Key protein that drives rheumatoid arthritis damage

 Scientists have identified a protein known as sulfatase-2 that plays a critical role in the damage caused by rheumatoid arthritis. A chronic disease in which the immune system attacks the body's own joint tissues, rheumatoid arthritis affects an estimated 1.5 million Americans.

Published in the journal Cellular & Molecular Immunology, the discovery sheds new light on the molecular processes that drive inflammation seen in rheumatoid arthritis. It could also someday lead to improved treatment of the disease, which currently has no cure.

"Tumor necrosis factor-alpha -- or TNF-alpha for short -- is one of the main inflammatory proteins that drive rheumatoid arthritis and is targeted by many currently available therapies," said senior author Salah-Uddin Ahmed, a professor in Washington State University's College of Pharmacy and Pharmaceutical Sciences. "However, over time patients can develop a resistance to these drugs, meaning they no longer work for them. That is why we were looking for previously undiscovered drug targets in TNF-alpha signaling, so basically proteins that it interacts with that may play a role."

Though sulfatases such as sulfatase-2 have been extensively studied for their roles in different types of cancer, Ahmed said no one had looked at how they might be involved in inflammatory or autoimmune diseases such as rheumatoid arthritis.

The research team first explored this idea using cells called synovial fibroblasts, which line the joints and keep them lubricated to ensure fluid movement.

"In rheumatoid arthritis, these normally quiescent cells get activated by TNF-alpha and other inflammatory molecules, and they take on this aggressive character," said first author Ruby J. Siegel, a PhD graduate in the WSU College of Pharmacy and Pharmaceutical Sciences. "They are not dying when they should, and they proliferate in a way that is almost tumor-like, forming this massive synovial tissue that should not be anywhere near that size and at the same time activating proteins that destroy cartilage and bone."

Using the joint-lining cells of rheumatoid arthritis patients, they removed sulfatase-2 from one group of cells before stimulating all cells with the inflammatory TNF-alpha. What they found was that cells lacking sulfatase-2 did not show the same exaggerated inflammatory response to TNF-alpha as cells that were left intact.

"Looking at sulfatases for their potential role in inflammation was an educated guess, but once we did we saw a very consistent pattern of increased sulfatase-2 expression throughout different tissues and samples we studied," Ahmed said. "This tells us that TNF-alpha relies on sulfatase-2 to drive inflammation, because as soon as we removed sulfatase-2 the inflammatory effects of TNF-alpha were markedly reduced."

Resulting from a series of experiments spanning four years, the researchers' findings open the door to future animal studies to test the effectiveness of inhibiting sulfatase-2 to ease rheumatoid arthritis symptoms. This could someday lead to the development of new combination therapies that along with other inflammatory proteins would also target sulfatase-2 to prevent bone loss, cartilage damage and deformed joints. Such therapies could help address the shortcomings of currently available rheumatoid arthritis drugs, many of which come with significant side effects.

"These drugs shut off TNF-alpha in your whole body, but it does have important immune functions," Siegel said, adding that patients who take these types of drugs are more susceptible to infection and have an increased risk of developing cancer with long-term use. She also noted that TNF-alpha inhibitors are not effective in all people and are not recommended for patients with certain other health conditions.

Funding support for the study came from the National Institutes of Health and the Rheumatology Research Foundation.

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Story Source:

Materials provided by Washington State University. Original written by Judith Van Dongen. Note: Content may be edited for style and length.

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Journal Reference:

1. Ruby J. Siegel, Anil K. Singh, Paul M. Panipinto, Farheen S. Shaikh, Judy Vinh, Sang U. Han, H. Mark Kenney, Edward M. Schwarz, Cynthia S. Crowson, Sadik A. Khuder, Basil S. Khuder, David A. Fox, Salahuddin Ahmed. Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts. Cellular & Molecular Immunology, 2022; DOI: 10.1038/s41423-022-00913-x

https://www.sciencedaily.com/releases/2022/09/220908100052.htm

China Restricts Domestic Travel as Covid Outbreaks Grow

 China is stepping up its Covid defenses as a key Communist Party meeting looms, restricting internal travel further as swathes of the country remain under tight lockdowns.

The National Health Commission on Thursday announced a raft of measures that will be in place until the end of next month to fight a virus that shows little sign of slowing. Authorities told citizens to minimize travel during the mid-Autumn festival next week and National Day holidays in October, ordinarily key periods for domestic tourism, and asked local governments to test all residents regularly for Covid regardless of infection levels. 

https://www.bloomberg.com/news/articles/2022-09-09/china-restricts-domestic-travel-as-covid-outbreaks-grow

Overall Survival Dips With Vitamin D Deficiency in Melanoma

 Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the 31st Congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

Dr Inés Gracia-Darder

The research adds to existing evidence that "vitamin D levels can play an important and independent role in patients' survival outcomes," study investigator Inés Gracia-Darder, MD, told Medscape Dermatology. "The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients," said Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Known Association, but Not Much Data

"It is not a new finding," but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven in Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

"Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor," De Smedt said in an interview, indicating that it's not just overall survival that might be affected.

"So we assume that also has an effect on melanoma-specific survival," she added.

That assumption, however, is not supported by the data Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.

Retrospective Cohort Analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, De Smedt said. "But there is a difference between countries and there's also a difference between societies," noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.

Independent Association With Overall Survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.

Time to Recommend Vitamin D Supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

"In our practice, we analyze the vitamin D levels of our patients," Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there's no real evidence to support upping vitamin D levels to date, so "future prospective studies are needed," Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that De Smedt has been involved with for the past few years.

Called the ViDMe study, it's a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

"The study is still blinded," De Smedt said. "We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results."

The study reported by Gracia-Darder did not receive any specific funding. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

Congress of the European Academy of Dermatology and Venereology: Poster Presentation P0762. Presented September 7, 2022.

https://www.medscape.com/viewarticle/980479?

Rand Paul: 'America Should Be Appalled' At Fauci Covering His Tracks

 by Steve Watson via Summit News,

Appearing on Fox News Wednesday, Senator Rand Paul slammed Anthony Fauci for taking the default position of trying to “cover up” his activities, including potentially encouraging social media companies to censor medical information.

After a federal judge ordered the release of emails Fauci sent to social media platforms concerning what he defined as ‘misinformation’, many want to know exactly what Fauci asked of them.

“His response was not that I’ll look into it or I’ll reveal that. His response was, by law, we don’t have to tell you which companies gave us how many royalties and to which scientists,” Paul said of Fauci, noting that the emails sent to social media bosses could reveal censorship efforts.

“I think that all of America should be appalled that America’s doctor, the leading expert on COVID in public health, doesn’t want to divulge information, doesn’t want to divulge his communications with Big Tech,” Paul urged, adding that Fauci’s “modus operandi” is to “cover up”.

Watch:

As part of a lawsuit brought by Louisiana Republican Jeffrey Landry, the federal judge ruled that Fauci and White House press secretary Karine Jean-Pierre need to make public all relevant communications with Big Tech within the next three weeks.

Landry and Missouri Attorney General Eric Schmitt argued in an initial filing that “having threatened and cajoled social-media platforms for years to censor viewpoints and speakers disfavored by the Left, senior government officials in the Executive Branch have moved into a phase of open collusion with social-media platforms under the Orwellian guise of halting so-called ‘disinformation,’ ‘misinformation’ and ‘malinformation.'”

Elsewhere during the interview, Senator Paul commented on revelations by Gun Owners of America that the FBI pressured Americans into signing forms that relinquished their right to purchase, possess and use firearms. 

“There is a certain irony to saying to someone you have to be mentally competent to sign this statement that says you’re not mentally competent to have a gun,” Paul noted, adding “So there is that that might be a quandary if you get into a court of law. How someone that’s mentally incompetent to own a gun could be competent to sign away their gun rights.”

“I think the whole problem we have right now is that there’s a burden upon the FBI to prove to the American public that they are not partisan,” Paul said, adding “This goes back to 2016 when they used a foreign intelligence warrant to go after Donald Trump and his campaign.”

“A foreign intelligence warrant which should be used on foreigners in a secret court was used to go after a major presidential, you know, candidate,” the Senator reiterated.

https://www.zerohedge.com/political/rand-paul-america-should-be-appalled-fauci-covering-his-tracks

FDA Flags Squamous Cell Carcinomas, More Lymphomas Tied to Breast Implants

 The FDA issued a safety alert warning patients and providers of reports of squamous cell carcinoma (SCC) and various lymphomas located in the capsule or scar tissue around breast implants.

"After an initial extensive review, we currently believe that the risk of SCC and other lymphomas occurring in the tissue around breast implants is rare," the FDA said. "However, in this case, and when safety risks with medical devices are identified, we wanted to provide clear and understandable information to the public as quickly as possible."

The agency noted that these new lymphoma reports differ from those of breast implant-associated anaplastic large-cell lymphoma, which the FDA began issuing warnings about more than a decade ago.

In all, the FDA said that after a review of published literature it has become aware of less than 20 cases of SCC and fewer than 30 cases of various lymphomas in the capsule around the breast implant. And as of September 1, it has received 10 medical device reports (MDRs) about SCC and 12 about various lymphomas related to breast implants.

The agency said these reports of SCC and lymphomas involved both textured and smooth breast implants, as well as both saline and silicone breast implants, and that in some cases patients were diagnosed years after receiving breast implants, with signs and symptoms including swelling, pain, lumps, or skin changes.

"Right now, we do not have enough information to say whether breast implants cause these cancers or if some implants pose higher risk than others," the agency said. "For this reason, instances of SCC, lymphoma and any cancer located in the scar tissue around breast implants should be reported to the FDA."

The FDA suggested patients should "promptly" talk to their surgeon or healthcare provider in case of abnormal changes in their breasts of implants, and encouraged patients to file a report through MedWatch, the FDA Safety Information and Adverse Event Reporting program, if they experience a problem.

https://www.medpagetoday.com/hematologyoncology/othercancers/100602

Biden Administration Reverses Trump-Era 'Public Charge' Rule

 Noncitizens can receive or apply for health benefits and other services without hurting their chances of securing permanent residency status -- a "green card" -- thanks to a final rule from the Department of Homeland Security (DHS) issued on Thursday.

The rule centers around the contentious "public charge" reason for inadmissibility and focuses on clarifying how DHS will not punish noncitizens, specifically noncitizens seeking admission into the U.S. or lawful permanent residency from within its borders, for availing themselves of health-related benefits and government services for which they qualify, such as Medicaid (with some exceptions, including long-term institutions like nursing homes) and the Children's Health Insurance Program (CHIP).

By spelling out in a written final rule the "totality of the circumstances" provisions in the DHS statute, the agency is demonstrating that "individual factors, such as a person's disability or use of benefits alone will not lead to a public charge determination."

In a press release, HHS Secretary Xavier Becerra said that "people who qualify for Medicaid, CHIP, and other health programs should receive the care they need without fear of jeopardizing their immigration status."

As the COVID-19 pandemic has made clear, it's in all Americans' best interest to leverage healthcare and other services to improve public health for everyone, he noted.

DHS will also not consider the use of the following non-cash benefits when assessing whether a person is likely to become a "public charge":

• Food and nutrition assistance (e.g., the Supplemental Nutrition Assistance Program [SNAP])
• Disaster assistance under the Stafford Act
• Pandemic assistance
• Benefits received through tax credits or deductions
• Government pensions or other earned benefits

"Receipt of cash-based benefits, such as Supplemental Security Income (SSI), Temporary Assistance for Needy Families (TANF), and other similar programs, will not automatically exclude an individual from admission or green card eligibility, and will instead be considered in a 'totality of the circumstances' analysis," noted the press release. "The final rule does not expand eligibility for Medicaid, CHIP, or other benefits to more people but clarifies DHS policy regarding recipients."

Under the Trump administration, DHS introduced a 2018 draft rule, finalized in 2019, that had the potential to deny green cards to certain legal immigrants if they relied too much on public programs.

In early February 2021, President Biden issued an executive order directing three federal agencies -- the Justice, State, and Homeland Security departments -- to review the "public charge" rule, which had been entangled in multiple state lawsuits. Two courts issued injunctions that, for a period, prevented the rule from being implemented, though both injunctions were ultimately lifted by the Supreme Court. On February 24 of this year, DHS issued a proposed rule.

The final rule will take effect December 23.

https://www.medpagetoday.com/publichealthpolicy/healthpolicy/100604

ESMO: Merck claims leap forward in head and neck cancer

 Germany’s Merck KGaA paid $237 million upfront for rights to Debiopharm’s  head and neck squamous cell carcinoma (HNSCC) therapy xevinapant last year in a deal valued at more than $1 billion, and it now has further data suggesting it was a solid deal.

At the ESMO cancer congress which gets underway in Paris tomorrow, Merck will report results from a phase 2 study which according to the drugmaker is the first in decades to show a significant improvement in overall survival in patients with unresected locally advanced HNSCC compared to standard care.

In the 96-patient study, 53% of those treated with xevinapant (Debio 1143) plus chemoradiotherapy were still alive after five years, compared to 28% of a control group given chemoradiotherapy and placebo.

Median survival time was just over 40 months with Merck’s drug, compared to 36 months in the placebo arm, and adding the drug to chemoradiotherapy did not seem to add to the toxicity burden of treatment.

Xevinapant, which is billed as a first-in-class antagonist of inhibitor of apoptosis protein (IAP), has been given breakthrough status by the FDA for HNSCC. It is thought to sensitise tumour cells to chemoradiotherapy by promoting programmed cell death and enhancing anti-tumour immune responses.

The drug is already in a pair of phase 3 trials in HNSCC, with results due from 2024 onwards. TrilynX has a similar design to the phase 2 study, while XRAY VISION is recruiting patients who have had surgery for their tumour but are not eligible for platinum-based chemo.

“There is a clear need for improved treatment options for patients with unresected locally advanced head and neck cancer,” commented Prof Jean Bourhis of the University Hospital of Lausanne, the lead investigator of the study.

“Chemoradiotherapy has served as the standard of care in this setting for the past several decades, yet half of patients treated with CRT see their cancer return, whether locally or as metastatic disease,” he added.

The new data “suggest the potential for xevinapant to increase the proportion of patients who achieve cure following definitive therapy.”

HNSCC is the sixth most common cancer, and is a notoriously debilitating and hard-to-treat disease causing significant impairment to patients when it is an advanced stage.

Around 40–60% of patients with locally advanced disease go on to develop recurrence or spread to other parts of the body.

Other IAP antagonists that have reached the clinical testing stage include Astex Pharma’s tolinapant (ASTX660), in phase 2 testing for peripheral T-cell lymphoma and cutaneous T-cell lymphoma and Ascentage Pharma/Clover Bio’s APG-1387 in phase 1/2 for advanced peritoneal carcinomatosis.

https://pharmaphorum.com/news/esmo-merck-claims-leap-forward-in-head-and-neck-cancer/