Drug combo reverses arthritis in rats (alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs)

People with osteoarthritis, or "wear and tear" arthritis, have limited treatment options: pain relievers or joint replacement surgery. Now, Salk researchers have discovered that a powerful combination of two experimental drugs reverses the cellular and molecular signs of osteoarthritis in rats as well as in isolated human cartilage cells. Their results were published in the journal Protein & Cell on January 16, 2020.

"What's really exciting is that this is potentially a therapy that can be translated to the clinic quite easily," says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk's Gene Expression Laboratory. "We are excited to continue refining this promising combination therapy for human use."

Affecting 30 million adults, osteoarthritis is the most common joint disorder in the United States and its prevalence is expected to rise in the coming years due to the aging population and increasing rate of obesity. The disease is caused by gradual changes to the cartilage that cushions bones and joints. During aging and repetitive stress, molecules, and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of the underlying bone, causing chronic pain and stiffness.

Previous research had pinpointed two molecules, alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extra-cellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.

While each drug alone had only moderately curbed osteoarthritis in animal models of the disease, Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.

"We thought that by mixing these two molecules that work in different ways, maybe we could make something better," says Paloma Martinez-Redondo, a Salk research associate and first author of the new study.

The researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.

Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals' disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.

"From the very first time we tested this drug combination on just a few animals, we saw a huge improvement," says Martinez-Redondo. "We kept checking more animals and seeing the same encouraging results."

Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works.

To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extra-cellular matrix formation and cartilage cell identity all increased.

"That's not the same as showing how these drugs affect the knee joint in humans, but we think it's a good sign that this could potentially work for patients," says Martinez-Redondo.

The research team plans to develop the treatment further, including investigating whether soluble molecules of the αKLOTHO and TGFβR2 proteins can be taken directly, rather than administered through viral particles. They also will study whether the combination of drugs can prevent the development of osteoarthritis before symptoms develop.

"We think that this could be a viable treatment for osteoarthritis in humans," says Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author.

https://en.wikipedia.org/wiki/Klotho_(biology)

https://en.wikipedia.org/wiki/TGF_beta_receptor_2

Drug combo reverses arthritis in rats

New drug limits cancer spreading

A research team that recently invented a drug to stop blood vessels from forming a treatment-resistant barrier around some cancers has now discovered the drug can be used to prevent cancer from spreading.

"We originally developed the drug to overcome a problem in some cancers that grow a chaotic barrier of blood vessels in the tumor which prevents the body's immune cells and treatments like chemotherapy entering the tumor," said Professor Ruth Ganss Co-Head of the Cancer and Cell Biology Division at Perth's Harry Perkins Institute of Medical Research.

"The drug also sets-up lymph-node-like structures within the cancer to draw in a patient's immune system and greatly enhance a patient's own capacity to shrink the cancer.

"What we've since discovered is that by 'normalizing' blood vessels the drug also stops cancer spreading because it counteracts the cancer's influence on blood vessels in other parts of the body.

"Cancer spreads when cancer cells travel through the blood stream and settle and grow in other organs, like the lung or brain.

 "They are able to establish themselves in a distant body part because the primary tumor secretes substances that make blood vessels in other organs 'leaky,' or easier to penetrate.

"So when cancer cells travel in the blood stream they typically settle and grow where there are optimal conditions that have actually been created by the primary tumor.

"The primary tumor effectively 'talks' to the site where the metastasis is going to form so when the floating cancer cells arrive, they find a nice cozy environment in which to grow.

"While this behavior of cancer was already known, what we have discovered is that we can interfere with this process because of the way this new drug affects blood vessels.

"We've discovered it restores the leaky vessels which result in the cancer cells flowing past and not setting up shop.

"For a patient, this means that in future it will be possible to remove the primary tumor, then use the new drug to prevent cancer cells in the blood system from successfully attaching themselves to another organ and growing.

"But, if the cancer cells have already settled elsewhere and started growing then the drug can also be used to increase the number of immune cells brought into the new tumor to help it shrink."

"So we now have a drug that not only opens up the primary tumor for increased immunotherapy and greater treatment access, but it prevents metastatic spreading and if cancer has already spread, then the drug escalates the patient's immune response to new cancer.

"We now know we can interfere early and late in cancer's journey," Professor Ganss said.

Co-author of the publication, Dr. Bo He who undertook laboratory work on the drug said the research focused on metastatic cancer because most patients succumb to secondary cancers, not the primary.

"Using the drug that the team developed and published in 2017 in Nature Immunology we explored whether it could prevent metastases as well as improve patient immune response."

"We're quite excited that we have moved into a different phase of exploring how this drug could be used.

"So far we've successfully applied it to melanoma and lung cancer models in a metastatic setting," said Dr.

Watch the Video

https://scx2.b-cdn.net/gfx/video/2020/newdruglimit.mp4

https://www.perkins.org.au/news/new-drug-limits-cancer-spreading

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Like pieces of tape that crumple, stick together, and can be turned into a ball, proteins that begin to lose their shape become sticky and tend to clump together. When this happens, rather than being transported to recycling sites within cells, old or dysfunctional proteins instead become trapped within cellular compartments. Eventually, they accumulate to the point that they gum up cellular machinery, causing major problems.

Fortunately, cells are equipped with molecular machinery that detects defective proteins, sorts them out, and then either removes or stabilizes them, preventing them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.

Now, scientists at the Lewis Katz School of Medicine at Temple University show that pharmacological chaperones could fill a critical role in Alzheimer's disease therapy. In a new study published online January 21 in the journal Molecular Neurodegeneration, they describe a novel pharmacological chaperone capable of preventing Alzheimer's disease in animals prone to developing the condition.

The study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss, and ultimately give rise to Alzheimer's disease.

"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained Domenico Praticò, MD, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine. Dr. Praticò was a senior investigator on the new study.

The trafficking of proteins from endosomes to the cell membrane or to another cellular compartment known as the Golgi apparatus is fundamental for normal cell function. VPS35 is of particular importance to this trafficking system since it separates out dysfunctional and old proteins and sends them off for recycling.

In previous work, Dr. Praticò and colleagues found that VPS35 actively clears the brain of potentially harmful proteins such as amyloid-beta and tau. However, in Alzheimer's disease, VPS35 levels are reduced. This reduction is associated with the formation of tau tangles inside neurons, as well as the accumulation of amyloid-beta outside neurons. Eventually, these deposits of abnormal proteins interrupt neuron activity and contribute to neurodegenerative disorders, including Alzheimer's disease.

In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer's disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.

Dr. Praticò's team found that, compared to untreated mice destined for Alzheimer's disease, the treated animals had much better memory and behaved just like normal, or wild-type, mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-beta plaques—another type of protein aggregate that contributes to Alzheimer's disease. The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.

"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Dr. Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."

Before moving to trials in human patients, however, Dr. Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice. "Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's disease," he added.

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0350-4

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

https://en.wikipedia.org/wiki/VPS35

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Dasatinib Tops Imatinib for Ph+ Acute Lymphoblastic Leukemia

In continuation of my update on dasatinib and imatinib

Dasatinib is associated with improved survival for pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), according to a study published online Jan. 16 in JAMA Oncology.

Shuhong Shen, M.D., Ph.D., from the Shanghai Jiao Tong University School of Medicine, and colleagues conducted an open-label randomized trial at 20 hospitals in China involving patients aged 0 to 18 years with Philadelphia chromosome-positive ALL. Patients were randomly assigned to either daily dasatinib or imatinib (92 and 97 patients, respectively) in the context of intensive chemotherapy without prophylactic cranial irradiation.

The researchers found that the four-year event-free and overall survival rates were 71.0 and 88.4 percent, respectively, in the dasatinib group and 48.9 and 69.2 percent, respectively, in the imatinib group. The four-year cumulative risk for any relapse was 19.8 and 34.4 percent in the dasatinib and imatinib groups, respectively; the four-year cumulative risk for an isolated central nervous system relapse was 2.7 and 8.4 percent, respectively. There was no difference between the treatment groups in the frequency of severe toxic effects.

"The present study provides promising early outcome data supporting the use of a dasatinib-based regimen for Philadelphia chromosome-positive ALL," write the authors of an accompanying editorial. "It also highlights some key challenges that remain in the management of this disease."

Several authors disclosed financial ties to pharmaceutical companies, including Bristol-Myers Squibb, which manufactures dasatinib.

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

Aspirin May No Longer Have Effect in Primary CVD Prevention

Aspirin may not be effective for primary prevention of cardiovascular disease and cancer mortality, according to research published online Nov. 21 in Family Practice.

Frank Moriarty, Ph.D., from the Royal College of Surgeons in Dublin, and Mark H. Ebell, M.D., from the University of Georgia in Athens, compared the benefits and harms of aspirin for primary prevention before (1978 to 2002) and after (2005 onward) widespread use of statins and screening for colorectal cancer.

The researchers found that for older versus newer studies, the relative risks for vascular outcomes were 0.89 (95 percent confidence interval [CI], 0.83 to 0.95) versus 0.93 (0.86 to 0.99) for major adverse cardiovascular events; 1.73 (1.11 to 2.72) versus 1.06 (0.66 to 1.70) for fatal hemorrhagic stroke; 0.86 (0.74 to 1.00) versus 0.86 (0.75 to 0.98) for any ischemic stroke; 0.84 (0.77 to 0.92) versus 0.88 (0.77 to 1.00) for any myocardial infarction; and 0.79 (0.71 to 0.88) versus 0.94 (0.83 to 1.08) for nonfatal myocardial infarction. In newer studies, there was no significant decrease observed for cancer mortality (relative risk, 1.11; 95 percent CI, 0.92 to 1.34). Significant increases were seen in major hemorrhage (older studies, relative risk, 1.48 [95 percent CI, 1.25 to 1.76] versus newer studies, relative risk, 1.37 [95 percent CI, 1.24 to 1.53]).

"In a modern era characterized by widespread statin use and population-wide cancer screening, aspirin no longer reduces the absolute risk of cancer death or myocardial infarction when given as primary prevention," the authors write.

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Coffee Consumption Does Not Affect Insulin Sensitivity

In continuation of my updates on coffee

Consumption of four cups of coffee daily does not impact insulin sensitivity, according to a study published online Dec. 31 in the American Journal of Clinical Nutrition.

Derrick Johnston Alperet, from the National University of Singapore, and colleagues conducted a 24-week trial involving 126 overweight, non-insulin-sensitive adults aged 35 to 69 years. Participants were randomly assigned to receive either four cups of instant regular coffee or four cups of a placebo beverage per day (62 and 64 in each group, respectively). The amount of glucose metabolized per kilogram of body weight per minute (Mbw) was measured as the primary outcome.

The researchers observed no significant change in insulin sensitivity with coffee consumption versus placebo (percentage mean difference in Mbw, 4.0 percent; 95 percent confidence interval [CI], −8.3 to 18.0 percent; P = 0.53). In addition, there were no between-group differences during 24 weeks of the intervention in fasting plasma glucose or biological mediators of insulin resistance such as plasma adiponectin. Compared with participants in the placebo arm, those in the coffee arm experienced a loss of fat mass (−3.7 percent; 95 percent CI, −6.3 to −1.1 percent; P = 0.006) and a reduction in urinary creatinine concentrations (−21.2 percent; 95 percent CI, −31.4 to −9.5 percent; P = 0.001).

• "Coffee consumption was associated with a modest loss in body fat mass compared with the placebo beverage, and this potential impact on adiposity warrants confirmation in additional trials," the authors write.

https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqz306/5686860?redirectedFrom=fulltext

Tivozanib Bests Sorafenib in Metastatic Renal Cell Carcinoma

In continuation of my update on Tivozanib  and  Sorafenib

Among patients with metastatic renal cell carcinoma, progression-free survival was longer in those receiving tivozanib versus sorafenib as third- or fourth-line therapy, according to a study published online Dec. 3 in The Lancet Oncology.

Brian I. Rini, M.D., from the Cleveland Clinic Taussig Cancer Institute, and colleagues conducted an open-label randomized trial at 120 academic hospitals in 12 countries and enrolled patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments, including at least one with a vascular endothelial growth factor receptor inhibitor. Patients were randomly assigned to either tivozanib 1.5 mg orally once daily in four-week cycles or sorafenib 400 mg orally twice daily on a continual basis (175 patients to each); patients were followed for a median of 19 months.

The researchers found that median progression-free survival was significantly longer with tivozanib than sorafenib (5.6 versus 3.9 months; hazard ratio, 0.73). Hypertension was the most common grade 3 or 4 treatment-related adverse event (20 and 14 percent of tivozanib- and sorafenib-treated patients, respectively). Serious treatment-related adverse events occurred in 11 percent of tivozanib and 10 percent of sorafenib patients. There were no reports of treatment-related deaths.

"These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including AVEO Oncology, which manufactures tivozanib and funded the study.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext

One-Cycle BE500P Seems Safe for High-Risk Early Testicular Cancer

 

Bleomycin                                                                             etoposide

Cisplatin

In continuation of my update on etoposide and cisplatin

For high-risk stage 1 nonseminoma germ cell tumors of the testis (NSGCTT), one cycle of adjuvant bleomycin, etoposide (500 mg/m²), and cisplatin (BE500P) is safe, resulting in a two-year malignant recurrence (MR) rate of 1.3 percent, similar to that reported for two cycles of BE360P, according to a study published online Jan. 1 in European Urology.

Michael Cullen, M.D., from the University Hospitals Birmingham NHS Foundation Trust in the United Kingdom, and colleagues compared recurrence rates for one cycle of BE500P to recurrence rates for two cycles of BE360P among 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT registered in a single-arm prospective study.

Patients were followed for a median of 49 months. Ten patients with increasing tumor markers were excluded at baseline. The researchers found that four patients had MR at six, seven, 13, and 27 months; all were treated with secondary chemotherapy, and at five years, three remained recurrence-free. The rate of two-year MR was 1.3 percent (95 percent confidence interval, 0.3 to 3.7 percent). Nonmalignant recurrences developed in three patients who had localized differentiated teratoma; after surgery, they were rendered disease-free. In 6.8 percent of patients, grade 3 to 4 febrile neutropenia occurred.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one -- making their treatment shorter, kinder, and cheaper," a coauthor said in a statement.

https://www.europeanurology.com/article/S0302-2838(19)30895-4/fulltext
https://en.wikipedia.org/wiki/Bleomycin
https://en.wikipedia.org/wiki/Etoposide
https://en.wikipedia.org/wiki/Cisplatin

Tea Drinking Linked to Reduced Risk for Atherosclerotic CVD

In continuation of my update on Tea

Habitual tea consumption is associated with a reduced risk for atherosclerotic cardiovascular disease (CVD) and all-cause mortality, according to a study published online Jan. 9 in the European Journal of Preventive Cardiology.

Xinyan Wang, from the Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues examined the association of tea consumption with the risk for atherosclerotic CVD and all-cause mortality among 100,902 general Chinese adults in 15 provinces in China. Standardized questionnaires were used to obtain information on tea consumption.

The researchers found that 3,683 atherosclerotic CVD events, 1,477 atherosclerotic CVD deaths, and 5,479 all-cause deaths were recorded during a median follow-up of 7.3 years. For habitual tea drinkers, the hazard ratios were 0.80, 0.78, and 0.85 for atherosclerotic CVD incidence, atherosclerotic CVD mortality, and all-cause mortality, respectively, compared with never or nonhabitual tea drinkers. At the index age of 50 years, habitual tea drinkers were free from atherosclerotic CVD for 1.41 more years and had a life expectancy of 1.26 years longer. Among participants who kept the habit during follow-up, the observed inverse associations were strengthened.

"Our findings give a further insight into the beneficial role of tea consumption, and have great public health implications for guiding primary prevention among general Chinese adults," the authors write.

FDA: Weight Control Drug Lorcaserin May Raise Cancer Risk

In continuation of my update on lorcaserin

The prescription weight control medicine lorcaserin (Belviq, Belviq XR) may increase the risk for cancer, according to the results of a clinical trial assessing the safety of the drug, the U.S. Food and Drug Administration says.

The agency said, "[W]e cannot conclude that lorcaserin contributes to the cancer risk" but "wanted to make the public aware of this potential risk. We are continuing to evaluate the clinical trial results and will communicate our final conclusions and recommendations when we have completed our review."

Health care providers should balance the benefits of taking lorcaserin against the potential risks when deciding whether to prescribe or continue patients on the medication, the FDA advised. It said that patients currently taking lorcaserin should talk to their health care professionals about the potential increased risk for cancer with use of the medication.

Lorcaserin is approved for use with a reduced-calorie diet and increased physical activity to help weight loss in adults who are obese or are overweight and have weight-related medical problems. Lorcaserin increases feelings of fullness so that people eat less. It is available as a tablet (Belviq) and an extended-release tablet (Belviq XR).

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