RBG’s Cancer Returns; She’s Still Working

Supreme Court Justice Ruth Bader Ginsburg said Friday she is on a course of chemotherapy to treat a recurrence of cancer after lesions were found on her liver. Her chemotherapy treatment is often given when pancreatic cancer spreads. She was first treated for pancreatic cancer in 2009.

In a statement from the Supreme Court, the 87-year-old senior member of the court’s four-member liberal wing says she is able to do her job ”full steam.”

Well wishes sprang up immediately after the announcement on Twitter, such as the anti-Trump Project Lincoln’s “We’re praying for RBG,” pleas to “hang in there,” and an offer to donate a liver. A 2018 documentary on Ginsburg’s life, RBG, helped make her a pop culture phenomenon.

She began a course of the chemotherapy drug gemcitabine on May 19, according to the statement. A periodic scan in February and a biopsy revealed the liver lesions, the statement says. The chemo appears to be working. “My most recent scan on July 7 indicated significant reduction of the liver lesions and no new disease,” she says in the statement. “I am tolerating chemotherapy well and am encouraged by the success of my current treatment.”

She plans to continue biweekly chemotherapy to keep the cancer at bay and says she is able to ”maintain an active daily routine.”

According to news reports, she also had radiation therapy for the pancreatic cancer in 2019 and lung tumors removed in 2018. She survived colon cancer in 1999.

In the statement, Ginsburg also says her recent hospitalization to remove gallstones and treat an infection were unrelated to her cancer recurrence.

In a statement on Twitter, American Cancer Society’s CEO Gary M. Reedy expressed his best wishes for RBG’s continued progress and said: “A cancer diagnosis is never good news, but as Justice Ginsburg’s cancer experience has taught us, there is always room for hope, even with a serious diagnosis.”

Mustafa Raoof, MD, a surgical oncologist at City of Hope, a comprehensive cancer center near Los Angeles, specializes in pancreatic and liver cancers. He did not treat Justice Ginsburg, but says: “Pancreatic cancer that has metastasized to other parts of the body such as the liver remains a challenging disease to treat. Most therapies are life-prolonging and cure is unusual. The goal of therapy is to not only prolong life but also to maintain or improve quality of life.”

Gemcitabine, FDA approved to treat pancreatic cancer that has spread, has been standard therapy since 1997, he says. “It is particularly well tolerated in older patients who are not a candidate for more aggressive chemotherapies.”

Born in Brooklyn, NY, in 1933, Ginsburg was instrumental in launching the Women’s Rights Project of the American Civil Liberties Union. President Bill Clinton nominated her as an associate justice of the Supreme Court; she took her seat Aug. 10, 1993.

https://www.medscape.com/viewarticle/934163

Freeline Therapeutics on deck for IPO

Freeline Therapeutics has filed preliminary prospectus for $100M, and intends to list its ADSs on Nasdaq Capital Market under the symbol “FRLN”.

Hertfordshire, UK-based company’s lead product candidate, FLT180a, an adeno-associated virus based gene therapy for hemophilia B, is currently in a Phase 1/2 trial and has dosed 10 patients as of June 15, 2020.

Recently, the company announced $120M in series C financing.

Financials as of Mar 31: Net loss: $7.8M; Cash:$88.5M

https://seekingalpha.com/news/3592404-freeline-therapeutics-on-deck-for-ipo

Melatonin Inhibits Covid-19-induced Cytokine Storm

Russel J. Reiter,^a,⁎ Ramaswamy Sharma,^a Qiang Ma,^a Alberto Dominquez-Rodriguez,^b Paul E. Marik,^c and Pedro Abreu-Gonzalez^d

…

A number of drugs have been proposed as treatments to prevent or reduce the severity of a COVID-19 infection. One agent that has been suggested to be potentially useful in this regard is the endogenously synthesized molecule, melatonin [^{[3], [4], [5], [6], [7]}]. Melatonin was initially discovered in and thought to be exclusively a product of the vertebrate pineal gland. However, in consideration of the identification of melatonin in prokaryotic bacteria [⁸], from which mitochondria evolved (the endosymbiotic theory) and the uncommonly high levels of assayable melatonin in mitochondria [⁹], it was speculated and eventually documented that this indoleamine is synthesized in this organelle [¹⁰]. Given that most cells (a few exceptions) contain mitochondria, it is now believed that melatonin production occurs in most cells in all organisms. This has also been specifically demonstrated in human lung monocytes/macrophages [¹¹].

In healthy cells, including macrophages, melatonin synthesis in mitochondria is maintained by the entrance of pyruvate, a glucose metabolite, into the mitochondria where it is metabolized to acetyl-coenzyme A by the enzyme, pyruvate dehydrogenase complex (PDC). Acetyl-coenzyme A feeds the citric acid cycle and supports ATP synthesis, but it is also a required co-factor/substrate for the rate limiting enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT) (Fig. 1). Thus, when mitochondria adopt aerobic glycolysis, pyruvate in mitochondria is no longer converted to acetyl-coenzyme A because PDC is inhibited by the enzyme pyruvate dehydrogenase kinase (PDK); Therefore, as a consequence of a COVID-19 infection the macrophage mitochondria cannot synthesize melatonin [¹²].

Because of melatonin’s potent antioxidant and anti-inflammatory activities, it would normally reduce the highly proinflammatory cytokine storm and neutralize the generated free radicals thereby preserving cellular integrity and preventing lung damage. In the absence of acetyl-coenzyme A, mitochondrial melatonin is no longer available to combat the inflammatory response or to neutralize the generated reactive oxygen species and the massive damage that occurs in the respiratory tree resulting in the primary signs of COVID-19 disease. Importantly, endogenous melatonin production diminishes markedly with age especially in frail older individuals. This is consistent with the more serious nature of a COVID-19 infection in the elderly.

Aerobic glycolysis is an important feature of highly proinflammatory state since it ensures the necessary high levels of ATP and the abundant supply of biomolecules to ensure synthesis and release of the damaging molecules that constitute the cytokine storm. This increased aerobic glycolysis coupled with the absence of locally-produced melatonin provides the optimal environment (the perfect “cytokine storm”) for the massive tissue damage that occurs in COVID-19 disease.

Given the above information, the use of supplemental melatonin as a treatment to overcome a COVID-19 infection is justified. Exogenously administered melatonin reverses aerobic glycolysis by repressing both HIF-1α and mTOR thereby disinhibiting PDC activity and allowing acetyl-coenzyme A synthesis which also ensures locally-produced melatonin production [¹³]. The functionally re-instated mitochondria-generated melatonin in combination with the parenteral melatonin provides a formidable weapon to reduce the cytokine storm as well as its damaging consequences thereby relieving the signs of a COVID-19 infection.

The anti-inflammatory and antioxidant actions of melatonin in protecting the lungs from damage in many experimental models that involve inflammation or oxidative stress (or both) is well documented [¹⁴]. Moreover, melatonin has anti-viral actions against viruses other than COVID-19 [^15,16]. The collective data, in addition to its very high safety profile, indicate that melatonin would be effective as a treatment for COVID-19 and support the recommendation of the published reports that encourage its use for this purpose [^{[3], [4], [5], [6], [7]}]. Melatonin is inexpensive, non-toxic over a very wide dose range, has a long shelf-life and can be self-administered which is a major advantage when large numbers of individuals are involved. Thus, the use of melatonin to mitigate the COVID-19 pandemic would be feasible and a socially-responsible measure to attempt.

Go to:

Acknowledgments

Not applicable.

Conflict of Interest

The authors declare no conflict of interest.

Authors’ contributions

All authors participated in discussions related to melatonin and COVID-19. The first draft of the manuscript was written by RJR; the paper was then reviewed and edited by all co-authors. The final version of the report was read and approved by all co-authors.

Funding

The authors received no funding to support this publication.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211589/

Banner to launch Tecfidera bioequivalent in U.S. September 1

Privately held Banner Life Sciences announces that the U.S. commercial launch of Bafiertam (monomethyl fumarate) for adults with relapsing forms of multiple sclerosis (MS) will commence on Tuesday, September 1.

Bafiertam is a bioequivalent to Biogen’s (NASDAQ:BIIB) top seller Tecfidera (dimethyl fumarate), a prodrug of monomethyl fumarate.

Biogen sued Banner for patent infringement aimed at blocking the med’s release but failed.

Tecfidera accounted for over 31% of the company’s Q1 revenue.

https://seekingalpha.com/news/3592356-banner-to-launch-tecfidera-bioequivalent-in-u-s-september-1

Factors Linked With Death in Critically Ill US Covid-19 Patients

Shruti Gupta, MD, MPH¹; Salim S. Hayek, MD²; Wei Wang, PhD³; et al

Key Points

Question  What are the characteristics, outcomes, and factors associated with death among critically ill patients with coronavirus disease 2019 (COVID-19) in the US?

Findings  In a cohort of 2215 adults with COVID-19 who were admitted to intensive care units at 65 sites, 784 (35.4%) died within 28 days, with wide variation among hospitals. Factors associated with death included older age, male sex, obesity, coronary artery disease, cancer, acute organ dysfunction, and admission to a hospital with fewer intensive care unit beds.

Meaning  This study identified demographic, clinical, and hospital-level factors associated with death in critically ill patients with COVID-19 that may be used to facilitate the identification of medications and supportive therapies that can improve outcomes.

Abstract

Importance  The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19.

Objectives  To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19.

Design, Setting, and Participants  This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020.

Exposures  Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds.

Main Outcomes and Measures  The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes.

Results  A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao₂:Fio₂<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30–5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46–4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies.

Conclusions and Relevance  This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2768602

Researchers Home in on COVID-19 Severity Biomarkers

About one-fifth of patients with coronavirus disease 2019 (COVID-19) have clinically severe or life-threatening infections requiring interventions such as immediate oxygen therapy or mechanical ventilation. Knowing early on which patients are likely to develop severe disease could help save lives.

To that end, several research teams are working to discover telltale blood biomarkers. In a study recently published in Cell, researchers in China found 93 proteins and 204 metabolites whose levels correlated with severe COVID-19. The scientists analyzed sera from 53 healthy people and 46 patients with severe and nonsevere COVID-19 to find the molecular markers.

They then trained a machine learning model to stratify disease severity using 29 of these serum factors. The model correctly classified 29 of 31 patients in the training cohort, for an overall accuracy of 93.5%, and 23 of 29 patients in 2 independent test cohorts.

Larger studies of patient samples collected at more time points will be needed to develop a clinical test that predicts severe cases before they develop. Still, the study provides “some of the first evidence that such a test might be possible,” National Institutes of Health Director Francis Collins, MD, PhD, wrote in a recent blog post.

Meanwhile, European researchers have designed a high-throughput platform to analyze serum and plasma proteins from COVID-19 samples. The system identified 27 potential protein biomarkers that are expressed differently in hospitalized patients depending on their case severity. Another team, led by New York University researchers, has developed a point-of-care mobile app that provides a COVID-19 severity score based on patients’ biomarker measurements and clinical risk factors.

https://jamanetwork.com/journals/jama/fullarticle/2768113

Canadian-made mask deactivates 99% of SARS-CoV-2 virus

An antimicrobial coating developed by Quebec company I3 BioMedical Inc. can deactivate more than 99 per cent of SARS-CoV-2 – the virus that causes COVID-19 – on the outer surface of medical masks, tests carried out by University of Toronto scientists have shown.

The scientists, led by Professor Scott Gray-Owen of the department of molecular genetics in the Faculty of Medicine, used the faculty’s high-tech containment level three (CL3) lab to test the efficacy of the TrioMed Active Mask’s antimicrobial coating.

They found that the novel coating deactivated more than 99 per cent of SARS-CoV-2 within minutes, a finding that could represent a huge boon for health-care workers who are at risk of being contaminated with the virus by touching or adjusting their face masks. Indeed, the coronavirus has been shown to be present and infectious on the outer layer of masks for up to seven days, according to a recent study published in The Lancet Microbe.

“A big challenge for most people in the population who usually never wear surgical masks is comfort and fit. Because of this, people tend to be constantly adjusting their masks,” said Gray-Owen. “So they’re either contaminating their hands or, if their hands are contaminated, they’re contaminating a mask that’s close to their face and maybe even depositing the virus there, which they might then inhale.”

Gray-Owen says I3 BioMedical’s proprietary TrioMed Active coating material had previously been demonstrated to kill most microbes on contact, and was shown to remain directly coupled to the outside surfaces of masks rather than leach out into the environment or onto the skin of wearers.

“They had done this before with other bacterial and viral pathogens including influenza, and we extended these studies for them to show that SARS-CoV-2 was also susceptible,” Gray-Owen said.

The CL3 lab – the only such facility in Toronto – was approached by I3 BioMedical on the recommendation of engineers at the Public Health Agency of Canada, said Gray-Owen, who is director of the lab.

“We were one of the first labs to receive fast-track approval to culture and manipulate the virus. Samira Mubareka and Robert Kozak brought samples from infected patients at the hospital and expanded the virus, so we ended up being one of the first places in Canada where the virus was being propagated.”

“And so because we had the virus, and the fact that our facility has been operational for over a decade now, we had the capabilities to work with it.”

When the antimicrobial coating was present on the masks, “we could not recover any infectious virus from the suspension that had been applied to the mask,” said Gray-Owen.

“We repeated the tests and this was a reproducible finding, so it was pretty clear that there was a difference between TrioMed coated and non-coated material.”

Gray-Owen says while the CL3 lab is very much a research facility rather than a validation lab, the I3 BioMedical testing project was taken on because of the potential of the antimicrobial coating product to contribute to curbing the spread of the virus, and the company’s stated desire to supply masks to the Canadian market.

https://www.utoronto.ca/news/u-t-tests-show-canadian-made-mask-deactivates-99-sars-cov-2-virus