Low doses of radiation promote cancer-capable cells

Low doses of radiation equivalent to three CT scans, which are considered safe, give cancer-capable cells a competitive advantage over normal cells in healthy tissue, scientists have discovered. Researchers at the Wellcome Sanger Institute and the University of Cambridge studied the effects of low doses of radiation in the esophagus of mice.

The team found that low doses of radiation increase the number of cells with mutations in p53, a well-known genetic change associated with cancer. However, giving the mice an antioxidant before radiation promoted the growth of healthy cells, which outcompeted and replaced the p53 mutant cells.

The results, published today (18 July) in Cell Stem Cell show that low doses of radiation promote the spread of cancer-capable cells in healthy tissue. Researchers recommend that this risk should be considered in assessing radiation safety. The study also offers the possibility of developing non-toxic preventative measures to cut the risk of developing cancer by bolstering our healthy cells to outcompete and eradicate cancer-capable cells.

Every day we are exposed to various sources of ionising radiation, including natural radiation in soil and rock, and important medical procedures like CT scans and x-rays.

Low doses of radiation, such as the exposure from medical imaging, are considered safe as they cause little DNA damage and apparently minimal effect on long-term health. Until now, other effects of exposure to low levels of radiation have remained hidden, meaning understanding the true risk associated with low doses of radiation has been difficult.

Researchers have previously shown that our normal tissues, like skin, are battlefields where mutant cells compete for space against healthy cells. We all have cancer-capable mutant cells in healthy tissues, including those with p53 mutations, which increase in number as we age, yet very few eventually go on to form cancer.

In this new study, researchers show that low doses of radiation weigh the odds in favour of cancer-capable mutant cells in the esophagus. The Sanger Institute researchers and their collaborators gave mice a 50 milligray dose of radiation, equivalent to three or four CT scans. As a result, the p53 mutant cells spread and outcompeted healthy cells.

Dr David Fernandez-Antoran, first author from the Wellcome Sanger Institute, said: “Our bodies are the set of ‘Game of Clones’ — a continuous battle for space between normal and mutant cells. We show that even low doses of radiation, similar to three CT scans’ worth, can weigh the odds in favour of cancer-capable mutant cells. We’ve uncovered an additional potential cancer risk as a result of radiation that needs to be recognised.”

Researchers then gave the mice an over-the-counter antioxidant — N-Acetyl Cysteine (NAC) — before exposure to the same level of radiation. The team discovered that the antioxidant gave normal cells the boost needed to outcompete and eradicate the p53 mutant cells.

However, the antioxidant alone without exposure to radiation did not help normal cells battle the mutant clones.

Dr Kasumi Murai, an author from the Wellcome Sanger Institute, said: “Giving mice an antioxidant before exposing them to low doses of radiation gave healthy cells the extra boost needed to fight against the mutant cells in the esophagus and make them disappear. However, we don’t know the effect this therapy would have in other tissues — it could help cancer-capable cells elsewhere become stronger. What we do know is that long term use of antioxidants alone is not effective in preventing cancer in people, according to other studies.”

Professor Phil Jones, lead author from the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge, said: “Medical imaging procedures using radiation, such as CT scans and x-rays, have a very low level of risk — so low that it’s hard to measure. This research is helping us understand more about the effects of low doses of radiation and the risks it may carry. More research is needed to understand the effects in people.”

The team suggests this research also highlights the possibility of developing therapies to prevent cancer. By making healthy cells fitter they naturally push out cancer-capable cells, without any toxic side effects for the patient.

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Story Source:

Materials provided by Wellcome Trust Sanger Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. David Fernandez-Antoran, Gabriel Piedrafita, Kasumi Murai, Swee Hoe Ong, Albert Herms, Christian Frezza, Philip H. Jones. Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation. Cell Stem Cell, 2019; DOI: 10.1016/j.stem.2019.06.011

https://www.sciencedaily.com/releases/2019/07/190718150933.htm

CDC links two deaths to multi-state salmonella from backyard poultry

Two people have died following a multi-state outbreak of salmonella infections linked to backyard poultry, U.S. health officials said on Friday.

One death was reported in Ohio and the other one in Texas, according to the Centers for Disease Control and Prevention (CDC).

An additional 489 people with salmonella infections have been added to an ongoing investigation since the last update in June, the CDC said, taking the total to 768 cases from 48 states.

Salmonella is a bacteria that can cause serious and severe infections in children, frail or elderly people and others with weak immune system.

https://www.reuters.com/article/us-usa-salmonella/cdc-links-two-deaths-to-multi-state-salmonella-outbreak-idUSKCN1UE2LH

Biohaven’s treatment for Lou Gehrig’s disease fails to win FDA nod

Biohaven Pharmaceutical Holding Co Ltd said on Friday the U.S. health regulator failed to approve its treatment for amyotrophic lateral sclerosis, or Lou Gehrig’s disease, sending its shares down nearly 6% in extended trading.

The company said the Food and Drug Administration issued a complete response letter, raising concerns related to an active pharmaceutical ingredient (API) used in a 2017 study that was made by Apotex Pharmachem India Pvt Ltd between 2014 and 2016.

Biohaven said that the API is now being sourced from another supplier, with which there are no chemistry, manufacturing, and control issues that have been identified.

Amyotrophic lateral sclerosis is a rare neurologic disease, which mainly affects the nerve cells responsible for controlling voluntary muscle movement such as walking or talking.

https://www.reuters.com/article/us-biohaven-pharma-fda/biohavens-treatment-for-lou-gehrigs-disease-fails-to-win-fda-nod-idUSKCN1UE2PQ

Health Care Down as Judge Backs Trump Administration’s Insurance Move

Health-care companies fell as doubts swirled over the future of the Affordable Care Act once more. A federal judge said the Trump administration could expand availability of certain health-insurance plans that don’t comply with the Affordable Care Act, a move that plaintiffs in the case warn could destabilize ACA insurance exchanges by undercutting the standardized plans sold there without offering the same benefits.

https://www.marketscreener.com/news/Health-Care-Down-as-Judge-Backs-Trump-Administration-s-Insurance-Move-Health-Care-Roundup–28931000/

Bayer recalls 2 US lots of Kogenate FS antihemophilic factor (recombinant)

Bayer is voluntarily recalling two lots of Kogenate^® FS antihemophilic factor (recombinant) 2000 IU vials in the United Statesto the patient level. Certain vials from these two lots that were labeled as Kogenate FS actually contain the FVIII hemophilia A treatment, Jivi^® antihemophilic factor (recombinant) PEGylated-aucl 3000 IU. The U.S. is the only country where affected products were distributed. We are working closely with the U.S. Food and Drug Administration to manage the recall and to minimize disruption to supply and inconvenience to patients. The affected lots, distributed from February 5, 2019 to July 15, 2019 from Bayer’s distribution sites in Berkeley, CA and Shawnee, KS, are listed below:

Product name	NDC Number	Product Code	Lot Number	Expiration Date
Kogenate FS antihemophilic factor (recombinant) 2000 IU	0026-3786-65	DR03	27118RK	06/12/2021
	0026-3786-65	DR03	27119CG	06/12/2021

While the majority of the mislabeled vials in the affected lots were recovered, approximately 990 of these vials were released in the U.S. The associated Jivi batch was expired as of August 2018. However, all stability specifications of this expired Jivi batch had continued to be met, as of April 2019. We have voluntarily recalled both lots in the interest of patient safety, and to ensure that any potentially impacted product is removed from pharmacy shelves, and that patients and their healthcare providers are alerted. Importantly, vials of Kogenate FS that are not associated with the affected lot numbers (27118RK and 27119CG) are not impacted and can continue to be used without interruption. There are no lots of Jivi or Kovaltry^® antihemophilic factor (recombinant) product affected by this recall.

Patient safety is Bayer’s highest priority. We are carefully monitoring for any complaints or adverse event reports that may be related to this recall. The company is issuing this notification after discovering the issue earlier this week. Following an immediate internal assessment, Bayer contacted the FDA to inform the agency of the situation.

Kogenate FS and Jivi are both medicines used to replace clotting factor (factor VIII or antihemophilic factor) that is missing in people with hemophilia A. Kogenate FS is approved to treat or control bleeding in adults and children with hemophilia A. Jivi is approved to treat and control bleeding in previously treated adults and adolescents (12 years of age and older) with hemophilia A.

Patients in possession of vials from the affected lot numbers should immediately stop using the product and contact their physician. In addition, patients should contact their pharmacy to return the affected product. Bayer is notifying its distributors in writing to check their stock immediately and to discontinue the distribution and use of any affected product. For distributors with questions regarding the recall process, please contact the Bayer Recall Coordinator, Inmar, at 855-707-7518.

https://www.biospace.com/article/releases/bayer-statement-on-voluntary-recall-of-two-lots-of-kogenate-fs-antihemophilic-factor-recombinant-in-the-united-states/

New protein target for deadly ovarian cancer

A new study shows that targeting a specific protein found within quickly spreading high-grade serous carcinomas (HGSC) of the ovary could help contain these cancers. HGSC is the most common and deadly form of epithelial ovarian cancer, which is itself the deadliest cancer of the female reproductive tract. When HGSC spreads outside the ovaries, within the peritoneal cavity, it forms detached balls called spheroids, which may look and act differently from the adherent cells of the primary tumor.

The study is published in the current issue of the journal Molecular Cancer Research.

70% of HGSC relapse despite treatment, becoming resistant to chemotherapy, which makes the new discovery a true potential breakthrough in the treatment of this tumor.

All life at cellular and organism level depends upon thousands of life processes that provide and degrade a range of chemicals required for proper function of the cells and tissues. These intricately interdependent processes together they make up the body’s metabolism.

However, as researcher Erika Dahl explains, “A hallmark of cancer cells is that their metabolic processes are often different from normal, healthy cells.”  This is called metabolic reprogramming. As one of the outcomes, study author Katherine Aird says, “Cancer cells can grow forever without stimulus.”

The good news about the newly discovered protein is that it can be inhibited, thus inactivating cell processes within ovarian cancer cells to switch them from a constitutively proliferative cell cycle to one which results in senescence, or going to sleep. The key role of the protein was identified on cell culture experiments by researchers at Penn State College of Medicine.

The current study focused on teasing out the differences in the metabolism of ovarian cancer cells by comparing them with cells from a normal fallopian tube.

The route used to achieve this was quantitative spectrometry, which helped analyze the metabolites produced by various cellular pathways in the two type of tissue. Among the differences, it was revealed that cancer cells utilized glucose, a form of sugar, via the key energy cycle called the citric acid cycle, far more often, as against the more common use of an oxygen-requiring pathway called aerobic glycolysis. This accounts for the presence of a high level of citric acid activity in all high-grade serous ovarian cancer cells.

This means that many therapies which inhibit the breakdown of glucose (glycolysis) to destroy cancer cells may be quite ineffective. Dahl commented that this could often result, in fact, in the production of toxins that harm normal healthy tissue.

Instead, the team in the current study looked at the effects of inhibiting the wildtype or normal form of an enzyme, isocitrate dehydrogenase 1 (IDH 1), which plays a vital part in the citric acid cycle. They selected this protein because it was the only one in this pathway that is expressed at higher levels in both adherent and spheroid tumor cells. Increased activity of this enzyme severely impacts progression-free survival, which is an important outcome measured in assessing the effectiveness of any cancer therapy.

Mutants of this protein are common in other tumors, but the wildtype form is typically present in cells within HGSC. The researchers hypothesize that the presence of this enzyme is an important advantage to these cells, and its inhibition is a key step to inducing senescence.

The researchers found that suppressing the work of this protein stopped cell division completely by suppressing the activity of multiple other genes, inhibiting vital metabolic pathways. Both adherent cells of the primary tumor, and spheroid cells of secondary HGSC, become senescent when the wildtype IDH 1 enzyme is inhibited. Thus, this could be an excellent way to treat HGSC at all stages. This is an important consideration, as ovarian cancers are rarely diagnosed at early stages.

While there are already FDA (US Food and Drug Administration)-approved drugs against one of the mutant forms of this enzyme, the team wondered whether they would work against the wildtype form as well. They found that one did, and this is now a part of their continued research agenda.

Aird says, “One of our long-term goals is to try and repurpose this already-approved drug as a treatment for this form of ovarian cancer.” Besides adapting existing drugs against the enzyme to fight this type of cancer, the researchers want to examine the differences in the metabolic functioning of normal and HGSC cells more closely. Another goal is to examine the effectiveness of combining IDH 1 inhibitors with other treatments.

Journal reference:

Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer, Erika S. Dahl, Raquel Buj, Kelly E. Leon, Jordan M. Newell, Yuka Imamura, Benjamin G. Bitler, Nathaniel W. Snyder and Katherine M. Aird, Mol Cancer Res June 17 2019 DOI: 10.1158/1541-7786.MCR-18-1233, http://mcr.aacrjournals.org/content/early/2019/06/17/1541-7786.MCR-18-1233

https://www.news-medical.net/news/20190714/New-protein-target-for-deadly-ovarian-cancer.aspx

FDA accepts 22nd Century’s application for very low nicotine cigarettes

The FDA has accepted for review 22nd Century Group’s (NYSEMKT:XXII) marketing application for very low nicotine content (VLNC) cigarettes under the proposed brand name “VLN.”

Shares are up 2% after hours.

https://seekingalpha.com/news/3479434-fda-accepts-22nd-centurys-application-vlnc-cigarettes