.

An allocation of six Severn class lifeboats will be upgraded initially, with the upgrades taking place at the RNLIs All-weather Lifeboat Centre in Poole, Dorset. Work is already underway on the first vessel to receive its life extension upgrade, with a relief fleet Severn being worked on now with the aim of undertaking sea trials at the end of the year.

The first five lifeboat stations due to receive a life extended Severn are Aberdeen, Kirkwall and Lerwick in Scotland, Tynemouth in the north east of England and Ballyglass in the Republic of Ireland. Aberdeen Lifeboat Station are due to receive the first upgraded Severn at the end of 2021.

The average anticipated cost of each life extension upgrade is 1.25M. This is significantly less than the cost of designing and building a brand-new class of lifeboat to replace the Severn. For context, a Shannon, which is significantly smaller and not as powerful as the Severn, costs 2.2M to build.

Since entering service back in 1996, Severn class lifeboats have launched over 16,500 times, going to the aid of over 22,500 people and saving over 900 lives.

Angus Watson, Engineering and Supply Director, said: I am so excited to announce our plans to extend the operational life of our Severn class lifeboats.

Our Severns are often located in the more remote locations across the UK and Ireland, where the crews are often required to sail out longer distances in the most challenging sea conditions. Being the largest class of lifeboat, it is well-suited for locations where mass casualty rescues are more likely, and its highly elevated upper steering position and greater length are ideal when negotiating large waves in the roughest seas.

While the systems and technology on board the Severn class need upgrading, the lifeboats hull and structure is still ideally suited to the challenging conditions these lifeboats face today. So rather than spending significantly more money to roll out a brand new class of all-weather lifeboat, supplying stations with upgraded Severn class lifeboats that we know can meet the demands of these challenging stretches of coastline is a much more efficient use of charitable funds, while still ensuring that our volunteer crews have lifeboats absolutely fit for purpose for the next 25 years.

The RNLI has launched its Save our Severns appeal, with the aim of raising 700,000 to help fund life extension upgrades to these incredible vessels. To donate, visit:RNLI.org/Severn25

The RNLI charity saves lives at sea. Its volunteers provide a 24-hour search and rescue service around the United Kingdom and Republic of Ireland coasts. The RNLI operates over 238 lifeboat stations in the UK and Ireland and more than 240 lifeguard units on beaches around the UK and Channel Islands. The RNLI is independent of Coastguard and government and depends on voluntary donations and legacies to maintain its rescue service. Since the RNLI was founded in 1824, its lifeboat crews and lifeguards have saved over 142,700 lives.

For more information please visit the RNLI website or Facebook, Twitter and YouTube. News releases, videos and photos are available on the News Centre.

Members of the public may contact the RNLI on 0300 300 9990 (UK) or 1800 991802(Ireland) oror by email.

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The magnificent Severn set to save lives for another 25 years - rnli.org

Recommendation and review posted by Bethany Smith

WASHINGTON In a move with sweeping consequences for the US Navy's battle force, the service is canceling plans to add 10 years to the expected service lives of their stalwart destroyer fleet, a cost-savings measure that would almost certainly hamper plans to grow the size of the fleet.

In written testimony submitted to the Senate Armed Services Committee, the Navy's Assistant Secretary for Research, Development and Acquisition James Geurts said performing service-life extensions on Burkes designed to bring them up from 35-year hull lives to 45 years was not cost effective.

"Service life extensions can be targeted, physical changes to specific hulls to gain a few more years, or a class-wide extension based on engineering analysis," the testimony reads. "The Navy has evaluated the most effective balance between costs and capability to be removing the service life extension on the DDG 51 class."

Army takes 40-mile shots from extended-range cannon in demo

The Navy's destroyers are the workhorses of the fleet, with sailors spending an average of one in every four days underway, the highest rate in the fleet, according a recent report from Defense News sister publication Navy Times.

The decision to ax the service life extensions for the Arleigh Burke class comes after years of assurances from Navy leaders that the destroyers would be modernized with an eye to growing the fleet over the coming decades. Navy leaders have offered assurances that the fiscal year 2021 budget continues to grow the fleet despite its significant cuts to shipbuilding and existing force structure, but it is unclear how the fleet will continue to grow past the next five years if service life extensions on the earliest Burkes don't go forward right away.

It would also seem to have significant impact on the current push from Acting Secretary of the Navy Thomas Modly to grow the fleet to 355 ships in a decade.

US Navy guided-missile destroyer USS Dewey conducts a Tomahawk missile flight test in the western Pacific, August 17, 2018. US Navy/MCS 2nd Class Devin M. Langer

In its FY2020 30-year shipbuilding plan, the Navy said extending the lives of the Arleigh Burkes was an imperative to growing the fleet to a battle force of 355 ships. Instead, the cancellation of the service life extensions means that between 2026 and 2034, the Navy is slated to lose 27 destroyers from its battle force.

Those losses would compound the impact of cutting 10 ships from the five-year projections in the 2021 budget, including five of the 12 proposed Flight III Arleigh Burke-class destroyers from the 2020 budget and a Virginia-class attack submarine.

The Defense Department has yet to submit its FY2021 30-year shipbuilding plan, which means that it's impossible to tell how the Navy thinks these cuts would affect its total ship count in the years when it would lose Burkes at a rate of more than three per year.

Europe ship-killing missile passes first firing trial

But the Burke retirements would begin in 2026 or 2027, years just after the service had completed shedding 13 cruisers from its fleet, leaving just nine of the Navy's largest combatants in the fleet.

In a statement, Capt. Danny Hernandez, spokesman for Geurts, said there are a lot of variables in getting the fleet to its goal of 355 ships, but that the Navy's top priority is keeping the recapitalization of its retiring Ohio-class ballistic missile submarines on track.

"Like Navy leaders have stated during testimony, the tradeoffs were complex to get the right balance," Hernandez said.

Sailors aboard guided-missile destroyer USS Nitze man the rails during sea and anchor detail in Duqm, Oman, November 29, 2016. US Navy/MCS 3rd Class Casey J. Hopkins

According to a Naval Sea Systems Command document obtained by Defense News in 2018, the earliest Arleigh Burke destroyers 27 so-called Flight I destroyers have an expected hull life of 35 years. The lead ship, the Arleigh Burke, was commissioned in 1991, meaning its hull life is up in 2026.

DDG-51 through DDG-78 the Flight Is were commissioned between 1991 and 1999. Later models Flight II and Flight IIA have 40-year hull lives.

In 2018, then-Deputy Chief of Naval Operations for Warfare Systems Vice Adm. Bill Merz told USNI News that there were distinct advantages to upgrading the entire class, and that instead of just a combat systems modernization aimed at boosting ballistic missile defense systems, the ships would get the full hull and mechanical upgrades that would extend the ships out to 45 year service lives.

Japan commissions its first submarine running on lithium-ion batteries

"This is an HM&E (hull, mechanical and electrical) extension, but every destroyer is already in the modernization pipeline, so every destroyer will be modernized," Merz said. "The modernization they receive that's already programmed may carry them through.

"Obviously, the threat's going to get a vote on that, but one of the beauties is, instead of doing an individual ship-by-ship extension and extending the entire class, now we have the visibility to actually plan for that. We can pace it, plan it, fund it efficiently instead of one-and-done, one-and-done, one-and-done. We can be a lot more deliberate about how we handle this class."

In testimony that year, Merz said ballistic missile defense was the biggest requirement driving the retention of the DDGs to 45 years.

Sailors on Arleigh-Burke class guided-missile destroyer USS Jason Dunham pose for a command photo, December 2, 2018. US Navy/Mass Comm Specialist 2nd Class Jonathan Clay

Compounded with cuts to the Flight III destroyers, it seems likely that the Navy by 2034 will have a significantly reduced ballistic missile defense capability with at least 32 fewer BMD-capable destroyers in the fleet, if this budget is enacted.

When asked during its FY2021 budget rollout if the cutting of five Flight III DDGs corresponded to a reduction in demand for ballistic missile defense-capable ships, Navy budget director Rear Adm. Randy Crites told reporters it was a decision based on "strictly affordability."

The Navy has in recent years declared the Arleigh Burke hull design maxed out, with the Flight III being packed to the gunwales with power and cooling to support the inclusion of Raytheon's SPY-6 air and missile defense radar. Future combatants will have to accommodate more power generations and storage to support systems such as laser weapons and rail guns.

The US Navy's top officer declares support for basing 6 destroyers in Spain

The excess electrical power capacity in the Ford-class aircraft carrier, for example, is one of the main reasons the Navy considers the new class valuable even as aircraft carriers become more vulnerable to high-speed anti-ship missiles.

Bryan Clark, a retired submarine officer and senior fellow at the Hudson Institute who recently authored a study with the Center for Strategic and Budgetary Assessments that called for canceling the DDG service life extensions, said the cuts were a necessary step.

"It's crazy to throw good money after bad for a bunch of ships you say you don't need," Clark said. "I think the Navy is coming to grips with the fiscal realities; the unsustainable nature of their current plan; and the recognition it is going to have a need for fewer large surface combatants in the future and needs to husband its resources to build a larger fleet of smaller surface combatants. Those are going to be the bulk of the distributed force they intend to have."

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The Navy is scrapping plans to extend the lives of its workhorse destroyers - Business Insider - Business Insider

Recommendation and review posted by Bethany Smith

Israels Elbit Systems will supply satellite communications on-the-move for Canadian Armed Forces in a deal with Rheinmetall Canada.

The company did not release the value of the contract, which is part of the Land Command Support System Life Extension program (LCSS LE) program.

The deal, announced March 3, will involve triple-band ELSAT 2100 SATCOM on-the-move (SOTM) systems that aid in real-time broadband communications for moving vehicles. It will use military and commercial satellites, including the U.S. Air Forces Wideband Global SATCOM constellation.

Haim Delmar, executive vice-president and general manager of Elbit Systems C4I and cyber Division, said the company is focusing on delivering technology to whats known as the Five Eye countries, which include the United States, Canada, New Zealand, UK and Australia. Elbits high technology have seen recent deals in most of those countries.

The program is part of Canadas integration of command-and-control system and subsystems and is intended to expand vehicle network equipment as well as enable connectivity with deployed vehicles and headquarters. One of those aspects is new satellite communications installed on what Canada says is a range of Army tactical vehicles to improve both command and control and the sharing of intelligence, surveillance and reconnaissance information while mobile.

The primary contractor has been Rheinmetall Canada since 2014. The initial contract foresaw 110 mobile and five transportable terminals.

The 2100-ELSAT SOTM systems, according to Elbit, will enable the Canadian Armed Forces to maintain long-range voice and data connectivity between mobile command vehicles, liaison elements, high-priority sensor vehicles, as well as tactical headquarters or command posts. It will provide them with high-capacity network services and battle command on-the-move capabilities. The system is ruggedized and has high download and uplink rates for wheeled and tracked modern vehicles.

Elbit was previously selected by Rheinmetall Canada to supply off-board electronic counter-measures for unmanned surface vehicles in Canada in 2019, as well as taking part in the 2014 Rheinmetall Canada deal for ELSAT 2100 Satellite-on-the-move systems. Elbit called the 2014 deal a milestone at the time.

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Elbit to help supply comms on-the-move for Canadian army - C4ISRNet

Recommendation and review posted by Bethany Smith

Image source: The Motley Fool.

Harpoon Therapeutics Inc(NASDAQ:HARP)Q42019 Earnings CallMar 12, 2020, 4:30 p.m. ET

Operator

Good day ladies and gentlemen, and welcome to Fourth Quarter and Full Year 2019 Financial Results Webcast and Conference Call. [Operator Instructions].

I would now like to turn the call over to Mr. Robert Uhl from Westwicke. Sir, you may begin.

Robert Uhl -- Senior Director of Investor Relations at Westwicke

Thank you, operator, and good afternoon everyone, thank you for joining us. On the call today from Harpoon Therapeutics are Gerry McMahon, President and Chief Executive Officer; and Georgia Erbez, Chief Financial Officer. Following management's prepared remarks we will be conducting a Q&A session.

I will now turn the call over to Georgia Erbez, CFO of Harpoon Therapeutics.

Georgia L. Erbez -- Chief Financial Officer

Thank you, Robert and good afternoon. Welcome to Harpoon Therapeutics webcast and conference call for a discussion of the company's fourth quarter and full year 2019, financial results and a corporate update. Before I turn the call over to Dr. McMahon, I would like to remind you that today's call will include forward-looking statements. These forward-looking statements are based on Harpoon's expectations and assumptions as of the date of this call. Each of these forward-looking statements involves risks and uncertainties that could cause Harpoon's clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements.

Please refer to Harpoon's filings with the SEC, including its Annual Report on Form 10-K for the year ended December 31, 2019, which was filed today and which are also available on Harpoon's website for information concerning factors that could cause Harpoon's actual results to differ from those expressed or implied in the forward-looking statements discussed on this call. Except as required by law, Harpoon assumes no obligation to update any forward-looking statements discussed on this call to reflect any change in the expectations, even as new information becomes available.

I will now turn the call over to Dr. Gerry McMahon, President and CEO of Harpoon Therapeutics.

Gerald McMahon -- President and Chief Executive Officer

Thank you, Georgia, and thank you all, for joining us on the call this afternoon. I am pleased with the achievement of significant clinical, scientific and operational milestones during the past year. We are committed to realizing the promise of our proprietary T-cell engager platform, which we refer to as TriTAC. This T-cell activating construct platform is designed to connect and convert a patient's own T-cells to kill tumors, or other disease tissues. Try near to optimize the therapeutic index of T-cell engagers, and our goal is to bring the successes seen in liquid tumors to solid tumors.

We are currently driving multiple products forward for the potential treatment of cancers and the benefit they could provide to patients, with limited treatment options. Some of the key accomplishments for Harpoon in 2019, included the continued advancement of our lead product candidate HPN424, which is currently in the dose escalation portion of a Phase I clinical trial in patients with prostate cancer.

We are also advanced our pipeline of three other TriTAC programs, including our second product candidate HPN536, which entered the clinic in April 2019, for the potential treatment of mesothelin expressing tumors, with an initial focus on ovarian cancer. We submitted an IND for our third product candidate, HPN217 at the end of last year, and we expect an initiate Phase I/II clinical trial for multiple myeloma in the first-half of 2020. Submission of an IND and initiation of a Phase I trial for HPN328, targeting DLL3 for small cell lung cancer and other tumors, is planned for the second-half of 2020.

Harpoon also strengthened its financial position in 2019, significantly, with our successful initial public offering in February, that raised approximately $70.7 million of net cash. As part of our partnering strategy, we evaluate opportunities to enhance our assets and inflection points that can bring the highest value to our shareholders. As an example of this strategy, in November last year, Harpoon and AbbVie announced an exclusive worldwide development and option transaction for HPN217 targeting BCMA, and in addition, an expansion of our existing discovery collaboration for up to six additional targets. These transactions were a major accomplishment for Harpoon in 2019, and we were pleased to have the opportunity to expand our relationship with AbbVie, and to further align our HPN217 asset, with a partner in multiple myeloma.

Under the terms of the development and option agreement, Harpoon granted AbbVie an option to license worldwide exclusive rights to HPN217, which may be exercised after completion of a Phase I/II clinical trial. This agreement represents a potential transaction value, up to $510 million in upfront option fee and milestone payments, royalties on global commercial sales.

In December, we received a $30 million upfront payment, and we expect to receive up to $50 million as a milestone payment, upon dosing the first patient in the HPN217 clinical trial, which we expect to accomplish in the first half of 2020. In addition, the expanded discovery collaboration represents a deal transaction value of up to $1.86 billion, and in December, we received a $20 million upfront payment under this expansion deal. The financial resources from these transactions are being put to work to support our clinical development and research programs, leading to multiple potential value creating milestones for our shareholders.

Now, let me review some key aspects of our TriTAC technology and after that, I will describe our clinical development programs. Harpoon's TriTAC technology platform is a novel and proprietary approach to engage T-cells. T-cell engagers are engineered proteins that physically connect a patient's own T-cells to target cells, that express its specific proteins or surface markers. This results in the activation of T-cells unleashing their natural power to kill the target cell by releasing potent cytokines and other factors.

Our current pipeline of product candidate focuses on oncology applications of our technology. Unlike other immuno-oncology approaches, like checkpoint inhibitor products, TriTACs do not rely on the existence of tumor specific T-cells, or recognition of the tumor cell through a T-cell MHC interaction. TriTACs can reprogram any T-cell to kill in the absence of MHC recognition and provide an alternative to checkpoint drugs such as PD-1 antibodies.

The first T-cell engager, also known as a BiTE or Bispecific T-cell Engager, was approved in 2014 for the treatment of acute lymphocytic leukemia. However, this first generation technology is limited by a short-half life, and must be administered through continuous intravenous infusion. With our TriTAC platform, we set to incorporate the appealing strengths of BiTE's, such as their small size and potent killing activity at low expression levels of tumor antigen, which are ideal for application in solid tumors, while improving on the administration limitations of the short-half life. Our TriTACs are modular by design, consisting of three primary components that perform three different functions; T-cell binding, half-life extension, and tumor cell binding. To address half-life extension, we utilized a domain that binds transiently to human serum albumin. We utilized single domain antibodies for target binding and human serum albumin binding, which makes our molecules smaller and more flexible than would be possible with larger antibody derived fragments.

Furthermore, these domains are inherently very stable, contributing to a platform that potentially has very little off target activity, and therefore expected to have a therapeutic window that is ideal for applications in solid tumors. Our TriTAC products or globular proteins that can be formulated in solution, and administered to patients by intravenous delivery in about an hour, infusion every one or two weeks. A TriTAC protein is approximately 50 kilodaltons, or about one third the size of a typical antibody. We believe the smaller size and shape of TriTACs allows them to diffuse more freely into tumor tissue, compared to antibodies.

Our TriTACs are about 75% identical to each other. Since the tumor target domain is the only component that varies between different clinical candidates. In addition, our TriTAC use standard methods of conventional, antibody based manufacturing techniques, which avoids the cost and complexity of personalized or cell based therapies such as CAR-T.

Now let me review where we are with our four pipeline development programs; our lead TriTAC product candidate HPN424 targets prostate specific membrane antigen or PSMA, for the treatment of metastatic castration resistant prostate cancer. PSMA is present in 85% to 90% of patients with advanced metastatic prostate cancer. Market research shows us that prostate cancer is the third leading cause of cancer death in the United States. There are approximately 164,000 new cases and 29,000 prostate cancer deaths, in the United States each year.

HPN424 is in a Phase I clinical trial, enrolling patients with metastatic castration resistant prostate cancer. The trial was designed with an initial dose escalation phase, followed by a dose expansion phase. We continue to enroll patients in the dose escalation phase of the trial, with the goal of entering an expansion phase of the trial in the second-half of 2020. Preliminary results announced early last year, suggested that HPN424 could activate T-cells in a manner consistent with tumor target engagement. These data also provided the first clinical evidence that the TriTAC platform has sufficient serum exposure to support weekly intravenous administration. We've continued to enroll patients in the trial, and have continue to increase the dose.

We have submitted an abstract with the intent to provide a trial update at the upcoming ASCO annual meeting in late May or early June. You can expect the data to include an interim look at the ongoing dose escalation phase of the trial. This data may include the number of dose cohorts, the number and features of enrolled patients, the doses explored in the escalation phase at the time of the presentation and preliminary measurement of drug safety, evidence for target engagement pharmacokinetics, pharmacodynamics and early evidence of clinical activity. We expect that dose escalation will continue beyond the data provided in the presentation at ASCO, and anticipate entering a dose expansion phase in the second-half of 2020.

Our second TriTAC product candidate HPN536 targets mesothelin and enter the clinic in April of 2019. It is being studied initially in platinum refractory ovarian cancer, and recently we've added our first metastatic pancreatic cancer patients to this trial. Mesothelin expressed on malignant cells of ovarian carcinoma, pancreatic carcinoma, mesothelioma, non-small cell lung cancer and breast cancer among others. While mesothelin has been the focus of some CAR-T efforts, HPN536 is the first mesothelin targeted T-cell engager to enter clinical development. Patients receive weekly infusions of HPN536 and the trial is proceeding in line with our expectations. The experience we have gained from HPN424 in prostate cancer has been beneficial in our conduct of the 536 trial, and we expect to provide interim data from the ongoing dose escalation portion of the trial, in the second-half of 2020.

Our third TriTAC product candidate HPN217, targets B-cell maturation antigen, or BCMA. We submitted an IND for HPN217 in late 2019, and are planning to initiate a Phase I/II clinical trial in the first-half of 2020, in the treatment of relapsed refractory multiple myeloma. As mentioned before, under the agreement with AbbVie, they will have an option to exclusively license this program upon completion of the Phase I/II clinical trial.

HPN328 is our fourth TriTAC product and it targets delta like ligand 3 or DLL3, a protein highly expressed in a majority of small cell lung cancer tumors and other neuroendocrine tumors. We presented preclinical data at the NCI-EORTC, AACR meeting in October 2019, demonstrating potent tumor cell killing pharmacokinetic data, supporting at least once weekly dosing and supportive safety data in nonhuman primates. We plan to submit an IND for HPN328, and begin a Phase I clinical trial in the second-half of 2020.

This past year has been a strong period of pipeline advancement. We are on track to meet our previously stated goal of having four programs in the clinic by the end of 2020. We look forward to providing additional clinical data from all product candidate programs over the next couple of years. We have a unique off-the-shelf platform for T-cell engagers that reprogram a patient's own immune cells to treat a wide variety of human malignancies. Our pipeline is well positioned to generate exciting data and drive shareholder value.

With that, I'll turn the call over to Georgia Erbez, for a discussion of our financial results, for the fourth quarter and full year 2019.

Georgia L. Erbez -- Chief Financial Officer

Thank you, Gerry. I will provide a brief overview of our financial results here on the call and invite you to review our 10-K filed today for a more detailed discussion. Revenue for the fourth quarter ended December 31, 2019 was $2.2 million, compared to $1.1 million for the fourth quarter ended December 31st, 2018. Revenue for the year ended December 31st, 2019 was $5.8 million, compared to $4.8 million for the prior year. Revenue consisted of the portion of the upfront payment received from our agreements with AbbVie, that was related to research and development services performed during the period.

Research and development expense for the fourth quarter of 2019 was $12.7 million, compared to $8.7 million for the fourth quarter ended December 31, 2018. R&D expense for the year ended December 31st, 2019 was $41.6 million compared to $26.4 million for the prior year. The increase is primarily due to clinical development expenses and an increase in personnel related expenses, including conducting preclinical studies, the continuation of clinical trials for HPN424 and HPN536, and manufacturing activities for our four TriTAC product candidates in various stages of development.

General and administrative expenses for the quarter ended December 31st, 2019 were $4.3 million compared to $2.2 million for the fourth quarter of 2018. General and administrative expenses for the year ended December 31st, 2019 were $22.4 million compared to $6.1 million for the prior year. The increase was primarily due to an increase in legal fees, consulting and accounting services, and an increase in headcount and other professional services to support our ongoing operations as a public company. Net loss for the fourth quarter ended December 31st, 2019 was $14.3 million, compared to $9.7 million for the fourth quarter ended December 31st, 2018. Net loss for the year ended December 31st, 2019 was $55.6 million compared to $27.4 million for the prior year.

We ended 2019 with $155.1 million in cash and cash equivalents compared to $89.5 million as of December 31st, 2018. Net cash provided by financing activities for the year ended December 31st, 2019 was $71.4 million, primarily comprised of $70.7 million in net cash proceeds, received from our initial public offering in February 2019. Net cash used in operations for the year ended December 31st, 2019 was $69.3 million. For 2020, we are estimating cash operating expenses and capital expenditures of approximately $60 million to $70 million.

The cash balance at the end of 2019 includes the $50 million upfront payment received from AbbVie in December, associated with the development and option agreement for HPN217, and the expansion of the existing discovery collaboration. Under the terms of the agreement, we expect to receive up to another $50 million payment, which will be triggered upon the first patient dose with HPN217. We anticipate the payment will be recognized in our quarterly income statement over the next 10 to 12 quarters. As a reminder, while we will recognize the cash payments from AbbVie as quarterly revenue, as required by GAAP. The quarterly revenue is not actual cash received in a period and does not offset cash expenses incurred in the period.

With that, I will now turn the call back over to Gerry.

Gerald McMahon -- President and Chief Executive Officer

Thank you, Georgia. I am very pleased with the tremendous progress Harpoon has made during the past year, the momentum with which we have entered into 2020, and the exciting potential for all of our product candidates in the proprietary TriTAC tech platform. Two of our product candidates HPN424 and HPN536 are in the clinic, and two more HPN217 and HPN328 are expected to begin clinical trials this year. Our financial position is strong, and we have the resources in place to advance our pipeline.

Before we jump into Q&A, let me quickly review our anticipated near-term milestones. For HPN424 our Phase I dose escalation portion of the clinical trial is ongoing and we submitted an abstract, with the intent to present interim data at ASCO during the second quarter of 2020. For HPN536, the Phase I/II trial is continuing to enroll patients in the dose escalation portion of the trial. We intend to present preliminary data from this trial by the end of 2020. For HPN217, we expect to dose the first patient in the Phase I trial in the first-half of this year, which will trigger a $50 million payment from AbbVie. For HPN328, we are planning for an IND submission followed by initiation of a Phase I trial in the second-half of 2020.

So with that operator, we are now ready for questions.

Operator

[Operator instructions]. Your first question comes from the line of Mr. Jonathan Chang from SVB Leerink. Your line is open sir.

David Ruch -- SVB Leerink -- Analyst

Hi, guys, this is David Ruch on for Jonathan. Thanks for taking our question and congratulations on the progress. First question from us is with regard to HPN424, how are you thinking about the benchmarks for response rate and progression free survival in this late line setting of prostate cancer?

Gerald McMahon -- President and Chief Executive Officer

Thank you for the questions. This is Gerry McMahon. So, we of course, look toward previous treatments in late stage prostate cancer and realized that, that these patients, of course, have various features that make it difficult to assess clinical activity in a traditional way. However, what we do follow and what we feel is very relevant is the time on study for patients, which we feel reflects disease progression, we feel PSA levels is another marker of disease. And of course, evaluation of RECIST in measurable disease in a subset of cancer patients. These have been the traditional hallmarks of clinical activity assessment in this late stage patient population.

David Ruch -- SVB Leerink -- Analyst

Got it. Thank you. Second from us, any additional clarity on the registrational strategy for 536 in terms of the different subpopulations of ovarian cancer. And have you seen any trends with the study enrollment to-date that have helped from this strategy?

Gerald McMahon -- President and Chief Executive Officer

It's a little early to strategize a regulatory path for the various diseases where this product could be used. Clearly, our focus initially is an ovarian cancer. And our goal really is to establish a dose, where we believe clinical impact can be observed in this particular disease. We hope that that dose also translate into clinical benefit for pancreatic mesothelioma, non-small cell lung cancer and breast cancer, but that would have to be proven in the clinic. And of course, having multiple diseases to go after with this product gives us many different potential paths toward registration. But we're still in the early phases of our clinical trials trying to establish a proof of concept dose. And until we get there, we really can't strategize our regulatory strategy at this time.

David Ruch -- SVB Leerink -- Analyst

Great. And then just one more kind of logistical question. For 328, will this study be primarily in patients with small cell lung cancer? Or do you potentially expect to enroll other tumor types? I know you mentioned neuroendocrine on the call earlier in the prepared remarks.

Gerald McMahon -- President and Chief Executive Officer

Yes, I mean, the protocol evolution for that trial is still active and in discussion. The focus will be in small cell lung cancer for sure, but we are entertaining going into other tumor types, where we believe DLL3 is expressed. But that is our intention is to move forward with a small cell lung cancer oriented trial, but also have some flexibility to treat other patients that might express this target.

David Ruch -- SVB Leerink -- Analyst

Awesome. Thank you so much for the clarity there.

Gerald McMahon -- President and Chief Executive Officer

Thank you.

Operator

Your next question comes from the line of Mike Ulz from Baird. Your line is open sir.

Michael Ulz -- Baird -- Analyst

Hey guys. Thanks for taking the question, and congrats on all the progress as well. I just had a few questions on HPN424 and maybe you can just give us a sense of where you are in a dose escalation currently. And if I remember, I think last year at the initial update, you were through the fourth cohort. So just curious where you are currently? And then if you can overlay that with what you think that the therapeutic range is, and how far into that are you at this point? And then I have a follow-up.

Gerald McMahon -- President and Chief Executive Officer

Yes. So we haven't specifically disclosed to-date where we are. What we did mention last August, is we spent last year, spent some time evaluating the use of steroid dexamethasone to mitigate mild CRS symptoms when patients were first being given this product. And at that time in August, we were treating our seventh cohort. So what I can say today, of course, moving into a potential medical presentation in the middle of this year, is that we've exceeded that cohort. And we continue to move the dose up and have really done a very good job mitigating this first dose effect that one sees with T-cell engagers. So that's all I can say at this point. Obviously, we're going to have a nice data set describing those who's in patient cohorts, when we hopefully give our medical conference presentation, but that's all I can say at this point.

Michael Ulz -- Baird -- Analyst

Got it. And then maybe in terms of the dose expansion, you mentioned maybe starting that later this year, but you also mentioned continuing to dose escalate past ASCO. So maybe just big picture if you can talk about how you're thinking about selecting that dose for the expansion? Thanks.

Gerald McMahon -- President and Chief Executive Officer

Yes. It might be worth just describing the trial concept in general. So, the goal of the dose escalation in any study is to determine the maximum tolerated dose, and that's usually dictated by dose limiting toxicities. So, if one were to achieve a maximum tolerated dose, by increasing the dose, the expansion cohort if one was to observe efficacy would be driven off of a dose that was obviously safe enough to proceed. At this point, we have no way to know whether we will achieve an MTD by ASCO and so therefore, we would anticipate if we do not get to a maximum tolerated dose, which is our expectation, then we would continue to dose escalation past ASCO. Again, we may get to a point in the trial and this is our expectation that we're seeing a sufficient efficacy to warrant an expansion cohort to explore a particular dose and regimen, that is not being dictated by the achievement of a maximum tolerated dose. In that scenario, that expansion cohort then would be triggered and we would continue to dose escalate above that dose, because we were not limited at that point.

But yes, there was enough reason to believe that there was evidence of clinical activity to warrant testing a patient population, at a particular dose and regimen. So, what's nice about this protocol is we have lots of flexibility to do expansion cohorts and escalations to generate, quite a bit of data that could be used to guide our decision into future regulatory studies. So, that's really what's going on in this particular trial at this point. Is that helpful?

Michael Ulz -- Baird -- Analyst

Yes, that's helpful. Thank you.

Gerald McMahon -- President and Chief Executive Officer

Okay. Thanks.

Operator

Your next question comes from the line of Yigal Nochomovitz from Citigroup. Your line is open.

Yigal Nochomovitz -- Citigroup -- Analyst

Hi, Gerald, thank you very much for taking the questions. If I could just go back to one of the earlier ones on the benchmarks for 424, and maybe ask the question, but more specifically. In terms of how you're thinking about proceeding with development of this asset, could you speak a bit about how you see the bar for success there in terms of a go-no-go decision? What would you like to see ideally, on PSA responses and RECIST responses, to feel good about taking the asset forward into dose expansions, and then into subsequent studies? Thank you.

Gerald McMahon -- President and Chief Executive Officer

Yes. I think if you look at the history of development in late stage prostate cancer, it became very clear to us and to others, that disease progression is the most likely endpoint to support a registrational strategy in this particular disease. So, the most informative, I think endpoint for any trial will be how long as a patient been on study. Remember, this is a weekly therapy, patient would continue to receive therapy on a weekly basis until disease progression, because that would align to a potential regulatory path.

That being said, any ancillary data to support direct anti-tumor effect either by PSA declines or by RECIST or both, would be supportive of that particular patient who is on study progression free. So, I think the primary focus will be keeping the patient from having a disease progression which ultimately would lead to lethality, but then to have some supportive ancillary data related to PSA declines and RECIST if you could measure. Remember, in this disease, only about 20% of patients are RECIST evaluable, so not every patient will have an ability to assess that.

But that being said, this is a trial which will measure all of those potential parameters to assess clinical benefit. I should mention, in addition to that, of course, we have a suite of other translational activities that are being measured in these patients to support mechanism of action, including cytokine changes, T-cell activation, and other parameters that would also be used to support, whether or not, let's say, clinical activities associated with a mechanism of action. Since the only drug these patients are being given is our drug, there's no combination here. So, any of the activities we observe in these patients, we can attribute directly to our mechanism of action. So, it's a long answer, but it's a complicated disease.

Yigal Nochomovitz -- Citigroup -- Analyst

All right, understood. But so just in terms of specific numbers, I guess you're saying it's a bit early for you to kind of put forth specifics as far as, what might be a threshold level of response rate and things like that. Would you prefer just to see how the data evolve?

Gerald McMahon -- President and Chief Executive Officer

It typically, most physicians would argue in this disease. A patient who stays on study greater than three months is good a patient who stays on study greater than six months is very good. And if that patient is also associated either with PSA declines or with some shrinkage of measurable tumors, that would support the notion that that patient is deriving clinical benefit. But given that this is an escalation study, and not an efficacy oriented study. It's hard to put a percentage on it, but that is the type of data that we're looking to generate to support further advancement of this product. Is that helpful?

Yigal Nochomovitz -- Citigroup -- Analyst

Yes, very helpful. Thank you. Again, I had a technology question. So, you're doing once weekly dosing now as I understand it across the programs. What does the technology allow? What is the potential rather for the technology potentially to extend to say, once every two weeks. Do you have that ability with the platform, or is that that's another level of development?

Gerald McMahon -- President and Chief Executive Officer

Yes. So now, we think, based on the data that we see emerging from both these programs, that it's very feasible to think of either HPN424 or 536, being dosed either weekly or possibly every two weeks. But because we're still measuring the exposure and of course, measuring the efficacy, it's hard to know which is optimal, but conceptually, the platform could be used either way. We would hate to not allow the patient to derive as much benefit from the product as possible in this first clinical trial.

But later, if we felt that the benefit could be maintained by moving to a once every two week regimen, the platform could support it. But it's still too early to make a call on what the ultimate frequency would be. But it's not unreasonable based on what we're seeing with the platform of either being once every week or once every two weeks. But we can't say that with surety at this particular time.

Yigal Nochomovitz -- Citigroup -- Analyst

All right, understood. Thanks very much, very helpful.

Operator

Your next question comes from the line of Asthika Goonewardene from SunTrust. Your line is open.

Asthika Goonewardene -- SunTrust -- Analyst

Hi, guys. Thank you for taking my questions and I appreciate all the progress updates here. So, maybe going back to what discussing the expectations for 424 at ASCO. Totally appreciate that the therapeutic window here for 424 is really broad. So, it's kind of hard for you to -- maybe hard to put answers but maybe could you give some sort of clarity as to how many of the cohorts that you will be presenting at ASCO are in that, which you feel Gerry, is the real therapy to be relevant dose range, and that's something will be the answer right now?

Gerald McMahon -- President and Chief Executive Officer

Excerpt from:
Harpoon Therapeutics Inc (HARP) Q4 2019 Earnings Call Transcript - Motley Fool

Recommendation and review posted by Bethany Smith

VANCOUVER , March 9, 2020 /CNW/ - GREAT PANTHER MINING LIMITED (NYSE American: GPL; TSX: GPR) ("Great Panther", the "Company") today announced its inaugural Mineral Resource and Mineral Reserve Estimate (the "MRMR") for its 100% owned Tucano Gold Mine ("Tucano") in Brazil and updated Mineral Resource Estimates for the two mines at its Guanajuato Mine Complex ("GMC") in Mexico. The Company also provides an update on its Topia Mine in Mexico regarding potential near term interruption of operations as a result of temporary cessation of tailings deposition activities at the existing tailings storage facility.

The MRMR reflects the first mineral resource and reserve estimate undertaken by the Company for Tucano since the Company's acquisition of the mine in March 2019. The MRMR has an effective date of September 30, 2019 and uses a more rigorous approach to mineral resource and reserve estimation at Tucano compared to the June 30, 2017 estimate of the previous operator. The MRMR reflects operating experience since acquiring the mine in 2019 and a better understanding of the mine's geology, and is therefore expected to improve mine forecasting reliability. Internationally recognized mining consultants Roscoe Postle & Associates ("RPA") acted as independent technical qualified persons for the MRMR.

At Tucano, after adjustments for mining depletion since June 30, 2017 , Mineral Reserves are now estimated to be approximately 646,000 ounces, a decline of approximately 489,000 gold ounces relative to the June 30, 2017 estimate. Mineral Resources (excluding Mineral Reserves) declined by approximately 500,000 gold ounces.

At the GMC, estimated Mineral Resources (Measured and Indicated) for the Guanajuato Mine were approximately 3.7 million silver equivalent ounces, up by approximately 1.5 million silver equivalent ounces from the prior estimate dated August 31, 2017 , due to a successful 2019 exploration program (see below for silver equivalency calculation). The mine was placed on care and maintenance in December 2018 pending the completion of a more focused exploration program. The Company believes that the increase in resources, together with ongoing drilling in 2020, could be the basis for a re-start of operations later this year.

Measured and Indicated Mineral Resources for the San Ignacio Mine were approximately 5.0 million silver equivalent ounces, a decline of approximately 6.4 million silver equivalent ounces from the prior estimate effective August 31, 2017 , due primarily to mining depletion of 3.8 million silver equivalent ounces. The new Mineral Resource Estimates for the Guanajuato and San Ignacio mines feature higher silver equivalent grades as a result of the application of higher Net Smelter Return ("NSR") cut off values.

"The completion of the MRMR is an important milestone following our acquisition of Tucano as it provides us with a more solid foundation for understanding the geology of Tucano," said Jeffrey Mason , Interim President and CEO. "While our inaugural update has resulted in a lower reserve and resource estimate, it provides us with a higher level of confidence for future mine and operational planning and the increase in average grades provides additional operational flexibility."

"Going forward we will be aggressively advancing opportunities for resource growth and mine life extension on multiple fronts," added Mr. Mason. "At Tucano, we are drilling new near-mine and regional targets in our more than 2,000 square kilometre, largely under-explored land package. We are also evaluating the potential for upgrading confidence in resources for conversion to reserves, and looking to improve and enhance the existing Prefeasibility Study supporting the development of an underground mining operation at Tucano. At GMC, in addition to the potential re-start of the Guanajuato Mine, we are advancing expanded exploration programs at both the Guanajuato and San Ignacio mines."

The Company expects to release 2019 financial results and provide its annual production and cost guidance by the end of March 2020. As part of the completion of its 2019 consolidated financial statements, and audit of those financial statements by the Company's independent auditors, the Company will assess the carrying value of Tucano based on the March 2019 purchase price. The assessment of carrying value will consider the MRMR which could lead to a material reduction in the carrying value and a corresponding material charge to the Company's income statement. Technical reports compliant with Canada's National Instrument 43-101 Standards of Disclosure for Mineral Projects ("NI-43-101") will be filed on the Company's SEDAR profile within 45 days of this news release.

Opportunities for Mineral Resource Increases and Mine Life Extension at Tucano

Based on a preliminary analysis of the updated reserve estimate (without consideration of resource conversion or underground mining), the Company estimates that its current open pit Mineral Reserves will continue to be mined to the fourth quarter of 2021. The Company has identified four key priorities at Tucano to increase reserves and extend the mine life:

1. Near Mine Exploration

The Company has further refined its previously announced 2020 near mine exploration drilling program of approximately 28,000 metres. The focus of the program will be on replacing ounces to be mined in 2020 and extending the mine life. This further refinement involves the prioritization of ten prospective target areas close to the existing pits. The Company has initiated drilling and expects to evaluate the results of drilling by July 2020 , noting that material drill results will be disclosed as received and analyzed. The evaluation will be used to determine whether to increase the program and/or reprioritize targets.

2. Potential Conversion of Existing Measured and Indicated Resources

The Company is pursuing the conversion of resources to reserves concurrent with ongoing mine planning and optimization. Of the approximately 150,000 ounces Measured and Indicated Resources incremental to the Mineral Reserves in table 1.1 below (excluding underground), the Company believes a portion located just below the reserve pit designs may prove to be economically viable if gold prices continue to prevail at or above the current level of approximately $1,675 per ounce, which compares favourably with gold prices used in the MRMR. In addition, the current Brazilian real to US dollar exchange rate is significantly more favorable than the rate of 3.80 used in the MRMR.

3. Underground Development

The Company continues to evaluate the potential for development of an underground mine below the Urucum North pit, which comprises the 288,000 ounces of underground Tucano Mineral Reserves (see table 1.3 below). A decision on whether to proceed with a Feasibility Study for an underground mine is anticipated in the fourth quarter of 2020, following an underground targeted drill program.

Current underground Mineral Reserves are based on previous designs, adjusted for current costs and cut-off grades ("COG"). Mining of up to 400,000 tonnes of ore per annum is contemplated, at an average grade of 4.13 g/t Au.

4. Regional Exploration

As disclosed in a news release dated February 6, 2020 , the Company initiated a 27,000-metre regional exploration drilling program for 2020 on various concessions that Great Panther holds in an under-explored land package consisting of more than 2,000 km2.

Beyond currently planned drilling, the Company is further collating, refining and reviewing all existing data from previous ownership to prioritize targets according to their geological potential and proximity to Tucano's mill.

Urucum Central South ("UCS") Pit Update

As noted in the Company's news releases on October 7, 2019 and October 15, 2019 , the west wall of the UCS pit underwent slope displacement on October 6 , 2019. Since then, the pit has been closed to mining and the Company has deployed significant effort and resources toward a remediation plan with the assistance of the independent consulting firm Knight Pisold & Co.

Pending completion of the remediation plan, the UCS pit continues to be included in the Company's MRMR, with a Mineral Reserve Estimate (Proven and Probable) of approximately 88,000 ounces of gold and potential for further conversion of Measured and Indicated Mineral Resources at higher gold prices than the Mineral Resource Estimate's US$1,500 per ounce. Current estimates for UCS include conservative adjustments to pit wall configurations based on preliminary geotechnical findings.

The Company believes that the reserves are recoverable but cautions that recovery is subject to further evaluation based on geotechnical data gathering now underway. The data gathering will include the collection of additional geotechnical information from five geotechnical core holes to be drilled commencing in April 2020 .

Following completion of data collection, an assessment will be made as to whether remediation of the UCS pit to mine the current reserves will be completed.If the remediation plan is determined not to be feasible, then the current UCS pit reserves may not be mined.

If the remediation can be implemented as planned, the Company expects to be in a position to begin remedial work on the west wall of the UCS pit during the third quarter of 2020 and to resume ore mining in the fourth quarter of 2020.

Summary of Tucano Mineral Resources

A summary of the estimated 2019 Mineral Resources is shown in Table 1.1 and a comparison with the 2017 Mineral Resources is shown in Table 1.2. Summaries of the Measured and Indicated Mineral Resources are presented in Appendix 1 below.

Table 1.1 Summary of Mineral Resources as at September 30, 2019 , Tucano

Location

Cut-off

Total Measured & Indicated

Inferred

Au (g/t)

oxide or fresh

Tonnes

('000's)

Grade Au

(g/t)

Ounces

('000's)

Tonnes

('000's)

Grade Au

(g/t)

Ounces

('000's)

OPEN PITS OXIDE AND PRIMARY FRESH

Urucum

0.40 or 0.55

4,364

2.08

291

7

3.94

1

Urucum East

0.40 or 0.55

143

2.09

10

0

0.00

0

Tap AB

0.40 or 0.55

1,607

2.33

120

0

0.00

0

Duckhead

0.40 or 0.55

183

2.87

17

12

2.79

1

Total Open Pits

0.40 or 0.55

6,296

2.16

438

18

3.21

2

STOCKPILES

Open Pit

0.50

1,887

0.71

43

0

0

0

Spent Ore

0.50

37

Link:
Great Panther Announces Its Inaugural Mineral Reserve & Mineral Resource Estimate for the Tucano Mine, Updated Mineral Resource Estimate at...

Recommendation and review posted by Bethany Smith

The key objective of Ashwagandha Extract Market 2020-2025 Trends and Global Insights report is to help the user understand the market in terms of its segmentation, influential trends, leading players, market potential, primary and secondary research, and the challenges that the market is facing

Deep researches and analysis were done during the preparation of the Ashwagandha Extract market report. The readers will find this report very helpful in understanding the market in depth. The data and the information regarding the market are taken from reliable sources such as websites, annual reports of the companies, journals, and others and were checked and validated by the industry experts. The facts and data are represented in the report using diagrams, graphs, pie charts, and other pictorial representations. This enhances the visual representation and also helps in understanding the facts much better.

The Key players covered in the Ashwagandha Extract Market research report are:

By Market Players:JIAHERB, RAJMOTI, Xian Sgonek Biological Technology, Arjuna, Baldwa, Phyto Life Sciences, NATURALIN BIO-RESOURCES, Quad Lifesciences, Parchem, Ideal Natural Extract, NOW Foods, Swanson, Life Extension, Solgar, Organic India, Taos Herb Company, Piping Rock, Jarrow Formulas

By ApplicationHealth Products, DrugCapsule, Liquid, Powder

Get Sample Copy of this report at https://www.abrreports.com/industry-insights/2020-2025-global-and-regional-ashwagandha-extract-industry-production-sales-and-consumption-status-and-prospects-professional-market-research-report?form=request-report-sample

The points that are discussed within the report are the major market players that are involved in the market such as manufacturers, raw material suppliers, equipment suppliers, end users, traders, distributors and etc.

The complete profile of the companies is mentioned. And the capacity, production, price, revenue, cost, gross, gross margin, sales volume, sales revenue, consumption, growth rate, import, export, supply, future strategies, and the technological developments that they are making are also included within the report. The historical data from 2012 to 2017 and forecast data from 2018 to 2023.

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The growth factors of the market are discussed in detail wherein the different end users of the market are explained in detail. Data and information by manufacturer, by region, by type, by application and etc, and custom research can be added according to specific requirements.

The report contains the SWOT analysis of the market. Finally, the report contains the conclusion part where the opinions of the industrial experts are included.

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Key pointers of the Table of Contents:

Chapter 1 Industry OverviewChapter 2 Production Market AnalysisChapter 3 Sales Market AnalysisChapter 4 Consumption Market AnalysisChapter 5 Production, Sales and Consumption Market Comparison AnalysisChapter 6 Major Manufacturers Production and Sales Market Comparison AnalysisChapter 7 Major Material AnalysisChapter 8 Major Type AnalysisChapter 9 Industry Chain AnalysisChapter 10 Global and Regional Market ForecastChapter 11 Major Manufacturers AnalysisChapter 12 New Project Investment Feasibility AnalysisChapter 13 ConclusionsChapter 14 Appendix

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Ashwagandha Extract Market Research Report Insights on 2025 Industry Outlook, Competitive Breakdown, Opportunities and Trends - News Times

Recommendation and review posted by Bethany Smith

Shinya Yamanaka's 2006 discovery of induced pluripotent stem cells (iPSCs) ignited a revolution in the field of stem cell biology (1). For the first time, nearly all human somatic tissues could be produced from iPSCs reprogrammed from blood or skin cells, in a process that took only weeks. This advance was particularly crucial for obtaining surrogate tissues from cell types that are otherwise difficult to procure and do not readily expand in vitro, such as cardiac or neural cells. Additionally, many ethical concerns are avoided, because this technology uses a patient's own genetic material to create iPSCs rather than relying on embryonic stem cells. In the aftermath of Yamanaka's discovery, entire biomedical industries have developed around the promise of using human iPSCs (hiPSCs) and their derivatives for in vitro disease modeling, drug screening, and cell therapy (2).

The hiPSC technology has had a particularly notable impact in cardiac regenerative medicine, a field where scientists and clinicians have been working to devise new methods to better understand how cardiovascular disease manifests and how to restore cardiovascular function after disease strikes (3). The heart is limited in its ability to regenerate lost cardiomyocytes (beating heart muscle cells), following an adverse event such as a heart attack (4). Cardiomyocytes derived from hiPSCs (hiPSC-CMs) may represent a potential replacement option for dead cells in such a scenario. However, certain issues remain to be addressed, such as whether hiPSC-CMs can integrate with host myocardial tissue in the long term (5).

While using hiPSC-CMs for in vivo cell therapy may become practical in the future, employing hiPSC-CMs for high-throughput drug discovery and screening is becoming a reality in the present (6). Cardiovascular diseases can be recapitulated in a dish with patient-specific hiPSC-CMs. For example, if a patient exhibits a cardiac arrhythmia caused by a genetic abnormality in a sarcomeric protein or ion channel, that same rhythm problem can be recapitulated in vitro (7). Thanks to advances in hiPSC differentiation protocols, hiPSC-CMs can now be mass-produced to study cardiovascular disease mechanisms in vitro (8).

My graduate thesis in the laboratories of Joseph Wu and Sean Wu at Stanford University focused on in vitro applications of hiPSC-CMs for cardiovascular disease modeling and for high-throughput screening of chemotherapeutic compounds to predict cardiotoxicity. I initially embarked on a project using hiPSC-CMs to model viral myocarditis, a viral infection of the heart, caused by the B3 strain of coxsackievirus (9). I began by demonstrating that hiPSC-CMs express the receptors necessary for viral internalization and subsequently found that hiPSC-CMs were highly susceptible to coxsackievirus infection, exhibiting viral cytopathic effect within hours of infection. I also identified compounds that could alleviate coxsackievirus infection on hiPSC-CMs, a translationally relevant finding, as there remains a shortage of treatments for viral myocarditis.

Using a genetically modified variant of coxsackievirus B3 expressing luciferase, I developed a screening platform for assessing the efficacy of antiviral compounds. Pretreatment with interferon-, ribavirin, or pyrrolidine dithiocarbamate markedly suppressed viral replication on hiPSC-CMs by activating intracellular antiviral response and viral protein clearance pathways. These compounds alleviated viral replication in a dose-dependent fashion at low concentrations without causing cellular toxicity.

I next sought to use hiPSC-CMs to screen anticancer chemotherapeutic compounds for their off-target cardiovascular toxicities (10). Cardiotoxicity represents a major cause of drug withdrawal from the pharmaceutical market, and several chemotherapeutic agents can cause unintended cardiovascular damage (11). Using cultured hiPSC-CMs, I evaluated 21 U.S. Food and Drug Administrationapproved tyrosine kinase inhibitors (TKIs), commonly prescribed anticancer compounds, for their cardiotoxic potential. HiPSC-CMs express the major tyrosine kinase receptor proteins such as the insulin, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors, lending validity to this cellular model.

Initially, human induced pluripotent stem cells (hiPSCs) can be produced by reprogramming skin or blood cells by nonviral or viral reprogramming methods. Cardiac differentiation protocols allow for the creation of cardiomyocytes derived from hiPSCs (hiPSC-CMs) for downstream applications, including in vitro disease modeling, drug screening, and regenerative cell therapy.

With data from a battery of cellular apoptosis, contractility, electrophysiology, and signaling assays, I generated a cardiac safety index to help align in vitro toxicity data to clinical drug safety guidelines (12). From the safety index, I determined that a subclass of VEGF receptor 2/PDGF receptorinhibiting tyrosine kinase inhibitors, some of which exhibit toxicity clinically, also elicited cardiotoxicities in hiPSC-CMs. These manifested as substantial alterations in cellular electrophysiology, contractility, and viability when administered at clinically relevant concentrations. I also discovered that cotreatment with either IGF or insulin partially rescued TKI-induced toxicity by up-regulating antiapoptotic signaling pathways. This work could prove useful for groups aiming to develop effective screening platforms to assess new chemotherapeutic compounds for cardiotoxic side effects.

I also collaborated with the Center for the Advancement of Science in Space (CASIS) to send a sample of hiPSC-CMs to the International Space Station. As humankind ventures beyond our home planet, it is imperative that we better understand how the heart functions for long periods of time in microgravity. Analysis of these hiPSC-CMs revealed microgravity-induced alterations in metabolic gene expression and calcium handling (13).

In recent years, the stem cell field has experienced an explosion of studies using hiPSC-CMs as a model cellular system to study cardiovascular biology. As improvements in hiPSC-CM mass production continue, we will see a rise in studies using these cells for disease modeling and drug screening. Thus, although hiPSC-CM technology is in its infancy, it holds great potential to improve cardiovascular health.

PHOTO: COURTESY OF A. SHARMA

FINALIST

Arun Sharma

Arun Sharma received his undergraduate degree from Duke University and a Ph.D. from Stanford University. Having completed a postdoctoral fellowship at the Harvard Medical School, Sharma is now a senior research fellow jointly appointed at the Smidt Heart Institute and Board of Governors Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles. His research seeks to develop in vitro platforms for cardiovascular disease modeling and drug cardiotoxicity assessment. http://www.sciencemag.org/content/367/6483/1206.1

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Stem cells to help the heart - Science Magazine

Recommendation and review posted by Bethany Smith

DUBLIN, March 12, 2020 /PRNewswire/ -- The "Cell Therapy - Technologies, Markets and Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

The cell-based markets was analyzed for 2018, and projected to 2028. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 309 of these are profiled in part II of the report along with tabulation of 302 alliances. Of these companies, 170 are involved in stem cells.

Profiles of 72 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 67 Tables and 25 Figures. The bibliography contains 1,200 selected references, which are cited in the text.

This report contains information on the following:

The report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

Key Topics Covered

Part I: Technologies, Ethics & RegulationsExecutive Summary 1. Introduction to Cell Therapy2. Cell Therapy Technologies3. Stem Cells4. Clinical Applications of Cell Therapy5. Cell Therapy for Cardiovascular Disorders6. Cell Therapy for Cancer7. Cell Therapy for Neurological Disorders8. Ethical, Legal and Political Aspects of Cell therapy9. Safety and Regulatory Aspects of Cell Therapy

Part II: Markets, Companies & Academic Institutions10. Markets and Future Prospects for Cell Therapy11. Companies Involved in Cell Therapy12. Academic Institutions13. References

For more information about this report visit https://www.researchandmarkets.com/r/sy4g72

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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Worldwide Cell Therapy Market Projections to 2028 - The Largest Expansion Will Be in Diseases of the Central Nervous System, Cancer and Cardiovascular...

Recommendation and review posted by Bethany Smith

Boston Children's Hospital researchers used an investigational gene therapy to treat heart failure in a mouse model of Barth syndrome. Barth syndrome is a rare genetic disorder in boys that results in life-threatening heart failure. It also causes weakness of the skeletal muscles and the immune system. The disease is caused by a mutation of a gene known as tafazzin or TAZ.

In 2014, William Pu and researchers at Boston Childrens Hospital collaborated with the Wyss Institute to develop a beating heart on a chip model of Barth syndrome. It used heart-muscle cells with the TAZ mutation that came from patients own skin cells. This was able to prove that TAZ was the cause of the cardiac problems. The heart muscle cells did not organize normally and the mitochondria, the cells energy engines, were disorganized, resulting in the heart muscle contracting weakly. By adding healthy TAZ genes, the cells behaved more normally.

The next step was an animal model. The results of the research were published in the journal Circulation Research.

The animal model was a hurdle in the field for a long time, Pu said. Pu is director of Basic and Translational Cardiovascular Research at Boston Childrens and a member of the Harvard Stem Cell Institute. Efforts to make a mouse model using traditional methods had been unsuccessful.

Douglas Strathdees research team at the Beatson Institute for Cancer Research in the UK recently developed animal models of Barth syndrome. Pu, research fellow Suya Wang, and colleagues characterized the knockout mice into two types. One had the TAZ gene deleted throughout the body; the other had the TAZ gene deleted just in the heart.

Most of the mice that had TAZ deleted throughout their whole bodies died before birth, likely from skeletal muscle weakness. Of those that survived, they developed progressive cardiomyopathy, where the heart muscle enlarges and is less able to pump blood. The heart also showed signs of scarring similar to humans with dilated cardiomyopathy, where the hearts left ventricle is dilated and thin-walled.

The mice that lacked TAZ only in their heart tissue that survived to birth had the same features. Electron microscopy indicated that the heart muscle cells and mitochondria were poorly organized.

Pu and Wang and their team then used gene therapy to replace TAZ in the newborn mice and in older mice, using slightly different techniques. In the newborn mice the engineered virus was injected under the skin; in the older mice it was injected intravenously. The mice who had no TAZ in their bodies and received the gene therapy survived to adulthood.

In the newborn mice receiving the gene therapy, the therapy prevented cardiac dysfunction and scarring. In the older mice receiving the therapy, it reversed the cardiac dysfunction.

The study also showed that TAZ gene therapy offered durable treatment of the cardiomyocytes and skeletal muscle cells, but only when at least 70% of the heart muscle cells had taken up the gene via the therapy. Which the researchers point out that when the therapy is developed for humans, that will be the most challenging problem. You cant just scale up the dose because of inflammatory immune responses, and multiple doses wont work either because the body develops an immune response. Maintaining the gene-corrected cell is also a problem. In the heart muscles of the treated mice, the corrected TAZ gene stayed relatively stable, but slowly dropped in skeletal muscles.

The biggest takeaway was that the gene therapy was highly effective, Pu said. We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle.

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Gene Therapy Reverses Heart Failure in Animal Model of Barth Syndrome - BioSpace

Recommendation and review posted by Bethany Smith

In a talk at UAB on March 6, the NIH director shared his thoughts on exceptional opportunities for science and young scientists and highlighted several exciting UAB projects.

NIH Director Francis Collins, M.D., Ph.D., visited UAB on March 6. In addition to his public talk, Collins had breakfast with UAB medical students and met with groups of young researchers and other investigators across campus.Speaking to a packed University of Alabama at Birmingham audience March 6, Francis Collins, M.D., Ph.D., director of the National Institutes of Health, shared his picks of 10 areas of particular excitement and promise in biomedical research.

In nearly every area, UAB scientists are helping to lead the way as Collins himself noted in several cases. At the conclusion of his talk, Collins addedhis advice for young scientists. Here is Collins top 10 list, annotated with some of the UAB work ongoing in each area and ways that faculty, staff and students can get involved.

I am so jazzed with what has become possible with the ability to study single cells and see what they are doing, Collins said. They have been out of our reach now we have reached in. Whether you are studying rheumatoid arthritis, diabetes or the brain, you have the chance to ask each cell what it is doing.

Single-cell sequencing and UAB:Collins noted that Robert Carter, M.D., the acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, was a longtime faculty member at UAB (serving as director of the Division of Clinical Immunology and Rheumatology). For the past several years, UAB researchers have been studying gene expression in subpopulations of immune cells inpatients with rheumatoid arthritis.

Join in:Researchers can take advantage of the single-cell sequencing core facility in UABsComprehensive Flow Cytometry Core, directed by John Mountz, M.D., Ph.D., Goodwin-Blackburn Research Chair in Immunology and professor in the Department of Medicine Division of Clinical Immunology and Rheumatology.

Learn more:Mountz and other heavy users of single-cell sequencing explain how the techniqueslet them travel back in time and morein this UAB Reporter story.

The NIHsBRAIN Initiativeis making this the era where we are going to figure out how the brain works all 86 billion neurons between your ears, Collins said. The linchpin of this advance will be the development of tools to identify new brain cell types and circuits that will improve diagnosis, treatment and prevention of autism, schizophrenia, Parkinsons and other neurological conditions, he said.

Brain tech and UAB:Collins highlighted thework of BRAIN Initiative granteeHarrison Walker, M.D., an associate professor in the Department of Neurology, whose lab has been developing a more sophisticated way to understand the benefits of deep brain stimulation for people with Parkinsons and maybe other conditions, Collins said.

Join in:UABs planned new doctoral program in neuroengineering would be the first of its kind in the country.

Learn more:Find out why neuroengineering is asmart career choicein this UAB Reporter story.

Researchers can now take a blood cell or skin cell and, by adding four magic genes, Collins explained, induce the cells to become stem cells. These induced pluripotent stem (iPS) cells can then in turn be differentiated into any number of different cell types, including nerve cells, heart muscle cells or pancreatic beta cells. The NIH has invested in technology to put iPS-derived cells on specialized tissue chips. Youve got you on a chip, Collins explained. Some of us dream of a day where this might be the best way to figure out whether a drug intervention is going to work for you or youre going to be one of those people that has a bad consequence.

iPS cells at UAB:Collins displayed images of thecutting-edge cardiac tissue chipdeveloped by a UAB team led by Palaniappan Sethu, Ph.D., an associate professor in the Department of Biomedical Engineering and the Division of Cardiovascular Disease. The work allows the development of cardiomyocytes that can be used to study heart failure and other conditions, Collins said.

Join in:UABs biomedical engineering department, one of the leading recipients of NIH funding nationally, is a joint department of the School of Engineering and School of Medicine. Learn more about UABsundergraduate and graduate programs in biomedical engineering, and potential careers, here.

Learn more:See howthis novel bioprinterdeveloped by UAB biomedical researchers is speeding up tissue engineering in this story from UAB News.

We have kind of ignored the fact that we have all these microbes living on us and in us until fairly recently, Collins said. But now it is clear that we are not an organism we are a superorganism formed with the trillions of microbes present in and on our bodies, he said. This microbiome plays a significant role not just in skin and intestinal diseases but much more broadly.

Microbiome at UAB:Collins explained that work led by Casey Morrow, Ph.D., and Casey Weaver, M.D., co-directors of theMicrobiome/Gnotobiotics Shared Facility, has revealed intriguing information abouthow antibiotics affect the gut microbiome. Their approach has potential implications for understanding, preserving and improving health, Collins said.

Join in:Several ongoing clinical trials at UAB are studying the microbiome, including a studymodifying diet to improve gut microbiotaand an investigation of the microbiomes ofpostmenopausal women looking for outcomes and response to estrogen therapy.

Learn more:This UAB News storyexplains the UAB researchthat Collins highlighted.

Another deadly influenza outbreak is likely in the future, Collins said. What we need is not an influenza vaccine that you have to redesign every year, but something that would actually block influenza viruses, he said. Is that even possible? It just might be.

Influenza research at UAB:Were probably at least a decade away from a universal influenza vaccine. But work ongoing at UAB in the NIH-fundedAntiviral Drug Discovery and Development Center(AD3C), led by Distinguished Professor Richard Whitley, M.D., is focused on such an influenza breakthrough.

Join in:For now, the most important thing you can do to stop the flu is to get a flu vaccination. Employees can schedule afree flu vaccination here.

Learn more:Why get the flu shot? What is it like? How can you disinfect your home after the flu? Get all the information atthis comprehensive sitefrom UAB News.

The NIH has a role to play in tackling the crisis of opioid addiction and deaths, Collins said. The NIHs Helping to End Addiction Long-term (HEAL) initiative is an all-hands-on-deck effort, he said, involving almost every NIH institute and center, with the goal of uncovering new targets for preventing addiction and improving pain treatment by developing non-addictive pain medicines.

Addiction prevention at UAB:A big part of this initiative involves education to help professionals and the public understand what to do, Collins said. The NIH Centers of Excellence in Pain Education (CoEPE), including one at UAB, are hubs for the development, evaluation and distribution of pain-management curriculum resources to enhance pain education for health care professionals.

Join in:Find out how to tell if you or a loved one has a substance or alcohol use problem, connect with classes and resources or schedule an individualized assessment and treatment through theUAB Medicine Addiction Recovery Program.

Learn more:Discover some of the many ways that UAB faculty and staff aremaking an impact on the opioid crisisin this story from UAB News.

We are all pretty darn jazzed about whats happened in the past few years in terms of developing a new modality for treating cancer we had surgery, we had radiation, we had chemotherapy, but now weve got immunotherapy, Collins said.

Educating immune system cells to go after cancer in therapies such as CAR-T cell therapy is the hottest science in cancer, he said. I would argue this is a really exciting moment where the oncologists and the immunologists together are doing amazing things.

Immunotherapy at UAB:I had to say something about immunology since Im at UAB given that Max Cooper, whojust got the Lasker Awardfor [his] B and T cell discoveries, was here, Collins said. This is a place I would hope where lots of interesting ideas are going to continue to emerge.

Join in:The ONeal Comprehensive Cancer Center at UAB is participating in a number of clinical trials of immunotherapies.Search the latest trials at the Cancer Centerhere.

Learn more:Luciano Costa, M.D., Ph.D., medical director of clinical trials at the ONeal Cancer Center, discusses the promise ofCAR-T cell therapy in this UAB MedCast podcast.

Assistant Professor Ben Larimer, Ph.D., is pursuing a new kind of PET imaging test that could give clinicians afast, accurate picture of whether immunotherapy is workingfor a patient in this UAB Reporter article.

The All of Us Research Program from NIH aims to enroll a million Americans to move away from the one-size-fits-all approach to medicine and really understand individual differences, Collins said. The program, which launched in 2018 and is already one-third of the way to its enrollment goal, has a prevention rather than a disease treatment approach; it is collecting information on environmental exposures, health practices, diet, exercise and more, in addition to genetics, from those participants.

All of Us at UAB:UAB has been doing a fantastic job of enrolling participants, Collins noted. In fact, the Southern Network of the All of Us Research Program, led by UAB, has consistently been at the top in terms of nationwide enrollment, as School of Medicine Dean Selwyn Vickers, M.D., noted in introducing Collins.

Join in:Sign up forAll of Usat UAB today.

Learn more:UABs success in enrolling participants has led to anew pilot study aimed at increasing participant retention rates.

Rare Disease Day, on Feb. 29, brought together hundreds of rare disease research advocates at the NIH, Collins said. NIH needs to play a special role because many diseases are so rare that pharmaceutical companies will not focus on them, he said. We need to find answers that are scalable, so you dont have to come up with a strategy for all 6,500 rare diseases.

Rare diseases at UAB: The Undiagnosed Diseases Network, which includes aUAB siteled by Chief Genomics Officer Bruce Korf, M.D., Ph.D., is a national network that brings together experts in a wide range of conditions to help patients, Collins said.

Participants in theAlabama Genomic Health Initiative, also led by Korf, donate a small blood sample that is tested for the presence of specific genetic variants. Individuals with indications of genetic disease receive whole-genome sequencing. Collins noted that lessons from the AGHI helped guide development of the All of Us Research Program.

Collins also credited UABs Tim Townes, Ph.D., professor emeritus in the Department of Biochemistry and Molecular Genetics, for developing the most significantly accurate model of sickle cell disease in a mouse which has been a great service to the [research] community. UAB is now participating in anexciting clinical trial of a gene-editing technique to treat sickle cellalong with other new targeted therapies for the devastating blood disease.

Join in:In addition to UABs Undiagnosed Diseases Program (which requires a physician referral) and the AGHI, patients and providers can contact theUAB Precision Medicine Institute, led by Director Matt Might, Ph.D. The institute develops precisely targeted treatments based on a patients unique genetic makeup.

Learn more:Discover how UAB experts solved medical puzzles for patients by uncovering anever-before-described mutationandcracking a vomiting mysteryin these UAB News stories.

We know that science, like everything else, is more productive when teams are diverse than if they are all looking the same, Collins said. My number one priority as NIH director is to be sure we are doing everything we can to nurture and encourage the best and brightest to join this effort.

Research diversity at UAB:TheNeuroscience Roadmap Scholars Programat UAB, supported by an NIH R25 grant, is designed to enhance engagement and retention of under-represented graduate trainees in the neuroscience workforce. This is one of several UAB initiatives to increased under-represented groups and celebrate diversity. These include several programs from theMinority Health and Health Disparities Research Centerthat support minority students from the undergraduate level to postdocs; thePartnership Research Summer Training Program, which provides undergraduates and especially minority students with the opportunity to work in UAB cancer research labs; theDeans Excellence Award in Diversityin the School of Medicine; and the newly announcedUnderrepresented in Medicine Senior Scholarship Programfor fourth-year medical students.

Join in:The Roadmap program engages career coaches and peer-to-peer mentors to support scholars. To volunteer your expertise, contact Madison Bamman atmdbamman@uab.eduorvisit the program site.

Learn more:Farah Lubin, Ph.D., associate professor in the Department of Neurobiology and co-director of the Roadmap Scholars Program,shares the words and deeds that can save science careersin this Reporter story. In another story, Upender Manne, Ph.D., professor in the Department of Pathology and a senior scientist in the ONeal Comprehensive Cancer Center, explains how students in the Partnership Research Summer Training Program gethooked on cancer research.

In answer to a students question, Collins also shared his advice to young scientists. One suggestion: Every investigator needs to be pretty comfortable with some of the computational approaches to science, Collins said. Big data is here artificial intelligence, machine-learning. We can all get into that space. But its going to take some training, and it will be really helpful to have those skills.

Join in:UAB launched aMaster of Science in Data Scienceprogram in fall 2018.

Learn more:Discover how UAB researchers areusing machine-learning in their labsand toimprove cancer treatment. Those looking for a free introduction cantake advantage of the Data Science Clubfrom UAB IT Research Computing.

See more here:
Looking to the future with Dr. Francis Collins - UAB News

Recommendation and review posted by Bethany Smith

The novel coronavirus disease 2019 (COVID-19) has grown to become a global public health emergency. Currently, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. Hence, there is a large unmet need for a safe and effective treatment for COVID-19 infected patients, especially the severe cases. A new study offers a promising pathway for developing such a treatment.

The new approach involves intravenous transplantation of mesenchymal stem cells (MSCs) into the patients. It was successfully tested in 7 COVID-19 patients, in Beijing YouAn Hospital, Capital Medical University, China. The results are published in the scientific journal Aging and Disease, entitled "Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia".

http://www.aginganddisease.org/article/0000/2152-5250/ad-0-0-216.shtml

The study was conducted by a team led by Dr. Robert Chunhua Zhao, with Shanghai University and Chinese Academy of Medical Sciences & Peking Union Medical College, China.

Moreover the study was reviewed by a scientific committee of the International Society on Aging and Disease (ISOAD) and the recently established UNESCO-affiliated committee on Anti-Aging and Disease Prevention http://www.aginganddisease.org/article/2020/2152-5250/ad-11-1-212.shtml

Based on the 14 days observation, MSCs could cure or significantly improve the functional outcomes of all the seven tested patients without observed adverse effects, contrary to 3 controls. The pulmonary function and symptoms of these seven patients were significantly improved after MSC transplantation. Among them, one severe and two common patients recovered and were discharged in 10 days after the treatment. The improvement was particularly dramatic for an elderly (65 y.o.) male patient in severe critical condition. All of his primary and secondary outcomes improved: the inflammation status, the oxygen saturation, and the functional biochemical indicators returned to normal reference values in 2~4 days after the treatment.

The presented evidence suggests that the therapeutic effects are based on the immunomodulatory capacity of mesenchymal stem cells (restoring the balance of the immune system). The coronavirus infection can stimulate a terrible cytokine storm in the lung, disrupting the balance of cytokines (signaling molecules of the immune system) such as IL-2, IL-6, IL-7, GSCF, IP10, MCP1, MIP1A and TNF cytokines, followed by the edema, dysfunction of the air exchange, acute respiratory distress syndrome, acute cardiac injury and the secondary infection, which may lead to death. The bone-marrow derived MSCs could inhibit the over-activation of the immune system and promote endogenous repair by improving the microenvironment, thus they could represent a safe and effective treatment for patients with COVID-19 pneumonia, especially for the patients in critically severe conditions. A larger validation study is required and is already underway, yet the initial results are encouraging.

Notably, the coronavirus-infected pneumonia is more likely to affect older individuals, especially older males, with comorbidities, resulting in their severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In other words, aging appears to be the main risk factor for bad outcomes. However, the cure essentially depends on the patient's own immune system. When the overactivated immune system kills the virus, it produces a large number of inflammatory factors, leading to the severe cytokine storms. This suggests that the main reason for the organs damage may be the virus-induced cytokine storm. Older subjects may be much easier to be affected due to immunosenescence. The study showed remarkable recovery of the elderly patients thanks to restoring their immune function.

Thus, the study may have a broader significance, even beyond the treatment of the severe coronavirus disease. This study exemplifies that the general therapeutic improvement of the immune system in the elderly can improve outcome and survival, which may have more general relevance for other aging-related communicable diseases. Thus, this study may inspire and pave the way for further promising directions to investigate the connection between aging and disease, and to treat both communicable and non-communicable aging-related diseases.

The Romanian journalist Laura tefnu spoke with Dr. Ilia Stambler about the broader implications of this research. Ilia Stambler is a co-author in this study who was involved in the study review, interpretation and discussion. He serves as the Outreach Coordinator of the International Society on Aging and Disease (ISOAD) and Director of Research and Development at Shmuel Harofe Geriatric Medical Center in Israel.

Q: How does it feel to be part of the team which discovered a groundbreaking treatment for what is currently considered one of the biggest global challenges?

A: I feel very honored to be included in this extended international team. I hope this team continues its work that will also involve additional collaborations.

Q: As a researcher, what did you find most interesting about this novel coronavirus? What seems most threatening about this new virus?

A: The spreading ability of this virus is relatively high and it has the capacity to affect the entire global population. This is what makes this virus a particularly strong concern for global public health. The social effects of this epidemic are also of great importance. In a sense, this virus is testing the strength of our public health systems. Will the immunity of our public healthcare be strong enough to contain it? I hope it is.

Q: Did the discovery of this groundbreaking new therapeutic approach make you more optimistic (when it comes to containing and limiting the damage of Covid-19)? In which sense (where was your optimism before the discovery)?

A: I was optimistic before, as I believe that, same as for many infectious diseases in the past, also for this disease, effective therapeutic and preventive measures will be found and used. This work further increased my optimism. Of course, this is an initial study, and this is only one of the potential means in the therapeutic, preventive and hygienic arsenal. More research and confirmation will be needed. Yet, even at this stage, the clear positive result of this study shows that it is indeed possible to improve the outcomes for COVID-19 patients even in severe conditions. Moreover, it gives more hope that effective treatments can be sought and found also for other aging-related infectious diseases and conditions.

Q: Is there an explanation regarding the reasons why Covid-19 seems to pardon children and affects the most elder individuals, especially men?

A: There is yet no clear or fully agreed explanation. But a plausible cause may be due to the so called immuno-senescence phenomenon, or the inability of the aging immune system to cope with new threats and restore the immune balance following the infection. In men the immuno-senescence effects are often more strongly present than in women. Thus, aging appears to be the main risk factor for this disease and if we really wish to defeat this epidemic, we need to address this main risk factor, in other words, we need to therapeutically intervene and ameliorate the degenerative aging process. The proposed mesenchymal stem cell therapy shows the so-called immuno-modulation effects or the ability to generally improve the immune system, help restore the immune balance after disturbances, especially for the elderly. And this can be the more general explanation for its effects against the aging-related COVID-19 pneumonia, as well as potentially other aging-related diseases.

Q: How did you manage to find so fast a treatment that is responding so well?

A: The mesenchymal stem cell treatment has been researched and developed by Dr. Zhao and his team for many years, and indicated positive effects for multiple health conditions. It is exactly because of the common and critical role of the immune system impairment in all these conditions, that the treatment developed by Dr. Zhaos team was already in place and could be immediately used also for this condition dependent on the immune function. Moreover, the success of this therapy against COVID-19 can further boost the research and therapy of other immunity-dependent health conditions and diseases, especially aging-related diseases, due to the common mechanisms of action.

Q: How may this discovery change the game?

A: Unlike other public health measures, like quarantine and hygiene, that can be very quickly applied, the research, development, regulatory approval and application of new therapies is a much slower process. So we should first of all apply the public health measures to contain the epidemic. But the hope is that this therapy will undergo further research and validation as soon as possible, and in case of validated efficacy and safety, will be used in as many patients who need it as possible, as soon as possible. That is exactly why we need to accelerate the research, development and application of promising new therapies. When the new therapy enters wide clinical practice, there are grounds to believe it can improve the health and even save the lives of many patients, not only suffering from COVID-19, but also other conditions.

Q: Which was the response/reaction of authorities after you published the results of your research?

A: The outreach to the authorities in several countries has only started. Moreover, the study is only initial and it is too early to make policy recommendations. A larger validation study is required. Yet, if there is even a slight possibility this could become a life-saving therapy for COVID-19 patients and others, this opportunity should not be missed by the decision makers.

Q: Some treatments are more expensive than others. Will the treatment you discovered be accessible to people, or the cost for producing it will limit its accessibility?

A: The cells for this treatment can be mass produced and can be rather affordable. Of course, the actual price will depend both on the scale of production and pricing policies. And this is already a question that goes beyond pure technology, but becomes a question about the social means to make new therapies available to all. This should also be a crucial part of the public discussion about the social need to promote the rapid research and development as well as broad application of new therapies that are proven to be safe and effective.

Q: Which are the best measures a country can take to limit the spread and the consequences of the novel coronavirus?

The usual quarantine and public hygiene measures are the most feasible and effective: minimization of large gatherings, minimization of travel, cleanliness. We should hope and work for new effective therapies to arrive as soon as possible. But so far public health measures are the most effective and feasible.

Ilia Stambler is an IEET Affiliate Scholar. He completed his PhD degree at the Department of Science, Technology and Society, Bar-Ilan University. His thesis subject, and his main interest, is the History of Life-extensionism in the 20th Century.

See more here:
A new therapeutic approach against COVID-19 Pneumonia - Institute for Ethics and Emerging Technologies

Recommendation and review posted by Bethany Smith

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

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Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Report on Recent Adoption 2025 3rd Watch News - 3rd Watch News

Recommendation and review posted by Bethany Smith

Women have two X chromosomes (homogametic sex), while men have an X and a Y (heterogametic sex). The unguarded X hypothesis suggests that as our chromosomes age, men dont have a backup plan when their X begins to falter, having a Y leaves that X unprotected. Alternatively, there is the toxic Y hypothesis, where the Y acts as a bit of a rogue adversely altering gene expressions and mutations. A group of researchers considered the life-span across all the species where two genes created homogametic or heterogametic genders. Their data set included 229 species, 99 families, 38 orders and eight classes [1]

Across a wide range of species including us mammals, insects, reptiles, and ray-finned fish (fish whose fins are supported by a bony infrastructure), the homogametic gender on average lives 17.6% longer. As it turns out, in birds, moths, and butterflies, the male is homogametic (noted as ZZ), and the female is heterogametic (ZW). Again, the homogametic gender lives longer. So it seems that the unguarded X hypothesis contains some truth.

The second finding by the researchers suggests a limit to the effect of an unguarded X.

that when males are heterogametic sex they die 20.9% earlier than their female counterparts, but when females are the heterogametic sex, they die only 7.1% earlier than their male counterparts.

Why might that be? The researchers suggest that those lonely Ys, and for the birds, their W genes are more degraded than those lusty Xs and Zs. Or that estrogen is protective of telomere length, or that the higher mortality in males [is a] side effects of sexual selection wooing and mating takes a lot out of us. In any case, an unguarded X fails to explain everything.

While we are tossing candidate theories into the ring, might I suggest that the 13.8% higher mortality for heterogametic males than heterogametic females has to do with estrogen, testosterone, and their effect on lifestyle? Men are less risk-averse; they take more chances, and perhaps that is fueled, in part by the testosterone milieu that baths their brains. Women, and yes, I recognize the generalization, maybe a little more risk-sensitive. Women are less likely to smoke than men, less likely to be overweight (although they are more likely to be obese), men tend to drive faster and are involved in many more high-speed car accidents.

Once again, it is not a question of nature or nurture, but how much do genetics and lifestyle contribute and interact in our life-span. It seems that in reality, at least for us mammals, men are the weaker sex.

[1] A refresher, the classifications are, Domain, Kingdom, Phyla, Class, Order, Family, Genus, Species

Source: The sex with the reduced sex chromosome dies earlier: a comparison across the tree of life

Biology Letters DOI: 10.1098/rsbl.2019.0867

Read the rest here:
Men, The Truly Weaker Sex - American Council on Science and Health

Recommendation and review posted by Bethany Smith

As sweeping efforts to contain theCOVID-19 pandemic go into effect around the globe, researchers are starting toget hints of just when patients are most contagious.

People infected with the SARS-CoV-2virus, which causes the disease, may test positive for the virus both beforeand after they have symptoms. But a new study of nine people who contracted thevirus in Germany suggests that people are mainly contagious before they havesymptoms and in the first week of the disease.

Infectious viruses were isolated fromabout 17 percent of nose and throat swabs and more than 83 percent of phlegmsamples during that first week, researchers report March 8 in a study posted atmedRxiv.org.

Patients produced thousands to millionsof viruses in their noses and throats, about 1,000 times as much virus as producedin SARS patients, Clemens Wendtner, director of infectious disease and tropicalmedicine at Munich Clinic Schwabing, a teaching hospital, and his colleaguesfound. That heavy load of viruses may help explain why the new coronavirus isso infectious.

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Scientists identified these nine peoplesome time after they had been exposed to the coronavirus, so researchers dontknow for sure when exactly people begin giving off virus. After the eighth dayof symptoms, however, the researchers could still detect the viruss geneticmaterial, RNA, but they could no longer find infectious viruses. Thats anindication that antibodies that the bodys immune system makes against SARS-CoV-2are killing viruses that get out of cells, Wendtner says.

The study brings an important point tolight; finding RNA or pieces of a virus in a swab or sample is no guaranteethat the virus is live, or infectious, says Ali Khan, dean of the College ofPublic Health at the University of Nebraska Medical Center in Omaha. Some ofit is discouraging news because when you are mildly [ill] or just [getting]sick, youre putting out a whole lot of virus, which explains why were seeingso much transmission within our communities, says Kahn, was not involved in thestudy.

But theres encouraging news, too.Plummeting numbers of infectious virus after antibody production turns onmeans that after about 10 days or so, youre not likely to be infecting otherpeople, Khan says. Other studies also suggest that people with very mild orasymptomatic infections dont shed as much virus and arent as likely to infectother people as people with more severe cases, he says.

Wendtner and colleagues put the nine patientsthrough tests every morning during their hospital stay, collecting blood,urine, stool, nasal and throat swabs and asking the people to cough up sputum,or phlegm. We were learning with the patients because we did not know whenwould be the best and safest time to discharge them, Wendtner says.

The high levels of virus shedding fromthe nose and throat happened very early in infection by the time of testing,most patients upper airway virus production had already peaked. As theinfection progresses, the virus moves deeper into the lungs, the findingssuggest.

The team never found evidence of thevirus in blood or urine and has stopped collecting those samples from a secondwave of 23 COVID-19 patients now being treated at the hospital. Researchersdid detect viral RNA in feces, but no infectious virus there. That suggeststhat the virus isnt spread through stool, an unknown until now.

All nine patients are employees ofWebasto, an auto supplier in Stockdorf. They caught the virus from a malecoworker, who became known as Patient 1. He originally got the virus from abusiness colleague from Shanghai who came to Germany in January for aseries of meetings (SN: 1/31/20). BothPatient 1 and his Shanghai colleague transmitted the virus before developingsymptoms, the first documented cases of asymptomatic spread.

As health officials tested otheremployees of the company, they found the study participants and placed them inisolation at the Munich clinic. In one case, Patient 1 sneezed during a meetingwith one person, Wendtner says. That was enough for infection. In othercases, they had simple business meetings, sitting together for 60 minutes, 90minutes [at a table or] in front of a computer, with no physical contact justone handshake, thats all, Wendtner says. The infectivity is quite high.

Most had coughs, but only two developeda fever, the most common symptom reported in other studies. Most symptoms were mild and one person neverdeveloped any at all. One patient developed severe pneumonia.

Two of the nine had runny noses,previously reported as a rare symptom of COVID-19. Another four had stuffynoses and reported that they couldnt smell or taste anything. In all of ourpatients, it cleared up, but it was a little bit annoying for two weeks or so,Wendtner says. They could order anything they wanted [to eat], but [if] youcant taste it, it doesnt matter.

A temporary lack of smell or taste also affectedsome SARS patients in 2003, he says. That symptom may indicate that in additionto causing swelling in the nose, the virus may infect nerve cells responsiblefor identifying odors, he says.

Patients in the study started makingantibodies against the virus about six to 12 days after symptoms started. Onceantibody production kicked in, researchers still found high levels of viral RNAin phlegm and in nose and throat swabs, but patients were no longer giving offinfectious virus.

The early and extreme contagiousness of the virus tell us that gatherings of people should be avoided, Wendtner says. But the results also may suggest that isolation periods could be shorter for people who have RNA but no virus. Researchers thought that because tests could still detect RNA for up to weeks after symptoms had cleared (SN: 2/28/20), patients were infectious for that long. Most patients are not released from the hospital until two separate tests within 24 hours come back negative, Wendtner says.

But Wendtner isnt suggesting letting people out of quarantine before their two weeks are up. Fourteen days is safe, and you have to keep it simple, Wendtner says. Maybe its safe 10 days after symptoms start, but you have to prove they have those neutralizing antibodies. Tests for the antibodies, however, are not widely available.

The reliable science journalism you count on is expensive. It takes professional reporters, editors, fact checkers, designers and digital producers to make sureScience Newsreflects the depth and breadth of science.We need your financial support to make it happen every contribution makes a difference.

Originally posted here:
Coronavirus is most contagious before and during the first week of symptoms - Science News

Recommendation and review posted by Bethany Smith

March 13, 2020 -Once people are aware of the issues surrounding genomic data sharing, collection, and security, individuals are more concerned with how their information will be used and expect to receive compensation for providing it, according to a survey published in PLOS One.

As the potential for personalized therapies continues to grow and genetic testing becomes more widely available, genomics entities have to find ways to advance the field while still protecting peoples genetic data.

The use of human genomic data collections is expanding, fueled by declining technological costs and enthusiasm for the promise of precision medicine, researchers said.

Accordingly, various organizations responsible for managing enormous genomic biobanks are developing and refining their governance systemsi.e., the organizational structures and policies that shape data collection, data integrity, data end uses, transparency, stakeholder input processes, and data securityseeking to balance the benefits of broad data use with the need to mitigate risk and meet societal responsibilities.

It's essential to measure the publics expectations surrounding the collection and use of genomic data, the research team stated. Prior research in this area has focused on the context of research biobanks owned by academic institutions, the group said, and has highlighted the idea that individuals providing their data are acting as altruistic donors.

READ MORE: Data Sharing Standards Needed to Address Patients SDOH

Findings in this context suggest that most participants, within the sole context of non-profit research biobanks, are generally willing to donate their data, are comfortable with indefinite use of their data, and are reassured by moderate privacy protections, the team said.

Yet the context of previous research presents an incomplete profile of public expectations for genetic database governance. We note that governance expectations for genetic databases in the future will be informed by two developing social phenomena: growing awareness of both the commercial value of genomic data and the emerging privacy risks for individuals providing data.

Researchers set out to assess individuals willingness to contribute genomic data to both nonprofit and for-profit organizations, as well as respondents views on genomic governance policies. The team provided 2,020 survey participants with a three-minute video created from mainstream coverage of genomic databases.

The group then asked participants questions about how governance policies or the ways genomic data is used, secured, and regulated would impact respondents willingness to provide data and the compensation they expect to receive.

The results showed that just 11.7 percent of respondents were willing to provide their data as an altruistic donation, while 50.6 percent said they would be willing to provide it if compensated with a payment of some amount. Nearly 38 percent said they were unwilling to provide it even if payment was available.

READ MORE: Can Healthcare Overcome Its Past Pitfalls to Leverage Genomic Data?

The researchers noted that these results contrast with previous surveys that focused on donating genomic data to academic research biobanks, which consistently report rates of willingness above 50 percent.

When people were more informed, they were a lot more interested in requiring greater security for their data, and they were a little bit more hesitant to give it up, said Ifeoma Ajunwa, assistant professor of labor relations, law and history at Cornell University and co-author of the study.

The team also evaluated the dollar amounts that people were seeking in exchange for their data. The median reported value among individuals was $130, which mirrors the amount paid per genome in a recent commercial transaction summarized in the video shown to participants.

This finding suggests that the pre-survey video influenced perceptions and responses, reflecting what could happen as individuals encounter real-life information alerting them to the value of genetic data.

In addition to compensation, the survey asked participants how 12 specific policies would impact their willingness to provide genomic data. The three policies that made them most willing to provide it were the ability to request their data to be deleted; assurance that their data wouldnt be sold or shared; and requiring specific permissions to use the data.

READ MORE: FDA Recognizes Genomic Database to Advance Precision Medicine

The three policies that decreased willingness the most were selling database access to pharmaceutical firms; providing data to the federal government; and retaining the data indefinitely without a specified date for destruction.

These results demonstrate the importance individuals place on control when it comes to data sharing.

A common denominator across these governance policy findings is a preference for restrictions on sharing or reuse, unless permission is specifically granted by the individual, researchers said.

These preferences appear to pose a challenge for the goals and business models of many database-owning organizations, which often envision that their databases will serve multiple, not-necessarily-specified scientific and commercial purposes, through access arrangements with multiple outside partners. This tension appears to hold equally for commercial as well as public organizations.

The group concluded that based on these findings, a one-size-fits-all approach wont meet public expectations for genomic data governance. Future research will need to continually evaluate evolving attitudes about genomic databases.

People need to know the full worth of their genetic data in order to make an informed consent, Ajunwa said. How much is the data worth, what kinds of safeguarding are necessary, is it OK to have something in digital form and therefore more vulnerable? There are all of these outstanding questions to be answered.

See the rest here:
More Than 50% of People Expect Compensation for Genomic Data Sharing - HealthITAnalytics.com

Recommendation and review posted by Bethany Smith

The clinic helps children at risk of developing heart disease in the future due to high cholesterol.

They can now attend a ground-breaking clinic run by the familial hypercholesterolemia (FH) service at York Teaching Hospital NHS Foundation Trust.

FH is an inherited condition which can lead to extremely high cholesterol levels and is passed down through families in the genes.

The FH service, led by Dr Chandrajay, Consultant in Chemical Pathology and Metabolic Medicine, and Claire Tuson, Familial Hypercholesterolaemia Specialist Nurse, has recently extended their service to include children and adolescents.

Claire explained: Research has shown that children with FH start to develop a build-up of fatty plaque in their arteries before the age of 10. Once diagnosed, FH is easy to treat so it makes sense to work with families as soon as possible.

Last year, with the support of Consultant Paediatrician Dr Dominic Smith, we extended gene testing to all children aged 10 years old and over, who have a parent affected with FH. Testing children for FH could prevent a potentially fatal heart attack or stroke.

The first six children from York and Scarborough that were identified with FH have recently attended our new Yorkshire and Humber joint paediatric clinic for children and their families, which launched at the end of January.

FH is estimated to affect 1 in 250 people in the UK, including over 56,000 children.

It is an inherited disorder of cholesterol and lipid metabolism, caused by an alteration in a single gene where people have higher levels of bad cholesterol levels from birth. If left undetected and untreated FH can lead to the early development of heart and circulatory problems.

Kiera Pickering, aged 12, and her brother Connor, aged 11, from Scarborough, were two of the first children to attend the clinic.

Claire added: Its a real breakthrough to be able to identify and treat children with FH so early. Alongside dietary and lifestyle advice to maintain a healthy body weight, children can be considered for statin therapy from as young as 10 years old.

"Statin treatment can not only prevent, but potentially reverse, the build-up of cholesterol and allow children and young people to live a perfectly healthy life.

Despite the availability of genetic testing, more than 85 percent of people with FH in the UK are undiagnosed.

The British Heart Foundation estimates that currently only around 600 children in the UK have been diagnosed with FH, meaning that thousands more are not on treatment and remain unaware of their future risk of heart disease.

For more information about the FH clinics contact claire.tuson@york.nhs.uk

Original post:
Scarborough brother and sister, aged 11 and 12, with the genetic cholesterol condition FH are helped by new clinic - The Scarborough News

Recommendation and review posted by Bethany Smith

The latest research report on the Direct-Access Genetic Testing Market published by Verified Market Research provides a profound awareness of the various market dynamics such as Trends, drivers, challenges and opportunities. The report explains in more detail the micro and macroeconomic elements that are expected to influence the growth of the Direct-Access Genetic Testing Market over the forecast period (2020-2026).

The Global Direct-Access Genetic Testing Market is growing at a faster pace with substantial growth rates over the last few years and is estimated that the market will grow significantly in the forecasted period i.e. 2019 to 2026.

This study highlights the key indicators of market growth that accompany a comprehensive analysis of this value chain, CAGR development, and Porters Five-Force Analysis. This data can enable readers to understand the quantitative growth parameters of this international industry, which is Direct-Access Genetic Testing.

The report also highlights the opportunities and future scope of the Direct-Access Genetic Testing Market on a global and regional level. The study includes a market attractiveness analysis in which the Service is evaluated based on Market Size, Growth Rate and general bioinformatics software industry share.

Segmentation:

The Direct-Access Genetic Testing Market has been divided into several important areas, including applications, types and regions. Each market segment is intensively examined in the report to take into account its market acceptance, value, demand and growth prospects. The segmentation analysis helps the customer to adapt their marketing approach so that they better master each Segment and identify the most potential customer base.

Regional insights into the Direct-Access Genetic Testing market

In terms of Region, this research report covers almost all major regions of the world, such as North America, Europe, South America, the Middle East, Africa and the Asia-Pacific region. Growth is expected for the regions of Europe and North America in the coming years. While the Direct-Access Genetic Testing Market in the regions in the Asia-Pacific region is expected to show remarkable growth in the forecast period. Cutting-edge technology and innovation are the key features of the North America Region, and this is why the US dominates global markets most of the time. The Direct-Access Genetic Testing Market in the South America region is also expected to grow in the near future.

Important questions answered in the report:

What is the main factor that takes this market to the next level?

What will the market demand and what will be growth?

What are the latest opportunities for the Direct-Access Genetic Testing Market in the future?

What are the strengths of the main players?

What is the key to the Direct-Access Genetic Testing Market?

The Direct-Access Genetic Testing Market report provides future growth drivers and the competitive landscape. This will be beneficial for buyers of the market report in order to obtain a clear overview of the important growth and subsequent market strategy. The detailed information on the market will help to monitor future profitability and make important decisions for growth.

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Market share analysis for the segments at regional and country level.

Bioinformatics software market share analysis of the best business players.

Strategic proposal for new entrants.

Market forecasts for the next five years of all segments, sub-segments and together of the regional markets.

Market opportunities, Trends, constraints, threats, challenges, drivers, investments, and proposals.

The Strategic Management in key business areas supported the market estimates.

Competitive landscape design that reflects the most important common Trends.

Company identification with careful methods, financial data and previous developments.

Provide chain trends that reflect the most important technological advances of recent times.

The conclusion of the report shows the overall scope of the global Direct-Access Genetic Testing Market in terms of the feasibility of investments in the various market segments, as well as a descriptive Passage describing the feasibility of new projects that could be successful in the market in the near future.

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Direct-Access Genetic Testing Market 2020 By Top Key Players/Manufacturers, Type and Application, Regions, Industry Analysis, Growth, Size, Trends and...

Recommendation and review posted by Bethany Smith

Coconut oil comes from the copra the kernel or meat of coconuts.

It contains a high percentage of saturated fats, particularly from medium-chain triglycerides (MCTs).

Coconut oil has various applications in cooking, beauty, skin care, and health.

Along with these applications, it has been suggested that coconut oil increases testosterone levels and improves sexual function, but research on the topic is scarce.

This article discusses everything you need to know about coconut oils effect on testosterone levels in men.

Testosterone is a powerful hormone.

While both men and women produce it, men produce 20 times more than women (1).

In men, testosterone plays an important role in muscle and body hair growth, bone health, and sexual function, among other areas (2).

Testosterone levels peak in men around the age of 19 and decline by approximately 16% by age 40, on average (3).

Most of the testosterone in your blood is bound to two proteins albumin and sex hormone-binding globulin (SHBG).

SHBG is strongly bound to testosterone, making the hormone unavailable for use by your body, whereas albumin is weakly bound and can be used by your body with some effort.

The remaining testosterone, which is known as free testosterone, is not bound to proteins and can be readily used by your body.

Free testosterone and albumin-bound testosterone make up your bioavailable or usable testosterone (4).

The sum of your bioavailable and SHBG-bound testosterone make up your total testosterone.

Testosterone is the predominant male hormone that increases muscle mass, maintains bone strength, and regulates sexual function.

While testosterone levels are influenced by a number of lifestyle factors, such as diet and exercise, coconut oils effects on testosterone levels in humans remain largely unknown (5).

Still, coconut oil contains a high percentage of fat from MCTs about 54% in the form of lauric acid (42%), caprylic acid (7%), and capric acid (5%). These MCTs have been shown to affect a hormone similar to testosterone called dihydrotestosterone (DHT) (6, 7).

Your body uses an enzyme called 5-alpha reductase to convert about 5% of free testosterone to DHT (8, 9).

DHT performs many of the same functions as testosterone but is thought to contribute to male pattern hair loss (10).

Interestingly, MCTs especially lauric acid have been shown to block the enzyme that converts testosterone to dihydrotestosterone (DHT) in test-tube and animal studies (11, 12, 13).

Medications called 5-alpha reductase inhibitors, which are prescribed for the treatment of male pattern hair loss, work in the same way by blocking the 5-alpha reductase enzyme.

Still, studies in humans are needed to determine whether consuming MCTs from coconut oil helps prevent or treat male pattern hair loss, as the condition is also influenced by genetics (14).

Animal and test-tube studies have demonstrated that MCTs inhibit the enzyme that converts testosterone to DHT, a hormone linked to male pattern hair loss.

Low testosterone has been linked to erectile dysfunction (ED), the inability to get or maintain an erection (15).

The condition can be debilitating for men, cause embarrassment and low self-esteem, and lead to an unsatisfactory sex life.

The global prevalence of ED ranges from 377% and tends to become more common with age (16).

Specific foods, including coconut oil, have been suggested to increase testosterone and improve sexual function (17, 18).

Still, there is no evidence to suggest that coconut oil can directly increase testosterone or alleviate ED.

ED is common among people with diseases or conditions that affect the blood vessels, such as diabetes, high blood pressure, high cholesterol, and overweight or obesity (19).

If any of these are present, you may be able to reduce or improve ED with lifestyle changes, such as engaging in regular physical activity, consuming a diet rich in fruits and vegetables, maintaining a healthy weight, and not smoking (20).

There is no evidence to suggest that coconut oil increases testosterone or alleviates ED. Exercising regularly, consuming a healthy diet, and maintaining a healthy weight are lifestyle factors that may improve ED.

Coconut oil is an oil thats extracted from the copra or meat of coconuts.

It contains a high percentage of MCTs, which animal and test-tube studies have shown can block the enzyme that converts testosterone to DHT the hormone linked to male pattern baldness.

Still, evidence that coconut oil can help treat this condition is lacking.

While coconut oil has been suggested to alleviate ED and improve sexual function by increasing testosterone, there is no research to support this theory.

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Coconut Oil and Testosterone: Is There a Connection? - Healthline

Recommendation and review posted by Bethany Smith

Updated March 11, 2020 09:35:21

Two incredibly rare white giraffes have been killed by poachers in Kenya, a spokesperson for the local conservancy has confirmed, leaving only one remaining in the world.

The Ishaqbini Hirola Community Conservancy said the country's only female white giraffe and her calf were found in a "skeletal state after being killed by armed poachers".

The giraffes gained global attention in 2017 when they were first captured on film. After the deaths, only one young male white giraffe remains at the Hirola Conservancy.

"This is a very sad day for the community of Ijara and Kenya as a whole," the conservancy's Mohammed Ahmednoor said.

"We are the only community in the world who are custodians of the white giraffe. Its killing is a blow to tremendous steps taken by the community to conserve rare and unique species, and a wake-up call for continued support to conservation efforts."

Experts believe the giraffes have a rare genetic mutation known as leucism, which causes a partial loss of pigmentation.

"This is a long-term loss given that genetics studies and research, which were significant investment into the area by researchers, has now gone down the drain," Mr Ahmednoor said.

"Further to this the white giraffe was a big boost to tourism in the area."

The African Wildlife Foundation estimates that 40 per cent of the overall giraffe population has been lost in the past 30 years.

Topics:animals,human-interest,kenya

First posted March 11, 2020 09:26:08

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Two rare white giraffes killed by poachers, Kenyan conservancy says, leaving only one left on Earth - ABC News

Recommendation and review posted by Bethany Smith

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Male Breast Cancer Treatment Market trends and Future demand as well as Top Players Pfizer, Roche, GlaxoSmithKline, Sanofi, Novartis etc. - Galus...

Recommendation and review posted by Bethany Smith

Guilherme S Lopes,1,2 Suzette J Bielinski,2 Ann M Moyer,3 John Logan Black III,3 Debra J Jacobson,1 Ruoxiang Jiang,1 Nicholas B Larson,1 Jennifer L St Sauver2

1Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; 2Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; 3Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Correspondence: Guilherme S LopesDivision of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USATel +1 507 422 6094Email lopes.guilherme@mayo.edu

Background: Several small studies have previously investigated associations between the cytochrome P450 2D6 (CYP2D6) metabolism and response to opioids. We used a large sample of patients to study associations between CYP2D6 phenotypes and estimated CYP2D6 enzymatic activity scores with pain control and adverse reactions related to codeine and tramadol use. We conducted additional analyses to determine whether our results were consistent among men and women.Methods: We used data from 2,877 participants in the RIGHT Protocol who were prescribed codeine and/or tramadol between 01/01/2005 and 12/31/2017 and who were not prescribed CYP2D6 inhibitors within 1 year prior to the opioid prescription. CYP2D6 phenotype categories were condensed into four groups: (1) Ultra-rapid and Rapid (n = 61), (2) Normal and Intermediate to Normal (n = 1,448), (3) Intermediate and Intermediate to Poor (n = 1,175), and (4) Poor metabolizer status (n = 193). Opioid-related outcomes included indications of poor pain control or adverse reactions related to medication use. We modeled the risk of each outcome using logistic regression, adjusting for age, sex, race, and ethnicity.Results: The results revealed a trend from poor to ultra-rapid and rapid CYP2D6 phenotypes in which the risk of adverse reactions incrementally increased and the risk of poor pain control incrementally decreased. This trend reached statistical significance among female (but not male) participants. Among normal and intermediate to normal metabolizers, a larger proportion of women experienced adverse reactions relative to men.Discussion: We replicated and extended the findings of previous research indicating associations between CYP2D6 phenotypes and response to opioids. In addition, the observed associations were stronger in women than in men. We recommend sex differences to be factored in future research investigating associations between pharmacogenomics and response to medications.

Keywords: opioids, codeine, tramadol, pharmacogenomics, sex differences, CYP2D6

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Sex Differences in Associations Between CYP2D6 Phenotypes and Response | PGPM - Dove Medical Press

Recommendation and review posted by Bethany Smith

Films set in mental institutions have long captivated audiences; consider, for example, The Snake Pit (1948), One Flew Over the Cuckoo's Nest (1975) and Girl, Interrupted (1999). Films that begin with a patient leaving a mental institution can be equally gripping. By "begin with", I mean that, within the first third of the movie, we either witness the patient leaving a hospital or learn about his or her recent commitment. By "leaving", I mean the patient has been released or has escaped. The 32 films compiled here, in chronological order, all build on the tension of a mental patient's readjustment -- or re-maladjustment -- to society.

Eighteen of these 32 films are dramas and comedies. The rest are horror films and thrillers. Most are North American films. Otherwise, these are films that gained an audience in North America. Nearly all center on white, middle- to upper-class characters. Twenty of the 32 films present discharged or escaped patients who are male, while ten center on female patients and two on both male and female patients.

As for the era, nine of the 32 films here are contemporary. Released between 1988 and 2012, they offer the subgenre's most authentic depictions (e.g., David Cronenberg's Spider). Eleven of these films were made between 1904 and 1966. The five earliest are all about escapees, yet they span genres, laughing off mental illness via slapstick or heightening anxiety about it via melodrama and mystery.

A golden age for this subgenre, offering 12 films, lasted throughout the '70s and into the early '80s. The abundance reflects deinstitutionalization, a mental health movement that began in the US in the 1960s and served to reduce the need for permanent care. During this time, many patients with mental disorders were able to reintegrate into society thanks to advances in antipsychotics, new government programs like Supplemental Security Income (SSI), and a wider array of community mental health services.

A marker of these films as a subgenre is how often their introductions rely on either the commentary of a mental health professional or a traumatizing backstory as a plot device; elements that are combined in no less than eight films. Trauma is pivotal, if overdetermined. Narratively, cinema tends to oversimplify the onset of a character's mental illness by rooting it tidily in a single trauma. This is called the "presumption of traumatic etiology", a term used by Steven E. Hyler, MD, Professor of Psychiatry at Columbia University Medical Center, in his Comprehensive Psychiatry article, "DSM-III at the Cinema".

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Another recurring myth is that of the "schizophrenic parent", which roots mental illness in a person's upbringing. Most commonly, it's a mother who is blamed for creating mental illness in her child. The theory has been out of favor among therapists for decades but has endured in films and how audiences read them.

The vulnerability of a newly released mental patient is a major factor in this subgenre, as is the vulnerability of a community into which a person with a mental health condition has escaped. Ranking the vulnerability of the patient on a scale of zero to five, with five being most vulnerable and zero being least vulnerable, only one of the women ranks below three, whereas men occupy the full range evenly.

How do gender, class, and race play into this vulnerability factor? Of the female characters starting new lives, only one is of a lower class and, therefore, doubly vulnerable. Even she, the escapee in The Woman in White, is less central to the plot than her upper-class foil (played by the same actress). As for race, minorities in mental institutions were long vulnerable to scientific racism and biased care, facing hostile limitations upon reentering society. Despite the dramatic potential, not one of the 32 films center on the experience of a racial minority.

So it is not greater vulnerability exploited in these films, but bourgeois vulnerability and privilege lost, privilege regained, privilege at risk. That rings true as well for escapee-killer movies in which privileged households and communities come under siege.

I must own up to my own fantasy of the nervous breakdown as a fantasy of privilege, induced by cinema and reinforced by this list. Eleven of the ostensibly recovered protagonists return to spacious, well-to-do homes; four can afford adventures; and five come to live in smaller yet cozy apartments. Only four start their new lives facing insufficiency or homelessness, in Touched, Sling Blade, Spider, and Clean, Shaven.

The latter three certainly qualify as the most hard-hitting and realistic dramas on the list. They also echo what the American Psychological Association (APA) considers an enduring truth, supported by study after study over decades: lower socioeconomic status is a risk factor for, if not a cause of, mental illness and psychiatric institutionalization.

These 32 films cohere as a subgenre even in their variations. Plot remains similar from film to film while tone mutates: absurd, inspiring, campy, gritty, or brutal. The portrayal of mental anguish bends from realistic to ridiculous, provoking sympathy and fear in turn. Sensitivity and insightfulness continually fluctuate alongside stereotyping and psychobabble, revealing decade-to-decade shifts in perceptions and practices. Furthermore, the films cross several genres, or bridge them, while ranging from obscure to ubiquitous, from cult classics and drive-in fare to Oscar winners.

Going by these films, there's not much reason to have faith in the security of mental institutions that house seriously psychotic patients, nor in the judgment of psychiatrists who release patients too easily destabilized by dysfunctional families or an aggressive society.

Indeed, in these films, newly re-stabilized characters tend to find themselves at the mercy of the unstable. They must adjust to the maladjusted. They are forced to accept being judged by others whose outwardly normal-seeming, yet in closed environments clearly toxic behaviors, have never themselves been subject to therapy, diagnosis, or stigmatization; thus, power is wielded over the mentally disenfranchised.

Whether underdog or maniac or underdog predisposed to seeming like a maniac, a character who has emerged from a mental institution embodies dramatic tension. If an escaped patient is not returned to the institution, society may be at risk. If the released patient does not adjust to society, he or she may be at risk of return to the institution. Consequently, post-institutionalization operates in these films as a framing device that heightens the meaningfulness of every action, every dialogue. There's everything to lose.

The success of this silent short film prompted an exact remake later the same year, Maniac Chase (dir. Edwin S. Porter), and similarly themed fare cashing in on the comedy of madness. The lunatic, in this case, believes himself to be Napoleon, dressing in the iconic uniform and bicorne hat. Asylum warders treat him so poorly that he jumps from his third-floor window to get away. A slapstick pursuit ensues, circling back to the asylum where the escapee returns himself to his cell. His warders find him there, reading a newspaper as if nothing's happened.

The Napoleon costume would have been understood as comic code for generalized lunacy, if not delusions of grandeur specifically. Stan Laurel's debut film role, in Nuts in May (1917), was also a Napoleon-dressed lunatic on the loose.

At the center of D.W. Griffith's dramatic short film is the unforgettable shot of an escaped lunatic (Charles Hill Mailes) warily peering around a tree, both childlike and deranged. He crawls into the window of a doctor's house and menaces the wife (Claire McDowell), home alone. Her piano playing saves her, soothing the psychotic man. The narrative then veers from a pearls-clutching thriller into public service message about the curative powers of musical therapy, a form of therapy just beginning to gain credibility (the first national association of musical therapists was founded in 1903).

Wilkie Collins' The Woman in White from 1859, one of the very first mystery novels, spawned seven film adaptations between 1912 and 1948. This full-length silent feature begins with the woman in white (Florence La Badie) escaping from an asylum. She was never insane, however, but a half-witted victim. The backstory is that she'd witnessed the misdeeds of a nobleman and institutionalization effectively silenced her.

Once she's escaped, she finds out the nobleman is engaged and warns his fiance (also played by La Badie) against marriage. As one woman tries to help another undermine the male forces against them, involuntary commitment to a mental institution -- or even the threat of it -- is exposed as a tool that can be used against any woman.

John Barrymore plays WWI veteran Hilary Fairfield, returning home "like a lost child" after 15 years in a mental institution. Discovering his wife (Billie Burke) has divorced him makes for powerful melodrama. More central to the plot is Sidney (Katherine Hepburn), on the verge of marriage, finding out that her father suffered not shellshock alone but latent insanity brought on by shellshock.

So insanity is in his blood and in hers too. Reflecting the era's fixation on eugenics, which advocated sterilizing persons deemed genetically unfit, Sidney fears she may "inflict" on her husband either mentally ill children or her own impending breakdown. A remake of a British film from 1922, A Bill of Divorcement was remade again in 1940 with screenplay by Dalton Trumbo.

Drogo Gaines (John Hubbard) decides to ditch his gold-digging fiance at the altar. When asked why he bleats like a goat. This faking of insanity backfires, alas, as he goes from the wedding chapel to booby hatch. The private hospital's entrance sign may pun "For the Rest of Your Life", but Drogo quickly escapes, traveling off with a carnival owned by Penguin Moore (Carole Landis). There seems little difference between asylum kooks and carnival kooks, all more sincere than the respectable set attending the wedding at the start of this uneven but pleasant musical comedy.

This film noir classic begins with Stephen Neale (Ray Milland) being released from Lembridge Asylum, having spent two years there after the mercy killing of his dying wife. His reentry into society is marked by unreality at every turn. For starters, the cake he wins at a charity fete contains sought after microfilm and the blind man on the train, to whom he offers a slice, is not blind but a Nazi spy. Stephen tumbles into an international conspiracy while London endures the Blitz. Such forces would make anyone nervous. Unlike the vulnerable protagonist in Graham Greene's original novel from 1943, however, Milland plays a hero so level-headed that his asylum-time seems all but irrelevant.

Charlotte (Jean Simmons) is the "overly emotional" wife of an unemotional academic (Dan O'Herlihy). She's released from a state hospital one year -- and eight electroshocks -- after a nervous breakdown. Many patients end up committed all over again, her doctor warns, if they are released to the same situation that precipitated the initial breakdown. Charlotte is certainly at risk, returning to a sexless marriage, a condescending stepmother, a glamorous cat of a stepsister, and her coldly bourgeois hometown.

Paranoia grates against clarity for Charlotte, the plot turning on the fact that her paranoia is not wholly unjustified. Why had her husband committed her to a state hospital, she demands to know in a confrontational scene, when they could afford a private one with superior doctors. The mention of electroshock (ECT) is ambiguous in tone. Though the therapy remained common throughout and beyond the '50s, public opinion on its humaneness was increasingly uncertain.

Bergman's stark classic, which won an Oscar for Best Foreign Language Film, begins a month after Karin (Harriet Anderson) is released from an asylum where she received electroshock therapy. Vacationing with family on an unnamed island, she asks her husband, "Am I so little or has the illness made a child of me?" She later sneaks a peek at her novelist father's diary and learns two distressing things. First, there is no cure for her illness, schizophrenia -- a fact her doctor spared her. Second, her father has become obsessed, as a writer, with constructing an accurate description of Karin's "gradual disintegration".

Kirk Douglas plays Jack Andus, a movie star and manic-depressive alcoholic who attempted suicide four years ago. Since Jack is wealthy, he was committed not to a state hospital but a private one, often referred to as a sanitarium (a term originally associated with tuberculosis clinics). Ridgewood Retreat boasts lilac bushes, shuffleboard, butler-like attendants, and elegant rooms.

Jack assumes his career is washed-up forever until he's offered a role in a film set in Rome. His psychiatrist deems him fit, if not cured, but old tensions prove rocky to navigate. And those against Jack don't bother with the euphemism "sanitarium". Instead they jab at him with terms like "asylum" and "nuthouse". Will Jack's rugged individualism win out?

Lucy Harbin (Joan Crawford) finds her husband in bed with a younger woman and goes insane, chopping off their heads with an axe as small daughter Carol watches from the next room. The asylum releases Lucy two decades later, right when Carol (Diane Baker) is vying to marry into wealth. In some scenes, Lucy's vulnerability makes her an underdog to root for; in others, we savor the body count as her instability impels her toward daggers, knitting needles, and axes.

William Castle's campy shocker was written by Robert Bloch, author of the novel Psycho, and built on the success of Whatever Happened to Baby Jane? costarring Joan Crawford and Bette Davis. These movies established a subgenre called "grande dame guignol" that centers on the "psycho-biddy".

Post-menopausal and mentally unbalanced, horror's "psycho-biddy" proved a recurring role in the '60s and '70s for big-name Hollywood actresses considered past their prime. Strait-Jacket exploits a grotesque conflation of mentally ill Lucy, obsessed with her faded youth, and the aging movie star playing Lucy, a specter of faded glamour.

German soldiers during the final days of WWI have planted a bomb somewhere in a French village. All the residents have fled except for those in the lunatic asylum. A bomb-defuser (Alan Bates) from a Scottish brigade, eluding a German patrol, hides out in the asylum and inadvertently releases the inmates. They dart about freely, playing at different roles in the town, alive in every moment and oblivious to the fact that the bomb is set to go off at midnight.

This French classic reflected aspects of the '60s zeitgeist, like war-weariness and the "anti-psychiatry" of R.D. Laing, though it achieved its cult status in the '70s thanks to New York's revival theater circuit.

Jessica (Zohra Lampert), just released from a mental hospital, arrives at a newly purchased farmhouse and her hold on reality is still fragile. She thinks she sees a red-haired young woman inside the house and it's telling how relieved she is when her husband and friend see the woman tooa squatter, it turns out, named Emily (Mariclare Costello). Equal parts charm and undertow, Emily is quickly invited to stay as a houseguest.

This beautiful independent film deserves its cult status, gently mingling psychodrama and the supernatural. Our identification with Jessica is strong thanks to Lampert's subtly modulated performance, the script heightening dramatic irony via her inner dialogues. Still, we can't quite trust Jessica's perception: Is the town really under Emily's spell?

This anti-masterpiece, from the heyday of drive-ins, roots Lynn's psychosis in childhood sexual abuse by her doting father. Troma Entertainment's DVD release of the film cuts the brief yet sleaze-radiating backstory to begin with eighteen-year-old Lynn killing her father and being committed, in denial about what she's done.

Lynn eventually escapes to find her new father figure, a lonely, unbalanced pig farmer named Zambrini. When she kills again, Zambrini feeds the corpse to his pigs. "It's no good to remember something that's terrible," he comforts her. "You must forget." Poignancy matches perversity, due partly to the characters being played by Marc Lawrence (known for gangster roles) and real-life daughter Toni Lawrence.

Albert (Zooey Hall) is an antisocial hipster in a black turtleneck and he hates his mother. He tried to kill the overbearing dowager once already and she had him committed to a private hospital. He escapes to try again but, with her gone into hiding, he fixates instead on the housekeeper's 11-year-old daughter whose "purity" attracts him, too much of a Shirley Temple-type to provoke his misogyny. Escaped mental patients like Albert also wreak havoc in Bell from Hell and Scream Bloody Murder, both from 1973.

A garish, darkly humorous chiller about co-dependence and cannibalism. It opens in 1957 with the trial of serial cannibal-killer Dorothy Yates (Sheila Keith) and her husband Edmund (Rupert Davies). Released after 15 years in a mental institution, they come to live in a small town about an hour outside London. Dorothy is neither cured nor harmless, though, her dottiness masking a hard-bitten sadism. She earns money giving tarot readings, dealing the death card to those who reveal they are alone in the world. Edmund, as before, covers up her gory crimes.

The movie orchestrates three plot elements found in other films here. One is the shading of mental health professionals as ineffectual. The other two -- that Dorothy's so-called "cannibanthropy" is rooted in a childhood trauma and that her daughter has inherited her psychotic inclinations -- seem to contradict each other.

Psychologically fragile characters prove vulnerable to the supernatural in a number of horror films. Robert Wise's The Haunting, based on a Shirley Jackson novel, is a classic example, as is Let's Scare Jessica to Death. In Voices from 1973, a mother grieving over her drowned son is released from a mental hospital and comes to stay in a haunted house, much like The Haunting of Julia. A gorgeous adaptation of Peter Straub's novel, it centers on a humble heiress, Julia Lofting (Mia Farrow), who accidentally kills her only daughter.

After two months in the psychiatric ward of a London hospital, Julia bolts from a husband who'd rather see her institutionalized than independent. She then purchases an antique-loaded townhouse to which only she has a key. Still, she feels she is not alone, coming to believe the house haunted by a sociopathic little girl who died there decades earlier. The more Julia fixates on the ghost of the little girl, the harder it is to tell where guilt-racked grief ends and the genuinely supernatural begins.

Disco-era Canada gave us this cult classic inspired by semi-autobiographical stories in Margaret Gibson's The Butterfly Ward. It's about Liza (Hollis McLaren), a schizophrenic escapee from a mental hospital, and her loyal friend Robin (Craig Russell) who takes her in. While Liza begins a new life, trying to stave off hallucinations, Robin begins a new career impersonating female celebrities.

Liza's storyline reveals an adversarial relationship between emerging patient and mental hospital. She wants to remain functional to spite the hospital: "They're powerless as long as I can function. I'll never go back to that locked ward." As for Robin, onstage he feels embraced by gay culture but offstage his genderqueerness is a turn-off for gay men. These two nonconformists may not change the social structures deeming them unfit, but they do begin to achieve personal stability and self-worth.

The original psycho himself, Anthony Perkins, plays Allan. He goes hysterically blind when his sister is scarred and his father killed in a house fire. Allan is released from a mental hospital after eight months, still partially blind. His psychiatrist insists that full recovery will require him to confront his feelings of guilt about the fire. Back home, Allan learns that his sister (Julie Harris) has taken in a boarder to help pay bills. Either this new boarder is out to get Allan or Allan has been released too soon. How Awful About Allan can be thought of as a male companion to the classic Curtis Harrington psychodrama What's the Matter with Helen? from 1971.

The most famous asylum escapee may well be Michael Myers in this stalker classic. It offers two beginnings: backstory about seven-year-old Michael killing his sister on Halloween night and, 15 years later, his escape from a state hospital to return home and kill again. His longtime psychiatrist Dr. Sam Loomis (an iconic role for Donald Pleasance) had insisted Michael cannot be rehabilitated -- "purely and simply evil" -- but the hospital board failed to step up security.

As a psycho killer, Michael Myers both emerges from and invades the small, middle-class town of Haddonfield; as a mental hospital escapee, holiday convention allows him to hide behind a mask like everyone else.

Here's an Italian horror oddity set in New Orleans, which means dubbed dialogue with a Southern accent. Jane Baker (Bernice Stegers) is a wealthy housewife having an affair. Her lover, speeding her home after a rendezvous, crashes the car and is decapitated; another backstory-intro doubles as "traumatic etiology", giving way to Jane's release a year later from a mental health center. She takes up residence in the apartment where she used to meet her lover, masturbating with his severed head that she's somehow managed to keep all this time in the freezer.

This winner of four Oscars, including Best Picture, is another example of a film that combines traumatic etiology and a schizophrogenic parent. The trauma that prompts Conrad (Timothy Hutton) to cut his wrists is his older brother's death in a boating accident, about which he feels survivor guilt. The parent who undermines Conrad's ego is not the sensitive patriarch (Donald Sutherland) but his composed-to-the-point-of-ungiving mother (Mary Tyler Moore) who didn't visit him once during his four months in a psychiatric hospital.

Conrad's return home is so tense for him that, despite the electroshock, he actually misses the hospital. "Because nobody hid anything there," he tells his psychiatrist.

Halloween blames Michael Myers' escape on lax hospital security, expressed through Donald Pleasance's character Dr. Loomis. Alone in the Dark casts Pleasance as a doctor known for his laxness. Dr. Leo Bain is a blunt parody of existential psychoanalyst R.D. Laing, just as Bain's "Psychiatric Haven" is a parody of Laing's Archway Community where therapists and patients lived together with little sense of boundaries between them (see the 1972 documentary Asylum).

Higher security is required for criminally insane patients, of course, but Bain's lockdown-triggering system fails the night of a power outage. Three killers (Jack Palance, Martin Landau, Erland van Lidth) escape to spend the bulk of the film terrorizing a newly hired doctor and his family in their home.

Opening credits roll and we watch a 27-year-old mental patient named Daniel (Robert Hays) on a group outing to the Wildwood Boardwalk in New Jersey. In voice-over we hear from a psychiatric report about Daniel's inability "to function effectively outside a hospital environment". This plot device should be familiar by now, raising the stakes as Daniel escapes from the hospital and takes a carnival job. A good-natured yet understandably forgotten drama.

Rain Man combined post-institutionalization with the road movie to become the top-grossing film of the year and win Best Picture at the Academy Awards. That Raymond (Dustin Hoffman) is an autistic savant upturns the expected plot, really, as he is concerned not with starting life anew but with fulfilling the same daily routine he'd established in the mental institution.

The administrator warns Raymond's brother Charlie (Tom Cruise) that "any break from this routine leaves him terrified". Nonetheless, Charlie drives Raymond halfway across the country, stopping in Las Vegas where Raymond's prodigious math skills come in handy.

Released or escaped mental patients are less present in horror of the '80s and '90s. There's Nightmares in a Damaged Brain (1981), Blood Rage (1987), The Johnsons (1992), and the iconic Stepfather II. In the original Stepfather from 1987, a family man (Terry O'Quinn), having murdered his wife and kids, alters his appearance and flees to another town to start a new life with an unsuspecting widow and her daughter.

The sequel begins at Puget Sound Psychiatric Hospital. Yet again in these films, mental health authorities underestimate a dangerous patient. The "family killer" escapes to reinvent himself as a family therapist this time. His career choice helps him to infiltrate the lives of a divorcee and her son. It's also a way for the film to mock the authority of the mental health field, by default making the escapee plot more conceivable.

Slapstick fuses with the erotic in this Spanish comedy inspired by Beauty and the Beast. Its anti-hero is an impetuous 23-year-old mental patient named Ricky (Antonio Banderas) who's been in the hospital since he was 16.

Every time he's escaped, he's returned himself because he "had nowhere to go". A notable aside: His sexual relationship with the hospital director grants him a privileged status. During his last escape, however, he met Marina (Victoria Abril) and, once legitimately released, he heads straight for her to begin their new life together. The problem is, she doesn't remember him. So he holds her hostage in her apartment.

We are lost in the dazed yet ever-startled silence of a schizophrenic (Peter Greene) just released from a mental institution. He has no dialogue for the first 18 minutes. Terrorized by auditory hallucinations, he believes some kind of device has been implanted into his scalp. The question is: Do institutionalization and pathological behaviors mean he could kill? A detective, investigating a child murder, seems to think so. His mother and the mother of his seven-year-old daughter would surely not doubt it.

Lodge Kerrigan has withheld proof, though, telling Film Freak Central: "(I)f people feel that he's guilty, I hope that the picture holds them responsible for drawing that conclusion. I hope that it forces the audience to challenge themselves as to why they believe that this man is responsible."

Karl (Billy Bob Thornton) is a mentally disabled man with a traumatic childhood. At 12, deranged by the sight of his mother having sex with someone who was not his father, he killed both using a sling blade. This Oscar-winning drama begins when he's released after decades in an Arkansas state hospital. With nowhere to live, sadly, he returns to the hospital -- to his "good bed."

The hospital director confesses, "The truth is, I don't know where they expect you to go. And I don't know what they expect you to do." Karl is not allowed to stay but the director helps him land a job at a fix-it shop. Also kind to Karl is 12-year-old Frank and his mother Linda, who take him into their home. Linda's abusive boyfriend, however, undermines the family vibe, provoking reactions from Karl that could bring about his recommitment.

Elling (Per Christian Ellefsen) had always lived with his mother, sharing her chronically reclusive nature. When she died, he was committed. Kjell (Sven Nordin) is Elling's simpleminded bear of a roommate at the mental hospital, obsessed with women yet a virgin. Both are middle-aged and, moving into a state-sponsored apartment in Oslo, they make for a cranky yet devoted "odd couple."

A social worker checks in on the two, reminding them that recommitment is certain should they fail to adapt. Elling's first big step is to leave the apartment and buy groceries. A charming entry from Norway, based on Ingvar Ambjornsen's novel, Elling received an Oscar nod for Best Foreign Language Film and was followed by two sequels.

According to the book Movies and Mental Illness: Using Films to Understand Psychopathology by Danny Wedding and Mary Ann Boyd, the London train station scene opening this gritty psychodrama depicts the flow of humanity: "the hustle of activity, and a multitude of people heading toward their destinations." In contrast, acutely schizophrenic Spider (Ralph Fiennes) is "slowly de-boarding, disoriented and isolated from everyone else."

Released from a mental institution after two decades, Spider is on his way to a group home. He mumbles, rarely saying a word aloud, and writes gibberish in a notebook. The film's plot unfolds as Spider's memories of a traumatic childhood surface -- not all of them necessarily accurate. "The only thing worse than losing your mind," insists the film's tagline, "is finding it again."

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32 Films That Begin With Someone Leaving a Mental Institution - PopMatters

Recommendation and review posted by Bethany Smith