Celgene exec jumps to head bluebird bio ops in Europe, where its $1.8M gene therapy Zynteglo is now available – Endpoints News

By Stem Cell Treatment

Days after shaking hands with German regulators over the launch and coverage of its beta-thalassemia gene therapy, bluebird bio has wooed a Celgene exec to lead its European operations.

Nicola Heffron, a biopharma vet with stints across Eli Lilly, GSK and Shire, jumps from a brief tenure overseeing marketing for Celgenes myeloid portfolio in Summit, NJ. She will now be based in Zug, Switzerland.

Shes replacing Andrew Obenshain as he joins CEO Nick Leschly and the leadership team in Boston, according to Bloomberg, which first reported the news. Obenshains new title is chief of wings.

On Monday bluebird announced that Germany will be the first country to commercially offer Zynteglo, their procedure encoding A-T87Q-globin gene in CD34+ cells extracted from patients. Under their value-based payment scheme, the $1.8 million price is divided into five installments. After an initial payment is made at the time of infusion, the payers wait and see and only pay if the patients continue to be transfusion-free.

Multiple statutory health insurances have signed onto the plan, bluebird said, and University Hospital of Heidelberg will host the first qualified treatment center.

The biotech has been busy sorting out manufacturing specs and talking to individual countries since the EU issued an historic OK last June. Its sanctioned for a specific group of beta-thalassemia patients those who are 12 years and older, transfusion dependent, do not have a 0/0 genotype and for whom hematopoietic stem cell transplantation is appropriate but a donor is not available.

For patients with TDT, lifelong chronic blood transfusions are required in order to survive, bluebird chief commercial officer Alison Finger emphasized in a statement. Their one-time infusion promises to do away with the transfusions for good.

A rolling BLA submission to the FDA has begun, bluebird added.

See the original post:
Celgene exec jumps to head bluebird bio ops in Europe, where its $1.8M gene therapy Zynteglo is now available - Endpoints News

Tolero Pharmaceuticals Announces First Patient Dosed in Phase 2 Zella 202 Study of Investigational Agent Alvocidib in Patients with Relapsed or…

By Stem Cell Treatment

SALT LAKE CITY, Jan. 15, 2020 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today announced that the first patient has been dosed in a Phase 2 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with a hypomethylating agent (HMA). The open-label, randomized study has two parts and will evaluate the safety and efficacy of alvocidib in monotherapy or in combination with low-dose cytarabine.

"Patients with AML who are resistant to or progressed following treatment with the BCL-2 inhibitor venetoclax in combination with an HMA have limited treatment options, and it has been well established in the literature that a key potential mechanism of resistance to BCL-2 targeted therapy is the switch to a dependence on MCL-1," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "The initiation of this study marks an important step toward understanding the potential of alvocidib as a monotherapy or in combination with low-dose cytarabine for these patients. We believe that patients whose cancers have progressed following treatment with venetoclax may be sensitive to alvocidib and this trial will help us to better understand this hypothesis."

The primary objective of the Phase 2 study is to determine the rate of combined complete remission (CR) and CR with incomplete hematological recovery (CRi), of alvocidib and alvocidib in combination with low-dose cytarabine in patients with AML. Secondary objectives include establishing the recommended treatment regimen for the second part of the study and evaluating the median overall survival (mOS) and CR rate. Additional secondary outcome measures include evaluating event-free survival (EFS), duration of composite CR (CRc), safety and tolerability of the regimen and mortality.

In the first part of the study, patients who are refractory to or have relapsed on venetoclax in combination with an HMA will be randomized into two arms. In Arm 1 of the study, patients will receive combination therapy of alvocidib and low-dose cytarabine. In Arm 2 of the study, patients will receive alvocidib monotherapy. In the second part of the study, patients will receive the regimen based on the outcome of the first part.

The trial is being conducted at sites in the United States. Additional information on this trial, including comprehensive inclusion and exclusion criteria, can be accessed at http://www.ClinicalTrials.gov(NCT03969420).

About AlvocidibAlvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the Phase 2 studies, Zella 202 in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine (NCT03969420) and Zella 201 in patients with relapsed or refractory MCL-1 dependent AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase 1 clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with cytarabine and daunorubicin (7+3) in newly diagnosed patients with AML (NCT03298984), and Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with decitabine (NCT03593915). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.1In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.2MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.1,3The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).4,5Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.4Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.1

About Tolero Pharmaceuticals, Inc. Tolero Pharmaceuticals is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with hematological and oncological diseases. Tolero has a diverse pipeline that targets important biological drivers of blood disorders to treat leukemias, anemia, and solid tumors, as well as targets of drug resistance and transcriptional control.

Tolero Pharmaceuticals is based in the United States and is an indirect, wholly-owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan. Tolero works closely with its parent company, Sumitomo Dainippon Pharma, and Boston Biomedical, Inc., also a wholly-owned subsidiary, to advance a pipeline of innovative oncology treatments. The organizations apply their expertise and collaborate to achieve a common objective - expediting the discovery, development and commercialization of novel treatment options.

Additional information about the company and its product pipeline can be found at http://www.toleropharma.com.

Tolero Pharmaceuticals Forward-Looking Statements This press release contains "forward-looking statements," as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products.The forward-looking statements in this press release are based on management's assumptions and beliefs in light of information presently available, and involve both known and unknown risks and uncertainties, which could cause actual outcomes to differ materially from current expectations. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.

References

View original content:http://www.prnewswire.com/news-releases/tolero-pharmaceuticals-announces-first-patient-dosed-in-phase-2-zella-202-study-of-investigational-agent-alvocidib-in-patients-with-relapsed-or-refractory-acute-myeloid-leukemia-following-treatment-with-venetoclax-and-hma-combinat-300987212.html

SOURCE Tolero Pharmaceuticals, Inc.

Read the original post:
Tolero Pharmaceuticals Announces First Patient Dosed in Phase 2 Zella 202 Study of Investigational Agent Alvocidib in Patients with Relapsed or...

How Exosomes Could Lead To Stroke Recovery – Technology Networks

By Stem Cell Treatment

Its been almost a quarter of a century since the first drug was approved for stroke. But whats even more striking is that only a single drug remains approved today.

In a publication appearing this month in the journal Translational Stroke Research, animal scientists, funded by the National Institutes of Health, present brain-imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke.

It was eye opening and unexpected that you would see such a benefit after having had such a severe stroke, said Steven Stice, Georgia Research Alliance Eminent Scholar and D.W. Brooks Distinguished Professor in the University of Georgias College of Agricultural and Environmental Sciences. Perhaps the most formidable discovery was that one could recover and do so well after the exosome treatment.

Stice and his colleagues at UGAs Regenerative Bioscience Center report the first observational evidence during a midline shiftwhen the brain is being pushed to one side to suggest that a minimally invasive and non-operative exosome treatment can now influence the repair and damage that follow a severe stroke.

Exosomes are considered to be powerful mediators of long-distance cell-to-cell communication that can change the behavior of tumor and neighboring cells. The results of the study echo findings from other recent RBC studies using the same licensed exosome technology.

Many patients who suffer stroke exhibit a shift of the brain past its center linethe valley between the left and right parts of the brain. Lesions or tumors will induce pressure or inflammation in the brain, causing what typically appears as a straight line to shift.

Based on results of the exosome treatment in swine, it doesnt look like lesion volume or the effects of a midline shift matter nearly as much as one would think, said Franklin West, associate professor of animal and dairy science in the UGA College of Agricultural and Environmental Sciences. This suggests that, even in some extremely severe cases caused by stroke, youre still going to recover just as well.

Trauma from an acute stroke can happen quickly and can cause irreversible damage almost immediately. Time is brain, a phrase coined by stroke advocacy organizations in the late 1990s, captures the importance of acting on the first signs of stroke. In less than 60 seconds, warns the Stroke Awareness Foundation, an ischemic stroke kills 1.9 million brain cells.

Data from the teams research showed that non-treated brain cells near the site of the stroke injury quickly starved from lack of oxygen and diedtriggering a lethal action of damage signals throughout the brain network and potentially compromising millions of healthy cells.

However, in brain areas treated with exosomes that were taken directly from cold storage and administered intravenously, these cells were able to penetrate the brain and interrupt the process of cell death.

Basically, during a stroke, these really destructive free radicals are all over the place destroying things, said Stice, director of the RBC. What the exosome technology does is communicate with jeopardized cells and work like an anti-inflammatory agent to interrupt and stop further damage.

According to the teams results, neuroimaging is an essential tool for evaluating brain tissue and managing stroke recovery.

In this observational study, the team analyzed brain images taken 24 hours after stroke. They then applied recovery scores, commonly used in human practice, based on swine gait, cadence, walking speed and stride length. By recording the relationship between brain measurements and functional outcomes, the new assessment scales can better help physicians predict how quickly a person will recover in real time.

What Im trying to do with this assessment data is come up with something that we can implement in the clinics right nowtodayto help with predicting patient outcomes, said Samantha Spellicy, a neuroscience graduate student and first author on the publication.

Spellicy, who is currently training under Stice, began her first two years at the Medical College of Georgia at Augusta University and has plans to return to MCG after completing her Ph.D. She anticipates a return to stroke care and one day using the same outcome assessments presented in the study with human patients.

When a patient arrives in emergency with a stroke, the available clinician would not be left crunching an arbitrary number based on some standardized scale assessment, Spellicy said. Instead, the clinician could take more of a personalized approach based on the patients midline shift measurement, and, say for instance, OK, in three months youre going to get better, but youre going to have issues with your gait. Lets talk to a specialist now to target that exact condition.

As for the future of the exosome treatment, Spellicy and the RBC team anticipate that the patented neural exosome technology, called AB126, will be filed for clinical trials by 2021.

Reference

Spellicy et al. (2019) Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model. Translational Stroke Research. DOI: https://doi.org/10.1007/s12975-019-00753-4

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

More here:
How Exosomes Could Lead To Stroke Recovery - Technology Networks

Denver Clinic Explores PRP Vs. Stem Cell Treatments And Choosing What Will Help Most – Press Release – Digital Journal

By Platelet Rich Plasma Injections

The Denver, CO based Denver Regenerative Medicine | Stem Cell Therapy, HRT, Testosterone Clinic (DRM) has been looking into PRP and stem cell treatments to determine which one of the two is more effective in any given situation. They provide a wide variety of treatments for a similarly wide range of problems and constantly commit research into which treatments are more effective for certain ailments. DRM specializes in highly advanced stem cell treatments.

The clinic has pioneered several unique treatment methods over the years. Their well-known AcCELLerate stem cell regeneration system, which was discovered and developed in-house, uses the patients own platelet-rich plasma to create a powerful mixture of activated stem cells and platelets. PRP therapy is then added to the mixture, which causes the stem cells to activate immediately.

Experience has shown that patients who receive our unique combination of activated platelets and Stem Cells, our AcCELLerate Stem Cell regeneration system, begin to notice results approximately 30% sooner when compared to patients that have received just stem cells without platelets, says the clinic. Additionally, those same patients show sustained improvement over a longer period of time. As a leading Denver PRP therapy and stem cell injection clinic, DRM has the knowledge and experience to help you heal naturally with AcCELLerate therapy.

Denver Regenerative Medicine was one of the first clinics in Denver to provide advanced stem cell therapy treatments along with alternatives to conventional intervention techniques. When done correctly, stem cell therapy injections in the knees, shoulders and other joints may serve as a better option than surgery for many patients. Stem cell therapy offers many advantages over surgery, such as faster recovery, much less pain, lower costs and less of a need for a sling or cast.

Stem cells are self-renewing and can grow into any type of cell needed by your body, says Denver Regenerative Medicine. Our regenerative medicine clinic in Denvers adult stem cell therapies use your own cells to create a customized treatment regimen that is readily accepted by your body. This can reduce the risk of rejection of these healing cells and can boost your own natural rejuvenating capabilities.

Anyone looking to boost their general health and vitality may be interested in Denver Regenerative Medicines Rejuvenate Therapy. Combining stem cell therapy and hormone replacement therapy, Rejuvenate therapy aims to combat the ailments caused by hormone imbalance (which often result from stress, toxins and a number of other natural factors) as well as reverse the effects of aging in the body. The clinics hormone replacement specialists know and understand how hormone imbalance can affect both men and women and lead to myriad ailments. Rejuvenate aims to fix these issues and restore the patients strength and vigor. Read about the clinic and some of their other procedures here: Denver Regenerative Medicine | Stem Cell Therapy, HRT, Testosterone Clinic.

Many of Denvers residents have already visited the clinic seeking treatment for any of a variety of problems. I wrecked my knees 30+ years ago, and my insurance has refused to do anything, says a patient named Mike Snider in a 5-Star Google review. I also developed Osteo-Arthritis in my thumbs. I went to Denver Regenerative in February and started the procedures on all four joints. When I went the first time I had to use the handrail to go up and down stairs and it was still painful. Now I do the stairs and very seldom use the handrail. My knees are about 90-95% now and my hands closer to 75-80% but overall much better. Dr. Gershon and the whole staff have been just great. I highly recommend using them to get relief.

Another patient, in a 5-Star review on the same platform, says, Excellent results for both knees. Six months ago, I had my stem cells injected in both knees. I could not sit in a cross leg position or climb a ladder or hike for more than 15 minutes. Dr. Gershon and stem cells healed my issues, and now I have no more pain and can hike, sit in a cross leg seated position and climb without pain or worry.

Denver Regenerative Medicine encourages those interested in the clinics many treatments to get in touch at their earliest convenience. Dr. Joel Cherdack is available to respond to any further inquiries. Visit their Google Maps page at the following link: Our Google Maps Listing.

###

For more information about Denver Regenerative Medicine | Stem Cell Therapy, HRT, Testosterone Clinic, contact the company here:

Denver Regenerative Medicine | Stem Cell Therapy, HRT, Testosterone ClinicDr. Joel Cherdack(720) 583-1648info@denverregenerativemedicine.comDenver Regenerative Medicine | Stem Cell Therapy, HRT, Testosterone Clinic2149 S Holly St #200Denver, CO 80222

Follow this link:
Denver Clinic Explores PRP Vs. Stem Cell Treatments And Choosing What Will Help Most - Press Release - Digital Journal

Everything You Want To Know About Bunions But Never Asked – Long Island Weekly News

By Platelet Rich Plasma Injections

A bunion deformity is one of the most common foot conditions. The big toe shifts toward the other toes and the inside of the joint bulges inward. The widening of the foot causes pain from tightness in shoegear something I call shoe conflict. As the joint becomes misaligned more pain occurs. This deformity can be corrected with foot surgery when indicated.

The medical term for bunion is Hallux Valgus which in Latin means big toe bending outward. Bunio means enlargement in Latin. The base of the big toe joint pushes inward as the big toe itself pushes over toward the other toes. The joint bulges inward causing a medial eminence (bump), which rubs in shoes and becomes red and inflamed over time. This pain and rubbing left unchecked often leads to greater complications.

Overpronation, aka over-flattening of the foot while standing or walking, puts extra pressure on the big toe joint. This extra stress makes the big toe joint (first metatarsophalangeal joint) unstable which causes the attaching tendons and ligaments to pull the bone out of place. Over time the joint moves over and a bunion forms. Overly elastic ligaments can also contribute to a bunions growth.

About 30 percent of the population develops bunions, which indicates how common they are. Genetics play a role as do foot type and structure. Women suffer with bunions more than men, but men are not immune. One study of aboriginal tribes showed that barefoot walkers developed bunions at a similar frequency as more traditional shoe wearing populations. Shoe gear may exacerbate symptoms of bunions but arent necessarily causative.

Conservative measures are tried first. These include: paring of calluses, changing shoegear, altering activity level, paddings and toe spacers, custom prescribed orthotics, anti-inflammatory injections, PRP (platelet rich plasma) therapy and physical therapy. When conservative measures do not work or the deformity is too large surgery may be recommended. Modern bunion surgery offers sophisticated and gentle options. Depending on the patient and type of bunion the right procedure is determined. I often employ a near pain-free procedure with a smaller, mini-invasive approach. The biomechanics of the foot and the patients lifestyle are taken into account. The days of crutches and non weight-bearing are behind us. A cast post procedure is not necessary. With proper bandaging and use of a surgical shoe one can actually walk and bear weight right away, albeit carefully and only as needed during the first week. Stitches are removed around two weeks after surgery. Bandages are changed weekly. Each patient varies; some return to work in a couple weeks. Others may return after 4-5 weeks.

Todays diagnostics and procedures available for bunion correction assure an optimal result. Less pain, less swelling and smaller and barely visible incisions have become commonplace when a thoughtful plan is used.

Dr. William Levine is a board certified podiatrist with 26 years of experience. He is the owner of Manhasset Podiatry, a private practice located at 1180 Northern Blvd. in Manhasset. Levine is on staff at Fifth Avenue Surgery Center in Manhattan and performs surgery there.

More:
Everything You Want To Know About Bunions But Never Asked - Long Island Weekly News

NBA Stars Most Ready to Break out in Season’s 2nd Half – Bleacher Report

By Platelet Rich Plasma Injections

0 of 5

The late-season surge is a fairly common phenomenon in the NBA. Sometimes, it just takes players a couple of months to get healthy, find their rhythm or otherwise settle into a season.

Take Donovan Mitchell in 2018-19, for example.

While battling a toe injury through December, he posted 20.1 points with a 46.4 effective field-goal percentage and an 11.7 average game score.

On Dec. 31, he tweeted, "New year, new me."

In every game after that, he put up 26.5 points with a 51.2 effective field-goal percentage and a 17.6 game score.

The jump isn't always as dramatic as Mitchell's leap from inefficient volume scorer to bona fide superstar, but these stories happen every year.

Which players might pull it off in 2019-20?

1 of 5

Kyle Kuzma

One thing Kyle Kuzma has shown in his young career is that he can score. It came on below-average true shooting, but he averaged 18.7 points per game for a losing team last season.

He just hasn't been able to show much of that scoring prowess for a team that includes Anthony Davis and LeBron James in 2019-20. He's more than perked up in AD's absence, dropping 62 points on 46 field-goal attempts in two games.

Perhaps this run without Davis will serve as a jolt for Kuzma's confidence. He's been in trade rumors already this season, but if he can play with this kind of purpose for the rest of the season, he may be exactly the kind of spark the team needs in LeBron-less minutes.

RJ Barrett

It's been a rough go for RJ Barrett in the NBA. There's no getting around that.His 13.8 points with a 45.9 true shooting percentage makes him one of the least efficient scorers in the league.

Every once in a while, though, you see the outline of the player who made some sense as the third overall pick. He has solid size (6'6") and playmaking ability for a wing. In theory, he should provide some switchability on defense. Reality has looked a little different.

But there have been signs of life of late. In his last five games, Barrett is averaging 18.4 points per game and shooting 47.7 percent from the field. Perhaps most encouraging is his 77.1 free-throw percentage in that span. Prior to that, he was at just 55.4 percent from the stripe.

Jaren Jackson Jr.

Jaren Jackson Jr. is already having a good season, averaging 18.0 points and 2.7 threes and shooting 41.6 percent from three.

He can still break out.

Averages of 4.9 rebounds, 1.5 assists and 1.4 blocks all feel a little low for a player of his talent. If Jackson starts making more wide-ranging contributions for the Grizzlies, they should be able to hang in the race for eighth in the West.

Lauri Markkanen

Lauri Markkanen's points, rebounds and three-point percentage are all down this season. Thanks to a big jump in three-point attempt rate, his true shooting percentage is actually up, but this certainlyfeelslike an off year for the 22-year-old stretch big.

He's already shown the ability to do more. Combining last season's aggressiveness with this season's shot selection would do wonders for both Markkanen and the Chicago Bulls, who still have a 14 percent chance to make the playoffs, according to FiveThirtyEight.

2 of 5

It's been nearly two years since Kristaps Porzingis tore his ACL as a New York Knick on Feb. 6, 2018. After spending all of 2018-19 rehabbing, he finally returned to NBA action on a new team and with a radically different role.

His slow start with the Dallas Mavericks makes plenty of sense in that context. He's averaging 17.3 points per game, his lowest output since his 2015-16 rookie campaign. He's also posting a negative net rating swing (meaning the Mavericks' plus/minus is better with him off the floor) for the first time in his career.

He's essentially been a floor-spacer for Luka Doncic this season, but the bigger culprit for his struggles may still be health. He's now experiencing soreness in his other knee.

ESPN's Tim MacMahon reported that KP had "...platelet-rich-plasma injection as part of the treatment for the soreness in his right knee..."

"The Mavs commonly use PRP injections to stimulate or assist healing and address symptoms such as pain in a variety of injuries, a source said, adding that the team occasionally uses it as part of preventative maintenance," he wrote. "The injections use elements of the patient's own blood, not medicine."

If the injections eliminate, or at least make manageable, the soreness in Porzingis' knee, expect an uptick in production over the second half of the season.

He's now had a few months to adapt to his role and NBA basketball generally. His new, smarter shot selection should help. He just has to start hitting those shots he's capable of hitting.

3 of 5

As was the case with Jaren Jackson Jr., putting Ben Simmons in this article almost feels nitpicky.

He's averaging a well-rounded 14.9 points, 8.5 assists, 7.5 rebounds and 2.2 steals per game. That last number leads the league, but the first one is a career-low.

Being part of a lineup that includes Joel Embiid, Tobias Harris, Josh Richardson and Al Horford probably necessitates a decrease in scoring from Simmons. And over the course of his career, the Philadelphia 76ers have been more likely to win when he takes fewer than 15 shots.

But Embiid's absence with ligament damage in his finger should force a little more aggression from Simmons. And though Embiid isn't expected to be out long, maybe this stretch will be the catalyst for Simmons to take a little more ownership over lineups thatdo include the big man.

That, in turn, could lead to a bounce back in the scoring column for Philly's do-everything point forward.

"Absolutely," ESPN's Jalen Rose said onGet Up!when asked whether Simmons might be better off with Embiid off the floor.

It will give him a chance to orchestrate every possession, get out and run and spend more time in his comfort zone at the rim.

4 of 5

It feels a little late in Mike Conley's career to be expecting a breakout. After 12 seasons with the Memphis Grizzlies, his inability to hit shots with the Utah Jazz might be easier to see as the beginning of the end than growing pains.

But this is a pretty dramatic change for a point guard who has had total command of his team's offenses over recent years. In Utah, Quin Snyder's 1s spend more time off the ball than most around the league, and the offense features plenty of complex actions and unique terminology.

"I think you need a Ph.D. to play here," Conley said earlier this season, per KSL's Ryan Miller. "They didn't tell us that before we came."

The veteran guard explained further:"It's not so much the plays. It's just a lot of terminology, a lot of things that are different words than most of the rest of the NBA, which is great once you learn them all. Nobody really knows what you're saying because you are speaking a foreign language than the rest of the leaguewhich is brilliant."

Perhaps Conley's extended absence with a lingering hamstring injury could end up being a blessing in disguise. It came right as the Jazz's schedule got significantly easier. And sometimes, observing everything from the sideline can be as instructive as trying to run the plays yourself.

Equipped with healthy legs and a deeper understanding of Utah's system, Conley should be able to produce numbers closer to his career norms when he returns to the lineup.

5 of 5

This one feels obvious. Zion Williamson, the No. 1 pick in this summer's NBA draft, hasn't played a single game in 2019-20. But after seeing what he did in the preseason, it's hard to imagine anything from his return feeling like less than a breakout.

Williamson got seemingly whatever he wanted in those four exhibition games.He averaged 23.3 points, 6.5 rebounds, 2.3 assists and 1.5 steals in just 27.2 minutes. He also shot an absurd 71.4 percent from the field.

All the traits that led to Williamson having one of the greatest seasons in college basketball history were on brilliant display when he suited up for the New Orleans Pelicans. The strength, explosiveness, ball-handling and feel for the game that allowed him to exploit cutting lanes and rebounding opportunities makes for what looks like an unparalleled combination.

His potential January return feels like almost perfect timing (having him all season, of course, would've been preferable).

The Pelicans have been solid since Derrick Favors' return from injury and currently sport a 40 percent chance of making the playoffs, according to FiveThirtyEight's projections.

If Zion is fully healthy, his fit alongside Favors makes plenty of sense. His talent should offer a significant boost to New Orleans' playoff prospects.

If he leads the Pels there, he'll surely be one of the stars of 2020.

Originally posted here:
NBA Stars Most Ready to Break out in Season's 2nd Half - Bleacher Report

MDA Awards Venture Philanthropy Funding of More Than $1M to AavantiBio to Develop Gene-Targeting Therapy for Friedreich’s Ataxia – P&T Community

By Gene Therapy Clinics

NEW YORK and GAINESVILLE, Fla., Jan. 13, 2020 /PRNewswire/ --The Muscular Dystrophy Association (MDA) and AavantiBio, a biotechnology company developing a gene-targeting therapy for Friedreich's ataxia (FA), today announced the award of MDA Venture Philanthropy (MVP) funding totaling $1,076,232 to advance AavantiBio's phase 2 clinical trial of a gene-replacement therapy for the disease.

MVP is MDA's drug development program, which is exclusively focused on funding the discovery and clinical application of treatments and cures for neuromuscular disorders. MVP evaluates and makes targeted investments in for-profit and not-for-profit companies and academics developing therapeutics.

FA is a rare, hereditary disease that causes damage to parts of the spinal cord and brain, and there is currently no cure. AavantiBio was founded with the aim of developing an effective treatment for the disease and improving the lives of FA patients.

"With the approval of several first-time gene-targeting therapies for neuromuscular diseases over the past several years, including the first-ever gene-replacement therapy for spinal muscular atrophy, our community should have much to hope for as more and more therapies continue to be developed," says Lynn O'Connor Vos, MDA's president and CEO. "MDA is thrilled to be a part of the quest to help further develop the first gene-targeting therapy for the treatment of Friedreich's ataxia. By partnering with AavantiBio, together we can address the unmet need faced by patients who live with this genetic disease, for which there are still no treatments and no cures."

Co-founders Manuela Corti, PT, PhD, assistant professor of Pediatrics at the University of Florida, Gainesville, and Barry Byrne, MD, PhD, associate chair of Pediatrics and director of the Powell Gene Therapy Center at UF, started working with the FA community five years ago and are thrilled about their new partnership with MDA.

"This is a great opportunity for AavantiBio, and we're thankful to the MDA for their generous contribution," Dr. Corti says. "We hope to strengthen our collaboration as we work together on this project."

Dr. Corti and Dr. Byrne aim to include both adults and children who have FA in their clinical trials, paving the way for new solutions.

"We're delighted to take the next step in fulfilling our commitment to patients and families living with FA based on this investment from MDA," Dr. Byrne says. "We're looking forward to initiating screening for the first clinical study and a pivotal study in FA before the end of the year. The endorsement and investment from the MDA will be key to our programmatic growth."

MDA's investment will help accelerate AavantiBio's mission and begin production of the clinical gene vector for its therapy program. Clinical trials are expected to begin in 2020.

Dr. Corti was previously awarded an MDA research grant to develop and test a gene-replacement therapy in a mouse model of FA. With the current funding, AavantiBio will sponsor a study at the University of Florida led by Sub Subramony, MD, professor of Neurology. The clinical trial will assess changes in neurological and cardiac function in patients with FA treated with both intravenous (systemic) and intrathecal (into-the-spine) injections of the company's gene-replacement therapy for the mutated FXN gene.

About Friedreich's ataxia

FA is a mitochondrial disease. Mutations in the frataxin gene (FXN) lead to decreased production of the frataxin protein, resulting in diminished energy production in cells, including those of the nervous system and heart. FA's major neurological symptoms include muscle weakness and ataxia, or a loss of balance and coordination. FA mostly affects the spinal cord and the peripheral nervesthat connect the spinal cord to the body's muscles and sensory organs, but it can also affect the cerebellum (causing ataxia) and heart. The prevalence of FA has been estimated at 1 in every 50,000 individuals worldwide. Symptoms typically begin between the ages of 5 and 15 years, and the rate of progression varies from person to person. There currently are no effective cures or treatments for FA.

About AavantiBio

Founded in 2017 and based inGainesville, Fla., AavantiBio is a biotechnology companyfounded on the vision of creating the first effective treatment for FA. The company's gene-replacement therapy approach uses an adeno-associated virus (AAV) vector to deliver a functional copy of the FXN gene to a patient's cells.

The co-founders bring more than 30 years of research experience in the field of neuromuscular disease, including their current work focusing on FA. Dr. Corti has more than 10 years of research experience in gene therapy approaches for the treatment of Duchenne muscular dystrophy and Pompe disease. Dr. Byrne has made significant contributions to theunderstanding and treatment of Pompe disease. He was previously awarded nearly $2 million in MDA funding to conduct foundational research in developing and testing AAV vectors in animal models of muscular dystrophy, and he was the first to show that AAV vectors are able to effectively express therapeutic genes in striated muscle cells.

About the Muscular Dystrophy Association

MDA is committed to transforming the lives of people affected by muscular dystrophy, ALS, and related neuromuscular diseases. We do this through innovations in science and innovations in care. As the largest source of funding for neuromuscular disease research outside of the federal government, MDA has committed more than $1 billion since our inception to accelerate the discovery of therapies and cures. Research we have supported is directly linked to approved, life-changing therapies across multiple neuromuscular diseases. We support the largest network of multidisciplinary clinics providing best-in-class care at more than 150 of the nation's top medical institutions, and each year thousands of children and young adults learn vital life skills and gain independence at MDA Summer Camp and through recreational programs. For more information visitmda.org.

View original content to download multimedia:http://www.prnewswire.com/news-releases/mda-awards-venture-philanthropy-funding-of-more-than-1m-to-aavantibio-to-develop-gene-targeting-therapy-for-friedreichs-ataxia-300985256.html

SOURCE Muscular Dystrophy Association

Read the rest here:
MDA Awards Venture Philanthropy Funding of More Than $1M to AavantiBio to Develop Gene-Targeting Therapy for Friedreich's Ataxia - P&T Community

Oncocyte Announces the Commercial Availability of DetermaRx, the First Test for Chemotherapy Benefit Prediction in Patients with Early Stage Non-Small…

By Gene Therapy Clinics

Leonard Cancer Institute at Mission Hospital, California and Florida Precision Oncology sign up as early access sites for the test

Canadian regulatory approval received allowing for path to reimbursement

IRVINE, Calif., Jan. 13, 2020 (GLOBE NEWSWIRE) -- Oncocyte Corporation (NYSE American: OCX), a molecular diagnostics company with a mission to provide actionable answers at critical decision points across the lung cancer care continuum, today announced that DetermaRx, formerly known as the Razor treatment stratification test, is now commercially available in the United States. Additionally, Oncocyte has received regulatory approval in Canada to begin distribution of DetermaRx in that country. DetermaRx enables the identification of early-stage lung cancer patients who may benefit from adjuvant chemotherapy post surgical resection. In a clinical study, high-risk patients identified by this test post-surgery and treated with adjuvant chemotherapy had a significant increase in survival rates.

Florida Precision Oncology and the Leonard Cancer Institute at Mission Hospital in Mission Viejo, California have signed up for early access to the test. The Leonard Cancer Institute at Mission Hospital is a brand new, state of the art regional cancer center and a part of the Providence St. Joseph Health network which consists of 119,000-plus caregivers and employees, serving 51 hospitals and more than 800 clinics delivering a comprehensive range of health and social services across Alaska, California, Montana, New Mexico, Oregon, Texas and Washington. Florida Precision Oncology, with locations in Aventura, Miramar and Boca Raton, is focused on delivering multidisciplinary cancer care in the community setting where most cancer is treated.

We are thrilled to officially transform Oncocyte into a commercial-stage company as we make DetermaRx available to lung cancer patients in the U.S., and in the near future, Canada, who are in need of additional clarity when making treatment decisions after surgery, said Ron Andrews, Chief Executive Officer of Oncocyte. Under the current standard of care, approximately 30%-50% of stage I IIA patients who have undergone surgery to remove lung tumors recur and die within five years of surgery. This is unacceptable. We believe DetermaRx, which has been extensively validated and published in top tier peer-reviewed publications, will address this critically underserved treatment decision point, helping physicians and patients make the right treatment decisions at the right time. We are also very pleased that Medicare, which covers ~70% of eligible patients, has proposed positive coverage for this test. This will promote broad access for patients who may stand to benefit from DetermaRx.

Dr. Samer Kanaan, medical director for the lung program at Mission Hospitals Leonard Cancer Institute added, Mission Hospital is honored to have been invited to serve as one of Oncocytes early access partners. This new diagnostic tool will allow us to further enhance our comprehensive lung cancer treatment program and optimize post-surgical treatment decisions. This test serves an important unmet medical need, and I look forward to making it available to patients across the Mission Hospital and Providence St. Joseph networks.

Dr. Edgardo S. Santos, Founding Partner of Florida Precision Oncology, further commented, There is no question that DetermaRx addresses an unmet need in thoracic oncology that we have had for decades. Lung cancer has an incidence of approximately of 225,000 patients per year; if we focus on those adenocarcinoma patients who have stage I and IIA disease, we are talking about 40,000 patients per year with a poor or suboptimal 5-year survival rate. If I have a tool such as DetermaRx which can identify those patients with early pathological stage (supposedly cured) carrying a high-risk for recurrence (based on their genomic profile), there is no question in mind that it will significantly impact the survival of my patients. We also must keep in mind that with the advent of lung cancer screening, we will be able to identify more patients at early stages. Hence, we must be ready to have a discussion regarding therapy post-operatively. Besides poor features from the tumor that we have used for years to decide for or against postoperative chemotherapy, now DetermaRx brings molecular analysis on board which from my standpoint is a kind of personalized management. For example, not all stages IA are the same; some carry higher risk for recurrence than others. We must target them.

Story continues

In bringing DetermaRx to market, Oncocyte will initially prioritize those cancer centers and physicians who manage the highest number of early stage lung cancer patients. Starting the first quarter of 2020, the Company will deploy an experienced salesforce which has a proven track record driving market leadership of novel high-volume molecular diagnostics.

About DetermaRx

DetermaRx is a molecular diagnostic test that enables the identification of early-stage lung cancer patients who may benefit from chemotherapy following surgery, allowing them to be treated when their cancer may be more responsive to adjuvant chemotherapy. The test utilizes a gene expression analysis of 14 specific genes from a patients tumor and a proprietary algorithm to stratify early stage NSCLC patients into one of two groups, one that may benefit from chemotherapy because of high risk of recurrence, and another that may avoid chemotherapy because of low risk of recurrence. DetermaRx is extensively validated and published with independent, blinded global studies in over 1,500 patients and seven publications in prestigious journals including the Lancet and JAMA.

About Oncocyte Corporation

Oncocyte is a molecular diagnostics company whose mission is to provide actionable answers at critical decision points across the lung cancer care continuum, with the goal of improving patient outcomes by accelerating and optimizing diagnosis and treatment. The Company is currently preparing to launch DetermaRx, a treatment stratification test that enables the identification of early-stage lung cancer patients at high risk for recurrence post-resection, allowing them to be treated when their cancer may be more responsive to adjuvant chemotherapy. DetermaDx, the companys liquid biopsy test in development, utilizes a proprietary immune system interrogation approach to clarify if a patients lung nodules are benign, which may enable them to avoid potentially risky invasive diagnostic procedures.

DetermaDx and DetermaRx are trademarks of Oncocyte Corporation.

Oncocyte Forward Looking Statements

Any statements that are not historical fact (including, but not limited to statements that contain words such as will, believes, plans, anticipates, expects, estimates and similar expressions) are forward-looking statements. These statements include those pertaining to the time to complete and the results of the Companys ongoing Clinical Validation study for DetermaDx, implementation and results of research, development, clinical trials and studies, commercialization plans, future financial and/or operating results, and future opportunities for Oncocyte, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential diagnostic tests or products, uncertainty in the results of clinical trials or regulatory approvals, the capacity of our third-party supplied blood sample analytic system to provide consistent and precise analytic results on a commercial scale, the need and ability to obtain future capital, maintenance of intellectual property rights, and the need to obtain third party reimbursement for patients use of any diagnostic tests we commercialize. Actual results may differ materially from the results anticipated in these forward-looking statements and accordingly such statements should be evaluated together with the many uncertainties that affect the business of Oncocyte, particularly those mentioned in the Risk Factors and other cautionary statements found in Oncocytes Securities and Exchange Commission filings, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Oncocyte undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Investor ContactBob YedidLifeSci Advisors, LLC646-597-6989bob@lifesciadvisors.com

Media ContactCait Williamson, Ph.D.LifeSci Public Relations, LLC646-751-4366cait@lifescicomms.com

Originally posted here:
Oncocyte Announces the Commercial Availability of DetermaRx, the First Test for Chemotherapy Benefit Prediction in Patients with Early Stage Non-Small...

Scientists Have Built The First-Ever Robots Constructed Entirely Out of Living Cells – ScienceAlert

By Embryonic Stem Cells

In another lifetime, if they had been allowed to follow their natural development, the stem cells taken from embryonic frogs would have turned into skin and heart tissue within living, breathing animals.

Instead, in configurations designed by algorithms and constructed by humans, those cells have been assembled into something new: the first-ever robots constructed entirely out of living cells.

The creators have called them xenobots; tiny, submillimetre-sized blobs containing between 500 and 1,000 cells that have been able to scoot across a petri dish, self-organise, and even transport minute payloads. These xenobots are unlike any living organism or organ we've encountered or created to date.

The possibilities for custom living machines designed for a variety of purposes, from targeted drug delivery to environmental remediation, are pretty mind-blowing.

"These are novel living machines," said computer scientist and roboticist Joshua Bongard of the University of Vermont.

"They're neither a traditional robot nor a known species of animal. It's a new class of artifact: a living, programmable organism."

Designing the xenobots required the use of a supercomputer, and an algorithm that could virtually put together a few hundred frog heart and skin cells in different configurations (somewhat like LEGO bricks), and simulate the results.

The scientists would assign a desired outcome - such as locomotion - and the algorithm would create candidate designs aimed to produce that outcome. Thousands of configurations of cells were designed by the algorithm, with varying levels of success.

The least successful configurations of cells were tossed out, and the most successful were kept and refined, until they were about as good as they were going to get.

Then, the team selected the most promising designs to physically build out of cells harvested from embryonic African clawed frogs (Xenopus laevis).This was painstaking work, using microscopic forceps and an electrode.

When they were finally put together, the configurations were actually able to move around, as per the simulations. The skin cells act as a sort of scaffolding to hold everything together, while the contractions of the heart cell muscles are put to work to propel the xenobots.

These machines moved about an aqueous environment for up to a week without the need for additional nutrients, powered by their own 'pre-loaded' energy stores in the form of lipids and proteins.

One design had a hole through the middle in an attempt to reduce drag. This hole could be exapted into a pouch for transporting objects, the team found; as they evolved the design, they incorporated the pouch and transported an object in a simulation.

(Kriegman et al., PNAS, 2019)

The xenobots moved objects around in the real world, too. When their environment was scattered with particulates, the xenobots spontaneously worked together, moving in a circular motion to push the particulates into one spot.

It's fascinating work. According to the researchers, their efforts can provide invaluable insight into how cells communicate and work together.

"You look at the cells we've been building our xenobots with, and, genomically, they're frogs. It's 100 percent frog DNA - but these are not frogs. Then you ask, well, what else are these cells capable of building?" said biologist Michael Levin of Tufts University.

"As we've shown, these frog cells can be coaxed to make interesting living forms that are completely different from what their default anatomy would be."

Although the team calls them 'living', that may well depend on how you define living creatures. These xenobots are not able to evolve on their own, there are no reproductive organs, and they are unable to multiply.

When the cells run out of nutrients, the xenobots simply become a small clump of dead cells. (This also means they are biodegradable, which gives them another advantage over metal and plastic robots.)

Although the current state of the xenobots is relatively harmless, there is the potential for future work to incorporate nervous system cells, or develop them into bioweapons. As this field of research grows, regulation and ethics guidelines will need to be written, applied and adhered to.

But there is plenty of potential good, too.

"We can imagine many useful applications of these living robots that other machines can't do," Levin said, "like searching out nasty compounds or radioactive contamination, gathering microplastic in the oceans, travelling in arteries to scrape out plaque."

The research has been published in PNAS, and the team has made their source code freely available on Github.

Original post:
Scientists Have Built The First-Ever Robots Constructed Entirely Out of Living Cells - ScienceAlert

Koepka Ready to Get Back to Work After Nearly 3 Months Off – The New York Times

By Stem Cell Treatment

HONOLULU Brooks Koepka hasn't been the same since he tied for third in the FedEx Cup final in August, and hasn't felt entirely healthy since last March.

He wouldn't rate himself full strength now.

Koepka returns to competition this week in the Abu Dhabi HSBC Championship, his first tournament since he reinjured his left knee in South Korea at the CJ Cup. He said Tuesday his left knee doesn't feel the same as my right.

It probably won't for a while, but it does feel stable, Koepka said. Leaving Korea and all the way up to about a month ago, it just didn't feel stable. It felt like it could either way. It could go left, out, back.

Koepka says he's had issues since March and just dealt with them. He still managed to win the PGA Championship for the second straight year and pick up his first World Golf Championship. During his short offseason, Koepka had stem cell treatment on his left knee because the patella tendon was partially torn.

Then, he was walking off a tee when he slipped on a wet piece of cement, went to brace himself from falling and reinjured the knee. He said his knee cap moved into the fat pad, which he described as excruciating.

He had physical therapy in San Diego for most of December and says he started hitting balls right before Christmas. Koepka said he wouldn't have flown to the United Arab Emirates if he didn't feel healthy, and that his speed and everything else about his game were the same as before he was hurt at the CJ Cup.

"From that moment on, after a couple days of hitting balls and not feeling pain, it was like, 'OK, I could get back here and do this and finally play,'" he said.

A NAME FROM THE PAST

The first player of note from an emerging golf nation is not always the best one. As Li Haotong of China was making his debut at the Presidents Cup, Guan Tianlang was preparing to qualify for the PGA Tour Series-China.

Guan, who won the Asia-Pacific Amateur and then made the cut at the Masters and Zurich Classic when he was 14, made it through. Despite closing with a 79, he tied for 10th last week to earn full status for the season in China.

Guan is a sophomore at Arizona and is still an amateur.

"I think I will turn pro soon," he said, adding there was a "good chance" he would play China's opening tournament. But I still need some time to think about everything. I might also balance school and play professional events.

Guan says he expected some highs and lows after his Masters performance. "I think that I'm trending in the right direction now," he said.

G-MAC STYLE

Graeme McDowell can add his name to the list of players who went searching for distance and lost sight of their game.

McDowell was enthusiastic at the Sony Open, and that was before he closed with rounds of 67-64 for the best weekend score at wet Waialae. It gave him a tie for fourth, his best finish since winning in the Dominican Republic last spring.

He attributes that to getting back to his normal flight with irons.

McDowell started working in August with Kevin Kirk, also the swing coach for Patrick Reed.

"The first thing I said was I've got to start hitting it lower again," McDowell said. I'm not playing the wind anymore. That was my bread and butter.

He still works with Pete Cowen, but McDowell said their schedules didn't mesh as much with McDowell out of the top 50 and not playing in all the majors or World Golf Championships.

Where did he lose his way?

"It probably came from trying to launch the drive too high in a little search for a wee bit of distance," he said. I got an iron in my hand, it was vertical. That's not me. I need to hit the ball back down to a good window.

For two weeks in the Hawaii wind, he said he was back to G-Mac style.

SHORT ROAD, LONG SHOT

For the host country of the Tokyo Olympics, Hideki Matsuyama (No. 21) and Shugo Imahira (No. 33) are the leading candidates to represent Japan.

Next in line is Ryo Ishikawa at No. 83. Ishikawa showed signs of getting back to form last year when he won three times on the Japan Golf Tour, his first titles since 2016 and his biggest year in Japan since 2010. The problem facing him now is a schedule.

Ishikawa is part of a solid field this week in the Singapore Open, co-sanctioned by Japan. Among those playing are Justin Rose, Henrik Stenson and Matt Kuchar. Otherwise, the Japan Golf Tour season doesn't start until a week after the Masters. That would leave Ishikawa only six events on his home tour before the cutoff for the Olympics.

Ishikawa is looking for sponsor exemptions, with his eye on the Genesis Invitational at Riviera and perhaps the Arnold Palmer Invitational at Bay Hill. He made his U.S. debut at Riviera in 2009 when he was 17.

POLICY BOARD

Six new players were selected for the 16-member Player Advisory Council this year, the group tasked with listening to players and conveying their thoughts to the four members of the PGA Tour's policy board. The newcomers include Russell Knox and Harry Higgs.

More telling was who was put up for election as PAC chairman, who next year would join the policy board Justin Thomas, Charley Hoffman and Peter Malnati. That assures a streak that probably should have ended long ago. No foreign-born player has ever been on the policy board.

Last year, 48 of the 125 players who qualified for the FedEx Cup postseason were international players, including 12 of the 30 who reached the Tour Championship.

The others on the PAC: Ryan Armour, Paul Casey, Zach Johnson, Anirban Lahiri, Rory McIlroy, Jon Rahm and Harold Varner III all served last year. Also new for this year are David Hearn, Billy Horschel, Ryan Palmer and Kevin Streelman.

Missing from the list is Bryson DeChambeau. Last year at The Northern Trust, when he was criticized for how long it took him to play a shot, DeChambeau said, I've asked to be on the PAC committee for three years, and it takes time to get on there.

Higgs is a rookie, although the PAC is evenly populated by players young and old, high and low in the FedEx Cup.

The election for PAC Chairman ends on Feb. 7.

DIVOTS

Collin Morikawa's three-putt from 4 feet on the final hole of the Sony Open took him from a potential four-way tie for ninth to a seven-way tie for 21st. Perhaps more than a difference of $108,900 if he had made the short birdie, Morikawa would have moved to No. 50 in the world. He's No. 53. Morikawa needs to be in the top 50 a week before the Masters to get an invitation. ... Inbee Park is returning to Australia for the first time in six years. Park, voted the LPGA Tour's best player of the last decade, plans to play the Vic Open and the Australian Ladies Masters in February. ... The last seven rounds on the PGA Tour in Hawaii were played under lift, clean and place rules.

STAT OF THE WEEK

Lanto Griffin was 7-under par on the 18th hole of the Sony Open. He played the other 68 holes in 1 under.

FINAL WORD

I think we know all four tournaments that I'm looking forward to. I think that's pretty obvious. Brooks Koepka. Four of his seven victories since 2017 have been majors.

Follow this link:
Koepka Ready to Get Back to Work After Nearly 3 Months Off - The New York Times