Statin use alone or with metformin may increase survival in high-risk prostate cancer patients

In continuation of my update on metformin

Among high-risk prostate cancer patients - those with high PSA and Gleason scores of 8 or more - many will develop a difficult-to-treat disease. Preliminary research suggests that two commonly prescribed medications, cholesterol-lowering statins and the diabetes therapy metformin may have anticancer effects. However, it is unclear which of these two medications - commonly prescribed together -- contributes the most and whether they can impact high-risk prostate cancer. New research shows that statins, alone or with metformin, increase survival in men with high-risk prostate cancer.

"Both metformin and statins have been associated with longer life in prostate cancer patients, yet because they are commonly prescribed together, no study we know of has looked at these two medications separately," says senior author Grace Lu-Yao, PhD, associate director of Population Science at the Sidney Kimmel Cancer Center--Jefferson Health, one of only eight NCI-designated cancer centers nationwide with a prostate cancer program of excellence.

The study, published in Cancer Medicine on Feb 8th, looked at a number of statin therapies, and metformin, an anti-diabetic medication, in high-risk prostate cancer populations.

Using data from the Surveillance, Epidemiology and End Results (SEER-18) database linked with Medicare files, Dr. Lu-Yao and colleagues looked at patients diagnosed with cancer from 2007 through to 2011. Based on 12,700 patients, the researchers observed that statins alone or in combination with metformin was significantly associated with reduced mortality from all causes.

Dr. Lu-Yao and colleagues saw the highest median survival of 3.9 months in men who took both metformin and statins, 3.6 with statins alone and 3.1 years with metformin alone. The median survival for those who did not use either drug was also 3.1 years.

With respect to prostate mortality, metformin plus statin was associated with a 36% reduction in risk of death followed by statins alone. Those taking metformin alone were relatively rare, and there was no significant association with all-cause mortality."

Interestingly, the study revealed that men who took atorvastatin, pravastatin, or rosuvastatin - but not lovastatin - demonstrated a reduction in mortality compared with non-users, which is consistent with the findings from a recent population-based cohort study using Taiwan National Health Insurance Research Data. The Taiwanese research showed that these three statins are more effective at lowering triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol than other statins in patients with hypercholesterolemia.

Of the three statins studied, men on atorvastatin did have a longer median time to progression on androgen deprivation therapy compared to those who weren't treated with statins. "Although the exact mechanisms remain unknown, it is worth noting that atorvastatin exhibits a potent lipid-lowering effect per dose of any statin, and has the greatest bioavailability and one of the longest half-lives," says to Dr. Lu-Yao.

The data presented in the current study provide crucial insight for the design of future randomized clinical trials of statin for high-risk patients with prostate cancer. Based on the existing evidence, a well-designed clinical trial is warranted to investigate the roles of statins and combination statins/metformin to reduce the mortality cancer of the prostate.

"Our study showed that the effects were more pronounced in patients taking statins after the diagnosis of prostate cancer, 54% reduction in PCA mortality among patients with high-risk prostate cancer," says Lu-Yao. "This magnitude of reduction is comparable to the results of men treated with androgen signaling inhibitors." Statins are relatively inexpensive with good safety records. Further studies to understand the mechanisms of the observed association and its potential clinical utility are warranted.

https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2862

Metformin could help leaky gut

In continuation of  my update on metformin

A team of researchers from University of California, San Diego, have successfully used gut organoids in their lab to show the effects of medications to treat conditions such as “leaky gut”. The study was titled, “The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer,” and was published in the journal Life Science Alliance today..

The team found that they could use 3 dimensional gut cells in a Petri dish in the form of a gut organoids and test the drugs for their efficacy on leaky guts. These organoids can successfully recreate the molecular system within the lab including intestinal lining cells etc. These cells are normally sealed to prevent leakage. In certain disease conditions, the seals may be dysfunctional leading to leaky guts, wrote the researchers. These conditions are commonly seen in cancers and among the elderly, they explained. In this condition there may be leakage of microbes as well as vital molecules from the intestines into the abdominal cavities.

To create these organoids the team used donated intestinal cells from the patients. The intestines typically have crests and crypts with peaks and valleys. From the crypts they could isolate stem cells. These cells were used to create the three dimensional organoids within the labs, the team wrote. The stem cells grew to become four types of cells that normally are noted within the gut. These cells then rolled up to become mini guts within the Petri dishes they wrote. Now the organoids were capable of being tested.

University of California San Diego School of Medicine researchers thus used 3D models of human intestines in the petri dishes. These cells were donated by real patients suffering from leaky gut. The cells were created into 3D mini organoids so that they could mimic the real intestines. The team then found certain biomarkers that were characteristic of intestines that had the leakage problem. The team speculates that these markers could help researchers diagnose this condition early and also track the progression of the disease over a course of time.

For their study they used a commonly used diabetes medicine Metformin to try and plug the leaks within the intestinal walls. The study led by Pradipta Ghosh, MD, professor of cellular and molecular medicine at UC San Diego School of Medicine and Moores Cancer Center, and senior author Soumita Das, PhD, associate professor of pathology at UC San Diego School of Medicine, revealed that this commonly used drug could help patients with a leaky gut.

Ghosh and Das had earlier, in another study showed that a mechanism called the stress-polarity signaling pathway could help close the gaps between the cells and prevent the leakage. In that study they had also noted that the connections and bonds between the cells came apart due to the stress.

This new study revealed that Metformin may work to activate certain chemical reactions that could tighten these junctions and thus prevent the leakage. The team says that their success has been seen only in the Petri dishes on the mini organoids of the gut yet. They need to replicate it in humans to see if the drug could actually help patients with leaky gut conditions. They added however that the success of the drug in these organoids is a big step in proving that the drug could actually help. Metformin, they wrote raise the levels of a protein called occluding that can tighten the junctions between cells. If successful, this could help a large number of patients, they explained.

Ghosh said, “Lots of research is done in mice that are inbred so that they are genetically identical, all in the same cage, eating the same diet, in order to remove these variables from the studies. But lab mice are far more standardized than the same human from day to day, or patients we see in the clinics. Here, our model is a better representation of humanity. On the other hand, it also means that each organoid is its own unique experiment. We have to test many organoids to be able to make any claim, which we did in our study.” Das added, “I think you'd be hard pressed to find a disease in which systemic inflammation is not a driver. That's why, even though there are so many things we still don't know, we're excited about the broad potential this model and these findings open for developing personalized leaky gut therapeutics that target AMPK and the stress-polarity signaling pathway.”

There may be several disease conditions that lead to weakening of the bonds between the cells and the junctional cells between two intestinal cells, wrote the researchers. This leads to leakage of the molecules from within the intestines as well as leakage of microbes. This can trigger the immune system leading to a state of chronic inflammation. Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease as well as other conditions such as liver damage, cancers, diabetes, atherosclerosis, arthritis and even dementia could be associated with leaky gut cells say researchers. Till date there have been no way this problem could be studied, let alone solved, wrote the researchers. This new study finally paves a way where the condition could be replicated in the lab and studied at its molecular level.

For this study the team took the mini organoids and opened up the rolled balls to expose the intestinal surface. Over these they used bacteria and other stressors to weaken the junctional cells and create leaky openings. Now they could study the molecular mechanisms as well as the drugs which could help tightening these bonds between the cells to prevent leakage.

https://www.life-science-alliance.org/content/3/3/e201900481

https://en.wikipedia.org/wiki/Metformin

Meta-Analyses Link Rosiglitazone to Increased Cardiovascular Risk

In continuation of my update on Rosiglitazone

Rosiglitazone seems to be associated with an increased cardiovascular risk, particularly heart failure, according to data from a systematic review and meta-analyses published online Feb. 5 in The BMJ.

Joshua D. Wallach, Ph.D., from the Yale School of Public Health in New Haven, Connecticut, and colleagues conducted a systematic review and individual patient-level data (IPD) and summary-level meta-analyses of randomized, controlled, phase II to IV clinical trials that compared rosiglitazone to any control in adults. Data were included from 33 eligible trials for which IPD were available (21,156 patients). Data from 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction and cardiovascular-related death (23,683 and 22,772 patients, respectively).

The researchers found that when analyses were limited to trials with IPD and trials with zero events in only one arm were accounted for, the risk for the composite outcome (acute myocardial infarction, heart failure, cardiovascular-related death, and non-cardiovascular-related death) was increased for rosiglitazone-treated patients versus controls (odds ratio, 1.33; 95 percent confidence interval, 1.09 to 1.61). The odds ratios were 1.17 (0.92 to 1.51) for myocardial infarction, 1.54 (1.14 to 2.09) for heart failure, 1.15 (0.55 to 2.41) for cardiovascular-related death, and 1.18 (0.60 to 2.30) for non-cardiovascular-related death. The odds ratios for myocardial infarction and cardiovascular-related death were attenuated for analyses including trials for which IPD were not available.

"This finding suggests that IPD might be necessary to accurately classify all adverse events when performing meta-analyses focused on safety," the authors write.

Several authors disclosed financial ties to the pharmaceutical, medical device, legal, and medical technology industries.

https://www.bmj.com/content/368/bmj.l7078

https://en.wikipedia.org/wiki/Rosiglitazone

New method to treat cancer with iron oxide nanoparticles

The concept is based on the interaction of resonant semiconductor iron oxide Fe2O3 nanoparticles with light. Particles previously loaded with the antitumor drug are injected in vivo and further accumulate at the tumor areas. In order to release the drug non-invasively, the carrier particles have to be light-sensitive. For this purpose, the polymer containers (capsules) can be modified with iron oxide resonant semiconductor nanoparticles. When irradiated with light, they get heated and induce drug release. The research was published in Laser and Photonics Reviews.

Nowadays, there are anti-cancer drugs that can effectively treat malignant tumors. Regrettably, they have an effect on not just malignant cells and tissues but also on healthy ones. Therefore, there is a need of new approaches to treat cancer. A powerful method to overcome the mentioned barrier is the delivery of drugs with micro- and nanoparticles that make it possible to accumulate large amounts of drugs near the tumor region with a minimum systemic concentration of these highly toxic drugs in the organism as a whole.

Another advantage of iron oxide nanoparticles is that it is not just an efficient nanoheater, but also a local nanothermometer. This means that you can control the temperature when heating the particles, therefore, preventing overheating of healthy cells and tissues.

We've tested our systems in-vitro on stem and tumor cells. Stem cells were used as a model of healthy cells in the experiment and tumor cells as a model of diseased cells. As a result, the anti-tumor drug affected tumor cells as they were irradiated with a laser, and almost no toxicity was observed in healthy cells. The control cells also survived the experiment, which means that tumor cells died as a result of the drug release. This is how we created efficient light-sensitive systems for optically driven drug delivery."

Mikhail V. Zyuzin, researcher at ITMO's Faculty of Physics and Engineering

The drug delivery systems can also be used as local nanothermometers, which makes them cross-functional.

"In this case, nanoparticles as both converters of light into heat and a thermometer. The point here is that it is very hard to measure temperature in such small areas. For example, there are methods that make use of dyes that burn out and stop giving light at a specific temperature. But the problem is that the only thing that we can understand from that if where the temperature is higher or lower than some specific value, yes or no. We will not get any details. On the other hand, semiconductor nanoparticles can efficiently absorb light and convert it into heat. Because of that, the oscillation frequency of their crystalline lattice slightly changes, and the light starts to dissipate in a different manner. We can use these changes to tell how much did we heat the particle, as well as see this data on a spectrometer," explains George Zograf.

In 2017, George Zograf, a PhD student at ITMO's Faculty of Physics and Engineering under the guidance of professor Sergei Makarov published a scientific work dedicated to optically-induced heating and simultaneous temperature measurement of resonant semiconductor nanoparticles. Some time later, Mikhail V. Zyuzin, a researcher at ITMO's Faculty of Physics and Engineering who specializes in biophysical research, joined the team. His help made it possible to apply the effects that George and Sergei studied earlier in the fields of biology and medicine, namely in drug delivery.

An international team of physicists, chemists and biologists performed an interdisciplinary study in the field of the non-invasive release of drugs encapsulated in polymer capsules under optical radiation. Scientists from ITMO University were responsible for the synthesis and optical characterization of iron oxide nanoparticles, as well as polymer capsules. Their French colleagues helped with structural characterization of synthesized materials. Chinese researchers helped to visualize the process of the release of bioactive compounds from capsules under laser irradiation, finally, researchers from the First Pavlov State Medical University of St. Petersburg conducted experiments on the delivery of an anti-cancer drug in primary tumor cells.

The researchers plan to continue their work and develop their current results. They have plans to conduct pre-clinical trials on animals in-vivo next year.

More....

Novel drug therapy shows promise for quality, quantity of kidneys available for transplant

Researchers from Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center (UH), Cleveland Clinic and Lifebanc (a Northeast Ohio organ-procurement organization) have developed a new way to preserve donated kidneys—a method that could extend the number and quality of kidneys available for transplant, saving more people with end-stage renal disease, more commonly known as "kidney failure."

    

The team identified a drug—ethyl nitrite-See structure 1—that could be added to the preservation fluid to generate tiny molecules called S-nitrosothiols (SNOs) see structure 2, which regulate tissue-oxygen delivery. This, in turn, restored flow-through and reduced resistance within the kidney. Higher flow-rates and lower resistance are associated with better kidney function after transplantation.

Their research was funded by a grant from the Roche Organ Transplant Research Foundation and recently published in Annals of Surgery.

The United States has one of the world's highest incidences of end-stage renal disease, and the number of afflicted individuals continues to increase. The prevalence of end-stage renal disease has more than doubled between 1990 and 2016, according to the Centers for Disease Control.

The optimal treatment is a kidney transplant, but demand far exceeds supply. Additionally, donation rates for deceased donors have been static for several years, despite various public-education campaigns, resulting in fewer kidneys available for transplant. And while the proportion and number of living donors has increased, this latter group still only makes up a small percentage of recovered kidneys for transplant.

Increasing the number of kidneys available for transplant benefits patients by extending lifespans and/or enhancing quality of life as well as the potential for reducing medical costs (a transplant is cheaper than ongoing dialysis). To help improve outcomes for kidney transplant patients, the team explored ways to extend the viability of donated kidneys.

Improvements in surgical techniques and immunosuppression therapies have made kidney transplants a relatively common procedure. However, less attention has been paid to maintaining/improving kidney function during the kidney-transport phase.

"We addressed this latter point through developing enhanced preservation methods," said senior author James Reynolds, professor of Anesthesiology and Perioperative Medicine at Case Western Reserve School of Medicine and a member of the Harrington Discovery Institute at UH.

For decades, procured kidneys were simply flushed with preservation solution and then transported in ice-filled coolers to the recipient's hospital. But advances in pumping technology slowly changed the field toward active storage, the preferred method for conveying the organ from donor to recipient.

"However, while 85% of kidneys are now pumped, up to 20% of kidneys are determined to be unsuitable for transplant during the storage phase," said Kenneth Chavin, professor of surgery at the School of Medicine, chief of hepatobiliary and transplant surgery and director of the UH Transplant Institute.

"For several years, our team has directed research efforts toward understanding and improving the body's response to medical manipulation," Reynolds said. "Organ-donor physiology and 'transport status' fit well within this metric. We identified a therapy that might improve kidney perfusion, a significant factor in predicting how the organ will perform post-transplant."

Previous work by Reynolds and long-time collaborator Jonathan Stamler, the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation and president of the Harrington Discovery Institute, determined that brain death significantly reduces SNOs, which impairs blood-flow and tissue-oxygenation to the kidneys and other commonly transplanted organs. The loss of SNOs is not corrected by current preservation fluids, so impaired flow through the kidneys continues during storage and transport.

https://journals.lww.com/annalsofsurgery/Abstract/publishahead/A_Novel_Method_to_Improve_Perfusion_of_Ex_Vivo.94769.aspx

https://en.wikipedia.org/wiki/Ethyl_nitrite

https://en.wikipedia.org/wiki/S-Nitrosothiol

New substance prevents vascular calcification

Researchers at ETH Zurich and ETH spin-off Inositec have developed a new substance to prevent vascular calcification, which affects many patients suffering from chronic kidney disease. As their metabolism is impaired, calcium salts may deposit in soft tissues, such as blood vessels or even the heart valves, causing them to stiffen. This often leads to severe, potentially fatal cardiovascular diseases. However, before patients can benefit from the substance further research and tests must be carried out.

"Calcification occurs when calcium phosphate crystals are deposited in tissue," explains Jean-Christophe Leroux, professor of drug formulation and delivery at ETH Zurich. "The compound adheres to calcium phosphate crystals, inhibiting their growth."

Derivative of a natural substance

The new molecule is structurally related to inositol hexakisphosphate, also known as IP6. Occurring naturally in legumes and cereals, IP6 binds phosphate and various minerals, such as calcium, magnesium and iron. The plants use the molecule in their seeds to provide the seedlings with a sufficient supply of these substances.

It has been known for some time that IP6 also has an effect in the human bloodstream. The molecule has to be injected as it cannot be absorbed after oral ingestion. Other scientists are currently conducting clinical trials to study how effectively IP6 prevents vascular calcification.

Screening the collection of molecules

"The problem, though, is that IP6 is not particularly stable and is metabolized by the body very quickly," Antonia Schantl says. A doctoral student in Leroux's group, she is the lead author of the paper that has been published in the journal Nature Communications. In order to overcome this problem, Leroux and his colleagues sought to stabilize the molecule by making specific chemical modifications. They developed a series of related molecules, which ETH then patented. To be able to market one or more of these derivatives as medication in the future, ETH Professor Leroux and others involved founded the spin-off Inositec, which acquired the licence from ETH to use the molecule family.

Leroux's group at ETH subsequently collaborated with Inositec and researchers from other universities to screen this collection of molecules in a project that was co-financed by the Swiss innovation agency Innosuisse. The scientists conducted in vitro experiments to study the molecules' ability to inhibit the growth of calcium phosphate crystals in the blood and check their stability. They also tested their effect in a disease model in rats. The studies singled out one of the molecules in the collection as particularly suitable.

For the next stage, the ETH scientists will work with Inositec and third parties to clarify various issues, such as drug safety and the optimal dosage.

https://www.nature.com/articles/s41467-019-14091-4
https://en.wikipedia.org/wiki/Phytic_acid

Team finds that their cancer-fighting compound fights obesity and diabetes, too

Eric Prossnitz, Ph.D., and his team hope to help 93 million obese Americans fight their fat.

In a paper published in Science Translational Medicine, they reported that G-1, a cancer-fighting compound they discovered some years ago, reduces fat in obese mice. Although G-1 is currently in phase 1 clinical trials for cancer, Prossnitz and his team are planning preclinical studies to use G-1 to fight fat in obese people.

Obesity affects 40% of adults in the United States, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the U.S. Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity don't effectively reduce it or have undesirable side effects.

Prossnitz and his team have been studying GPER, the G protein-coupled estrogen receptor that G-1 activates, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block estrogen receptors in a cell's nucleus, they also activate GPER, which is found in cell membranes.

Prossnitz's previous studies showed that GPER may play a role in resistance to tamoxifen and similar drugs, and that led him to wonder how G-1 affects non-cancerous cells when estrogen is lacking.

Estrogen is considered a female hormone, although men produce it at low levels. Low estrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. So to understand whether G-1 might affect metabolism in postmenopausal women, Prossnitz and his team studied mice with low estrogen levels.

In their studies, low-estrogen female mice gained weight rapidly, even on a normal diet, and quickly became obese and diabetic. When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went away.

The researchers determined that the weight loss wasn't due to the mice eating less or moving around more; it resulted from what their bodies did with the calories they ate. Instead of storing calories as fat, the mice used them as fuel.

"Their metabolism changed," Prossnitz says. "The mice showed an increased energy expenditure."

Prossnitz's team also studied male mice, which have naturally low levels of estrogen. The male mice were fed a high-fat diet, which made them obese and diabetic, and then some were treated with G-1. Although the treated mice did not lose weight, they did not gain additional weight either, like the untreated mice. More importantly, their diabetes improved.

"This result suggests that G-1 has separate effects on obesity and diabetes," Prossnitz says. "The G-1-treated male mice were metabolically healthier, even though they were still obese."

Finally, the team also fed a high-fat diet to low-estrogen female mice. These mice became obese very quickly, but just like their sisters on a normal mouse diet, they lost weight and their diabetes improved when they were treated with G-1. These results, says Prossnitz, could point to a sex difference in the effects of the drug or in the way GPER signals in the cells of males and females.

To learn about how G-1 increases energy expenditure, the team studied brown fat cells, which generate heat instead of storing excess calories as fat. What they found surprised them: when treated with G-1, the cells expended more energy.

"This fits nicely with what we saw in mice," Prossnitz says, "and suggests that G-1 may reduce obesity by targeting brown fat cells that burn extra calories."

In a future series of experiments, Prossnitz plans to study how signals from GPER induce the cellular changes that cause more energy to be used. He hopes that one day soon G-1 could revolutionize the treatment of metabolic disorders.

In the meantime, he and his team are starting the long path toward clinical trials that will test the ability G-1 to fight obesity and diabetes in people.

https://stm.sciencemag.org/content/12/528/eaau5956/tab-figures-data

Chinese scientists ask for patent on US drug to fight virus

In continuation of my update on Remdesivir

Scientists in the city at the center of China's virus outbreak have applied to patent a drug made by U.S. company Gilead Sciences Inc. to treat the disease, possibly fueling conflict over technology policy that helped trigger Washington's tariff war with Beijing.

The government-run Wuhan Institute of Virology said this week it applied for the patent in January along with a military laboratory. An institute statement acknowledged there are "intellectual property barriers" but said it acted to "protect national interests."

Granting its own scientists a patent might give the Chinese government leverage in negotiations over paying for the drug. But it also might fuel complaints Beijing abuses its regulatory system to pressure foreign companies to hand over valuable technology.

On Thursday, the official Xinhua News Agency said clinical trials of the drug, remdesivir, were due to start.

Gilead, headquartered in Foster City, California, said it applied in 2016 for a Chinese patent on use of remdesivir against coronaviruses and is waiting for a decision. The coronavirus family includes the novel coronavirus, or 2019-nCoV, blamed for the outbreak in Wuhan.

"Gilead has no influence over whether a patent office issues a patent to the Chinese researchers," said a company spokesman, Ryan McKeel. "Their application has been filed more than three years after Gilead's filing and will be considered in view of what is already known about the compound and pending patent applications."

The institute said its application was filed Jan. 21. Two days later, Chinese authorities suspended most access to Wuhan, a city of 11 million people. That lockdown has expanded to surrounding cities and some in other provinces, isolating a total of about 60 million people in the most sweeping anti-disease measures ever imposed.

China has the right under World Trade Organization rules to declare an emergency and compel a company to license a patent to protect the public. It would be required to pay a license fee that is deemed fair market value.

The government might be able to avoid that fee if the patent were granted to the Wuhan institute, part of the elite Chinese Academy of Sciences.

The institute said it applied for a "use patent" that specifies the Wuhan virus as the drug's target. Gilead's patent application, filed before the virus was identified, cites only the overall family of coronaviruses.

The Chinese researchers made their patent application "from the perspective of protecting national interests," said the institute statement.

"If relevant foreign companies plan to contribute to China's epidemic prevention and control, we both agree that if the state needs it, we will not require enforcement of rights given by the patent," it said.

Gillead said last week it was working with U.S. and Chinese health authorities on studying remdesivir. The company said it has provided the drug for emergency use in a small number of patients with the Wuhan virus "in the absence of any approved treatment options."

https://www.bloomberg.com/news/articles/2020-02-03/gilead-drug-to-undergo-human-trials-in-china-to-cure-coronavirus

https://www.med-chemist.com/search?q=remdesivir

Chemical found in drinking water linked to tooth decay in children

Children with higher concentrations of a certain chemical in their blood are more likely to get cavities, according to a new study by West Virginia University School of Dentistry researchers.

Manufactured chemical g roups called perfluoroalkyl and polyfluoroalkyl substances are universal as a result of extensive manufacturing and use. Although manufacturers no longer use PFAS to make nonstick cookware, carpet, cardboard and other products, they persist in the environment. Scientists have linked them to a range of health problems—from heart disease to high cholesterol—but now R. Constance Wiener and Christopher Waters are exploring how they affect dental health.

They investigated whether higher concentrations of PFAS were associated with greater tooth decay in children. One of them—perfluorodecanoic acid—was linked to dental cavities. Their findings appear in the Journal of Public Health Dentistry.

"Due to the strong chemical bonds of PFAS, it is difficult for them to breakdown, which makes them more likely to be persistent within the environment, especially in drinking water systems," said Waters, who directs the School of Dentistry's research labs. "A majority of people may not be aware that they are using water and other products that contain PFAS."

The 629 children who participated in the study were 3 to 11 years old and were part of the National Health and Nutrition Examination Survey. Samples of the children's blood were analyzed for PFAS in 2013 and 2014. Their tooth decay and other factors—such as their race, their BMI and how often they brushed their teeth—were assessed.

Of the seven PFAS that Wiener and Waters analyzed, perfluorodecanoic acid was the one that correlated with higher levels of tooth decay.

"Perfluorodecanoic acid, in particular, has a long molecular structure and strong chemical bonds; therefore, it remains in the environment longer. As a result, it is more likely to have negative health consequences such as dental caries," said Dr. Wiener, an associate professor in the Department of Dental Practice and Rural Health.

But how does that influence happen? Wiener and Waters have a hypothesis. According to other research, perfluorodecanoic acid may disrupt the healthy development of enamel, which is what makes teeth hard. That disruption can leave teeth susceptible to decay.

However, when it comes to cavities, scientists haven't parsed perfluorodecanoic acid's mechanism of action yet. The topic warrants further investigation.

"While the findings of this study are important, there are some study limitations, and more work is needed to fully understand how this molecule impacts normal tooth formation," said Fotinos Panagakos, the School of Dentistry's vice dean for administration and research.

"The good news is that, in our study, about half of the children did not have any measurable amount of PFAS. Perhaps this is due to certain PFAS no longer being made in the US," Wiener said.

Another piece of good news is that the study reaffirmed the importance of dental hygiene and checkups. Children who brushed once a day or less frequently had significantly higher tooth decay than those who brushed at least twice daily.

Likewise, children who had not been to the dentist within the previous year were twice as likely to have higher rates of tooth decay than kids who hadn't.

So, even though parents cannot control what is in their children's drinking water, they can still protect their children's teeth by fostering thorough, regular brushing and scheduling dental exams.

The School of Dentistry will hold Give Kids a Smile Day on Friday, Feb. 7, at the Pediatric Dentistry Clinic. Dental students will treat more than 100 children for free that day. Each visit includes an exam, a cleaning, a fluoride treatment and—if appropriate—X-rays.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jphd.12329

https://www.epa.gov/pfas

https://www.epa.gov/pfas/basic-information-pfas

https://www.epa.gov/pfas/basic-information-pfas

Botanical drug is shown to help patients with head and neck cancers

In continuation of my update on Curcumin

In a UCLA-led phase I clinical trial, a new plant-based drug called APG-157 showed signs of helping patients fight oral and oropharyngeal cancers. These cancers are located in the head and the neck.

APG-157  (a botanical drug containing multiple polyphenols, including curcumin see above structure), is made up of multiple compounds produced by plants, including curcumin. UCLA Jonsson Comprehensive Cancer Center researchers found that treatment with this botanical drug resulted in high concentrations of curcumin and its byproducts circulating in the blood and absorbed by tumor tissues within three hours after being taken orally.

APG-157 reduced the concentration of cytokines—proteins involved in inflammation—in the saliva when administered to cancer patients. The therapy also reduced the relative abundance of Bacteroides species, a group of gram-negative bacteria. Gram negative refers to a group of dangerous bacteria that have an outer layer which hides them from the immune system. The relative abundance of gram-negative bacteria compared to the presence of other types of bacteria is correlated with oral cancer.

APG-157 also resulted in the expression of genes that are associated with attracting immune system T cells to the tumor area. This therapy could have a beneficial effect when used in combination with immunotherapy drugs that help immune system T cells recognize and kill tumors.

The treatment did not have any adverse effects on the study's participants.

Cancers of the head and neck account for 4% of all cancers. About 650,000 new cases are reported each year around the world. People with advanced head and neck cancers have a low survival rate and current treatment options such as surgery, radiation and chemotherapy can have adverse effects. Therefore, more effective and less toxic therapies are needed to help improve the quality of life and outcome for those with these cancers.

APG-157 is a botanical drug developed under the FDA's Botanical Drug Guidance, which includes requirements for production of plant-based therapies that are marketed as prescription medications. The drug is made up of botanical compounds including curcumin from the Curcuma longa plant, which is commonly referred to as turmeric and is a member of the ginger family.

Curcumin is one of the medicinally active or therapeutic molecules that has been tested as a possible treatment to help fight multiple cancers because it is an antioxidant that reduces swelling and inflammation. However, there is poor absorption into the bloodstream when curcumin is taken orally. In this study, UCLA researchers found that when APG-157 is taken through oral mucosal absorption, patients have high levels of curcumin circulating in their blood and absorbed by cancer tissues.

UCLA researchers conducted the study of APG-157 comparing 12 people who had oral and oropharyngeal cancer with a control group of 13 people who did not have cancer. The reason both the people with cancer and without cancer were part of the study was to show that the drug was not toxic to either people with cancer or those without cancer.

The medication was given each hour for three hours and was delivered as a lozenge that slowly dissolved in the mouth. Blood and saliva samples were collected beforehand—each of the three hours the medication was administered—and 24 hours after the last dosage. The medication was given to 12 people (some who had cancer and some who did not) and a placebo was given to 13 people. Blood and electrocardiogram tests did not show increased toxicity in the people who took the active medication in comparison with the people who took the placebo, regardless of whether they had cancer or not.

For the cancer patients who took the medication, there was a decrease in Bacteroides and an increase in T cells in the tumor tissue as compared to cancer patients who took the placebo. Neither the subjects nor the investigators knew whether the drug or a placebo was given when reviewing the blood and saliva test results of the blinded study.

APG-157 is a botanical drug that has low toxicity. It works effectively to reduce inflammation that contributes to the growth of cancer cells. It also attracts T cells to the tumor micro-environment. When used in combination with immunotherapy drugs, APG-157 might have the ability to make the immune system more effective in attacking head and neck cancers. With potential to inhibit the growth of Bacteroides species, APG-157 could also improve cancer therapy through oral microbial changes.

https://acsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/cncr.32644

Discovery of compound that reverses the fertility clock

                                

Nicotinamide adenine dinucleotide (NAD)     

 Nicotinamide mononucleotide ("NMN", "NAMN", and "β-NMN") 

The reproductive years of a woman are at their peak before the age of 30. Beyond that, fertility starts to decline, and by the age of 40, fertility potential is about half the level it was before 30 years old. Many women experience fertility issues, but now a new study on mice may help reverse the clock on eggs, offering new fertility hope to older women.

A team of scientists at the University of Queensland reports that they have lifted fertility rates in older female mice with the use of a compound, which can reverse the aging process in eggs. The discovery may pave the way for human use in the future, offering hope for some women who are struggling to conceive.

When women reach the age of 40, conceiving is harder and nearly impossible for some women. This loss of fertility is due to poor egg quality, something that becomes a problem in developed countries where women would wait until they're older before they get married and bear children.

Newfound hope

Published in the journal Cell Reports, the study highlights reversing the fertility clock, improving egg quality that's important for pregnancy success. The team found that losing egg quality due to aging was because of the declining levels of a cell molecule that's vital for producing energy.

Taking an oral dose of a precursor compound, which is utilized to create the molecule, can help boost fertility. The molecule called nicotinamide adenine dinucleotide (NAD) and the precursor, nicotinamide mononucleotide (NMN), are key drivers to promote reversal of aging fertility.

To arrive at their findings, the team treated aging female mice with low doses of NMN infused in their drinking water for one month. They found that the mice had restored egg quality and increased live births during a breeding trial.

Assisted reproductive technologies

The new treatment, if applicable to humans, can help maintain and restore egg cell quality during aging. Further, it helps reduce a rate-limiting barrier to pregnancy for older women. With more aging women facing fertility problems, there had been a sharp increase in the demand for assisted reproductive technologies, including In vitro fertilization (IVF).

However, since the study involved mice models, it's essential to conduct further research on humans to determine if the effect of the compound is the same.

"IVF cannot improve egg quality, so the only alternative for older women at present is to use eggs donated by younger women," UQ's Professor Hayden Homer said in a statement.

"Our findings suggest there is an opportunity to restore egg quality and, in turn, female reproductive function using oral administration of NAD-boosting agents – which would be far less invasive than IVF. It is important to stress, however, that although promising, the potential benefits of these agents remains to be tested in clinical trials," he added.

Infertility by the numbers

Infertility is a growing concern among couples who are having a hard time conceiving. The Centers for Disease Control and Prevention (CDC) defines infertility as the inability to get pregnant after one year of unprotected sex; it may be longer for some. For women who are 35 years old and beyond, doctors may begin treatment if they fail to conceive within six months of regular and unprotected sex.

In the United States, about 6 percent of married women between the age of 15 and 44 are having problems conceiving after one year of trying. Moreover, approximately 12 percent of women of the same age group have issues getting pregnant or carrying a pregnancy to term.

About 12 to 13 of 100 couples have trouble becoming pregnant in the country, while ten in 100 or 6.1 million women have problems getting pregnant. Fertility issues in women cause one-third of all infertility cases.

Worldwide, one in every four couples in developing countries are experiencing infertility, but the exact rates are hard to determine. The latest data were responses from women in Demographic and Health Surveys in 2004. However, in a 2010 study by the WHO, it shows that the rates in 190 countries remained similar to the estimated numbers between 1990 and 2010.

https://www.sciencedirect.com/science/article/pii/S2211124720300838?via%3Dihub

https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide

https://en.wikipedia.org/wiki/Nicotinamide_mononucleotide

FDA Approves Ukoniq (umbralisib) for Marginal Zone Lymphoma and Follicular Lymphoma

TG Therapeutics, Inc,   announced the U.S. Food and Drug Administration (FDA) approval of  Ukoniq (umbralisib), for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20 based regimen and adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.


Ukoniq is the first and only, oral, once daily, inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. Accelerated approval was granted for these indications based on overall response rate (ORR) data from the Phase 2 UNITY-NHL Trial (NCT02793583). Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. This application was granted priority review for the MZL indication. In addition, Ukoniq was granted Breakthrough Therapy Designation (BTD) for the treatment of MZL and orphan drug designation (ODD) for the treatment of MZL and FL.
Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, “Today’s approval of Ukoniq marks a historic day for our Company with this being our first approval and we are extremely pleased to be able to bring our novel inhibitor of PI3K-delta and CK1-epsilon to patients with relapsed/refractory MZL and FL. We have built a commercial team with significant experience who will immediately start to engage our customers to educate them on Ukoniq and how to access the product for patients in need and expect to make Ukoniq available to US distributors in the next few days.” Mr. Weiss continued, “We want to thank the patients, physicians, nurses and clinical coordinators for their support and participation in our clinical trials, and the FDA for their collaboration throughout this process. We remain dedicated to patients with B-cell diseases and our mission of developing treatment options for those in need.”
“Despite treatment advances, MZL and FL remain incurable diseases with limited treatment options for patients who relapse after prior therapy and no defined standard of care. With the approval of umbralisib we now have a targeted, oral, once-daily option, offering a needed treatment alternative for patients,” stated Dr. Nathan Fowler, Professor of Medicine at The University of Texas MD Anderson Cancer Center and the Study Chair of the UNITY-NHL MZL &FL cohorts.
“The approval of umbralisib for the treatment of relapsed/refractory marginal zone lymphoma and follicular lymphoma offers patients a new treatment option, and new hope in the fight against these diseases,” stated Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation.
The safety of Ukoniq monotherapy was based on a pooled population from the 221 adults with MZL and FL in three single arm, open label trials and one open label extension trial. Patients received Ukoniq 800 mg orally once daily. Serious adverse reactions occurred in 18% of patients who received Ukoniq. Serious adverse reactions that occurred in ≥2% of patients were diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (>15%), including laboratory abnormalities, were increased creatinine (79%), diarrhea-colitis (58%, 2%), fatigue (41%), nausea (38%), neutropenia (33%), ALT increase (33%), AST increase (32%), musculoskeletal pain (27%), anemia (27%), thrombocytopenia (26%), upper respiratory tract infection (21%), vomiting (21%), abdominal pain (19%), decreased appetite (19%), and rash (18%).

EFFICACY & SAFETY DATA IN RELAPSED/REFRACTORY MZL AND FL

The efficacy of Ukoniq monotherapy was evaluated in two single-arm cohorts, within the Phase 2 UNITY-NHL clinical trial, in 69 patients with MZL who received at least 1 prior therapy, including an anti-CD20 regimen, and in 117 patients with FL who received at least 2 prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The UNITY-NHL Phase 2 trial is an open-label, multi-center, multi-cohort study with patients receiving Ukoniq 800 mg once daily. The primary endpoint was independent review committee (IRC) assessed overall response rate (ORR) according to the Revised International Working Group Criteria.

https://en.wikipedia.org/wiki/Umbralisib