The scientists of the “Biology and Mars Experiment” (BIOMEX) project had already sent kombucha cultures to the International Space Station (ISS) in 2014 with the support of the European Space Agency. The aim was to learn more about the robustness of cellulose as a biomarker, the genomic architecture of kombucha, and its survival behaviour under extraterrestrial conditions. After one and a half years under simulated Martian conditions outside the ISS, the samples were reactivated on Earth and cultivated for another two and a half years.

The head of the University of Göttingen’s Institute of Veterinary Medicine, Professor Bertram Brenig, was responsible for the sequencing and bioinformatic analysis of the metagenomes of the reactivated cultures and individual kombucha cultures in a team with researchers from the University of Minas Gerais in Brazil. “Based on our metagenomic analysis, we found that the simulated Martian environment drastically disrupted the microbial ecology of kombucha cultures. However, we were surprised to discover that the cellulose-producing bacteria of the genus Komagataeibacter survived.” The results suggest that the cellulose produced by the bacteria is probably responsible for their survival in extraterrestrial conditions. This also provides the first evidence that bacterial cellulose could be a biomarker for extraterrestrial life and cellulose-based membranes or films could be a good biomaterial for protecting life and producing consumer goods in extraterrestrial settlements.

Another interesting aspect of these experiments could be the development of novel drug delivery systems, for example for the development of medicine suitable for use in space. Another focus was on investigations into changes in antibiotic resistance: the research team was able to show that the total number of antibiotic and metal resistance genes — meaning that these microorganisms might survive despite antibiotics or metals in the environment — were enriched in the exposed cultures. “This result shows that the difficulties associated with antibiotic resistance in medicine in space should be given special attention in the future,” the scientists said.

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The federally funded review, which will be updated on an ongoing basis, was published today in the Annals of Internal Medicine.

Researchers did find evidence to support a short-term benefit in treating neuropathic pain — caused by damage to peripheral nerves, such as diabetic neuropathy resulting in pain described as burning and tingling, involving two FDA-approved synthetic products with 100% tetrahydrocannabinol, or THC: dronabinol (under the trade name Marinol) and nabilone (Cesamet). Both products also lead to notable side effects including sedation and dizziness, according to the review.

Another product, a sublingual spray of equal parts THC and cannabidiol, or CBD, extracted from the cannabis plant, known as nabiximols, also showed evidence of some clinical benefit for neuropathic pain, although that product is not available in the U.S. This product also led to side effects, such as nausea, sedation and dizziness.

“In general, the limited amount of evidence surprised all of us,” said lead author Marian S. McDonagh, Pharm.D., emeritus professor of medical informatics and clinical epidemiology in the OHSU School of Medicine. “With so much buzz around cannabis-related products, and the easy availability of recreational and medical marijuana in many states, consumers and patients might assume there would be more evidence about the benefits and side effects.

“Unfortunately, there is very little scientifically valid research into most these products,” she said. “We saw only a small group of observational cohort studies on cannabis products that would be easily available in states that allow it, and these were not designed to answer the important questions on treating chronic pain.”

Voters in Oregon, Washington and 20 other states have legalized medical and recreational marijuana, however the researchers found many of the products now available at U.S. dispensaries have not been well studied.

“For some cannabis products, such as whole-plant products, the data are sparse with imprecise estimates of effect and studies had methodological limitations,” the authors write.

This situation makes it difficult to guide patients.

“Cannabis products vary quite a bit in terms of their chemical composition, and this could have important effects in terms of benefits and harm to patients,” said co-author Roger Chou, M.D., director of OHSU’s Pacific Northwest Evidence-based Practice Center. “That makes it tough for patients and clinicians since the evidence for one cannabis-based product may not be the same for another.”

The living review, including a visual abstract summary of the findings, will also be shared on a new web-based tool launched by OHSU and VA Portland Health Care System early this year to help clinicians and researchers evaluate the latest evidence around the health effects of cannabis. Known as Systematically Testing the Evidence on Marijuana, or STEM, the project includes “clinician briefs” to help health care workers translate the clinical implications.

“This new living evidence review is exactly the type of resource clinicians need to clarify for patients the areas of potential promise, the cannabis formulations that have been studied and, importantly, the major gaps in knowledge,” said co-author Devan Kansagara, M.D., M.C.R., professor of medicine in the OHSU School of Medicine and a staff physician at the VA Portland.

Reviewers searched more than 3,000 studies in the scientific literature as of January of this year and landed on a total of 25 with scientifically valid evidence — 18 randomized controlled studies and seven observational studies of at least four weeks.

The effects of cannabis and related products are based on their ability to mimic the body’s own endocannabinoid system. The system is composed of receptors and enzymes in the nervous system that regulate bodily functions and can affect the sensation of pain. In the evidence review, researchers sorted the types of product into high, comparable and low ratios of THC to CBD and compared their reported benefits and side effects.

Dronabinol and nabilone fit into the high THC to CBD ratio category, with 100% THC (no CBD), showing the most benefit among the products studied, with meta-analysis of the six randomized controlled studies demonstrating statistically valid benefits for easing neuropathic pain compared to a placebo.

“Honestly, the best advice is to talk to your primary care physician about possible treatments for chronic pain,” McDonagh said. “If you want to consider cannabis, you need to talk to your doctor.”

In addition to McDonagh, Chou and Kansagara, co-authors included Benjamin J. Morasco, Ph.D., Jesse Wagner, M.A., Azrah Y. Ahmed, B.A., and Rongwei Fu, Ph.D.

The project was funded by Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, contract number 75Q80120D00006. Statements in the report should not be construed as endorsement by the AHRQ or the Department of Health and Human Services.

The National Cancer Institute cites infection with H. pylori as the primary identified cause of certain types of stomach cancer. H. pylori is a bacterium that grows in the mucosa, or membrane layer that lines the stomach.

“This study is proposing that if you are carrying this particular allele, you are more likely to have an aggressive type of response to the bacteria that can result in complications,” said the study’s senior author, Juanita L. Merchant, MD, PhD, Regents Professor of Medicine and chief of the Division of Gastroenterology at the UArizona College of Medicine — Tucson.

In the United States, H. pylori is more prevalent in Hispanics, African Americans and the elderly. Dr. Merchant cited data suggesting that 1-3% of people with H. pylori will develop gastric cancer and that the cure rate is around 30%, which is low compared with some other types of cancer.

Current diagnosis of stomach or gastric cancer requires the patient to undergo an upper endoscopy, where a doctor looks for signs of cancer and takes a tissue sample for analysis.

For years, Dr. Merchant and colleagues have been investigating new ways to diagnose stomach cancer in its earliest possible stages. In 2020, they published research on a promising biomarker that appears in some patients before stomach cancer develops.

The new study focused on the molecular pathways that control the activation of immune cells in response to H. pylori infection, specifically the action of toll-like receptor 9 (TLR9).

Located within immune cells, TLR9 signals the immune system when to fight an infection. However, H. pylori infection can constantly trigger TLR9 activation over long periods of time, leading to the chronic inflammation. The long-term presence of inflammation caused by H. pylori infection is believed to be one of the triggers for cancer developing in the stomach.

“This addresses the question of what role the immune microenvironment has in gastric cancer,” said Dr. Merchant, who is a research member of the UArizona Cancer Center. “We have shown that these immune cells do play an important role.”

Researchers found that the chronic activation of TLR9 in the stomach triggers a series of events that includes increased production of interferon α, a signaling protein that can change the genetic signature of specialized immune cells known as myeloid-derived suppressor cells, or MDSCs. Prior research has linked MDSCs with H. pylori infection.

Dr. Merchant and her team focused on each step of the pathway and identified a specific genetic change — allele rs5743836 TLR9 minor C — that was linked to higher levels of TLR9 and interferon α and a greater incidence of gastric tumors. The allele is a single nucleotide polymorphism, or SNP, which is a genetic change in the DNA between genes.

“Because TLR9 and the SNP can be tested by DNA, they could be used as biomarkers to help us identify which patient populations are going to be more susceptible to the cellular changes that might lead to cancer based on their genetic background,” Dr. Merchant explained. “Those are the patients who could benefit from increased endoscopic surveillance.”

Eventually, the findings may also lead to new therapeutic options for patients.

“We have previously found a real-time biomarker in a blood test, and now we have something we can see in DNA,” Dr. Merchant said. “Our next step is to look at therapy options.”

Approximately 5-10% of rectal cancers are molecularly characterized as being deficient in mismatch repair enzymes (dMMR). These cancers tend to be less responsive to chemotherapy and radiation, which increases the chance that surgical treatment is necessary. Unfortunately, surgery can result in notable health consequences, including nerve damage, infertility, and bowel and sexual dysfunction.

“Over 45,000 people in the United States were diagnosed with rectal cancer last year, and many of those cases were in people under the age of 65. Historical treatment of the disease has included radiation, surgery and chemotherapy, which can be debilitating despite its curative potential, pointing to the need for better and more effective treatments that can prolong longevity while maintaining quality of life,” said Sanoff, who is the quality and innovation officer of the North Carolina Cancer Hospital and professor in the UNC School of Medicine Division of Oncology. “These initial findings of the remarkable benefit with the use of dostarlimab are very encouraging but also need to be viewed with caution until the results can be replicated in a larger and more diverse population.”

Sanoff also cautioned that little is known about how long the benefit of the drug will last or whether it will be curative in the long-term. Patients in this trial have only been observed for six months to two years so far.

“The responses in these first 12 of a planned-for 30 patients in the trial were remarkable and exceed what we would expect with the standard chemotherapy plus radiation,” Sanoff said. “Although quality of life measures have not been reported yet, it’s encouraging that some of the most difficult symptoms, such as pain and bleeding, all resolved with the use of dostarlimab.”

Sanoff noted there are other immunotherapy drugs that could also be tested against this form of rectal cancer. “As a gastrointestinal medical oncologist, I can think of nothing better for my patients than being able to offer them a drug that is more effective, less toxic and avoids surgery, chemotherapy, and radiation; that day can’t come soon enough,” she said.

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The multi-institutional, international study, led by researchers at the Johns Hopkins Kimmel Cancer Center and WEHI in Melbourne, Australia, found that testing for ctDNA after surgery and directing chemotherapy to ctDNA-positive patients reduced the use of chemotherapy overall without compromising recurrence-free survival.

There are several prior research studies demonstrating that circulating tumor DNA can be detected in blood and that the presence of ctDNA post-surgery predicts a risk of cancer recurrence. However, this is believed to be the first clinical study showing that the measurement of circulating tumor DNA prior to therapy may benefit patients.

These findings will be published in the New England Journal of Medicine and presented at the annual meeting of the American Society of Clinical Oncology on June 4.

“Previous studies have theorized that ctDNA measurements might be useful in guiding patient management, and this study provides real-world clinical evidence that supports these theories,” says Bert Vogelstein, M.D., Clayton Professor of Oncology, co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator. Vogelstein and group were the first to show that colon cancer is caused by a sequence of genetic mutations and showed that DNA shed from tumors could be detected in blood, stool and other body fluids.

Currently, the use of chemotherapy in stage II colon cancer, which is defined as a colon cancer that has grown through the wall of the colon but does not extend to the lymph nodes or other organs, is controversial. There is no consensus among cancer experts on its benefit. This study was aimed at helping solve the controversy by assessing whether ctDNA could be used to provide a more precise prediction of recurrence risk after surgery. Patients who were ctDNA-negative could be spared the toxicities of chemotherapy, and those who had remaining cancer could receive chemotherapy to attack the lingering malignant cells.

In the study, 455 patients with stage II colon cancer were randomized after surgery 2:1 to standard treatment or ctDNA-guided management. Of these patients, 153 received standard management, which includes monitoring over time for recurrence or chemotherapy. An additional 302 patients underwent blood tests within seven weeks after surgery to search for ctDNA. If ctDNA was detected, patients received fluoropyrimidine or oxaliplatin-based chemotherapy. If ctDNA was not detected, patients did not receive chemotherapy.

The ctDNA-guided approach reduced the use of chemotherapy compared with the standard management group (15.3% of patients in the ctDNA-guided group received chemotherapy versus 27.9% in the standard management group). The two- and three-year survival with no cancer recurrence was similar between the ctDNA-guided group and the standard management group.

“Stage II colon cancer presents a unique challenge,” explains Anne Marie Lennon, M.B.B.Ch., Ph.D., professor of medicine, and director of the division of gastroenterology and hepatology. “In stage I colon cancer, patients do not receive chemotherapy because their prognosis for survival is over 90%. The risk of discomfort and toxicities from the therapy outweigh the benefits it can provide. On the other hand, every stage III colon cancer patient currently receives chemotherapy because the risk of relapse is high.”

The goal of chemotherapy in colon cancer is to eradicate micrometastases, cancer cells not yet visible on radiologic images that travel through the bloodstream and cause the cancer to come back or spread it to other parts of the body. Using ctDNA to detect these invisible cells can now identify which patients are most likely to have micrometastases and, therefore, are most likely to benefit from chemotherapy.

“Using ctDNA to guide treatment, a stage II colon cancer patient who is negative for ctDNA has a lower chance of cancer recurrence than the average stage I colon cancer patient, so we have an opportunity to change clinical practice,” says Joshua Cohen, a lead author of the study and M.D./Ph.D. candidate at the Johns Hopkins University School of Medicine.

The researchers hope these findings will stimulate the study of ctDNA in patients with other stages of colon cancer and other types of cancer. In future studies, the researchers will explore patients with early-stage pancreatic cancer and stage III colon cancer to see if ctDNA can similarly identify patients who are most likely to benefit from more aggressive chemotherapy than is currently used. They also plan to explore whether the presence of residual ctDNA can be used to help optimize the management of individual patients following surgery or other forms of therapy.

Using ctDNA to stratify treatments among patients is part of the movement toward precision medicine — individualized care that tailors therapies to the unique characteristics of a cancer.

The researchers also believe the findings will provide opportunities to test promising new drugs in patients with earlier stages of cancer.

“All drugs work better in patients with cancers that are detected relatively early, before they have given rise to large metastatic masses. However, new drugs are usually first tested in patients whose cancers are very advanced,” says Vogelstein. “We hope that ctDNA analysis will enable testing of new drugs in patients with early-stage cancers and micrometastases, when the new drugs are most likely to save lives.”

In addition to Vogelstein, Cohen, Lennon, other researchers were Kamel Lahouel, Ph.D., Yuxuan Wang, M.D., Ph.D., Janine Ptak, M.S., Natalie Silliman, B.S., Lisa Dobbyn, B.A., Maria Popoli, M.S., Ralph Hruban, M.D., Nicholas Papadopoulos, Ph.D., Kenneth Kinzler, Ph.D., and Cristian Tomasetti from Johns Hopkins, and Jeanne Tie, M.D., Serigne Lo, Ph.D., Suzanne Kosmider, M.B.B.S., Jeremy Shapiro, M.B.B.S., Margaret Lee, M.B.B.S., Sam Harris, M.B.B.S., Adnan Khattak, M.B.B.S., Matthew Burge, M.B.B.S. Marion Harris, M.B.B.S., James Lynam, M.B.B.S., Louise Nott, M.B.B.S., Fiona Day, Ph.D., Theresa Hayes, M.B.B.S., Sue-Anne McLachlan, M.B.B.S., Belinda Lee, M.B.B.S., and Peter Gibbs, M.D., from the Walter and Eliza Hall Institute of Medical Research, Peter MacCallum Cancer Centre, or University of Melbourne in Melbourne, Australia.

This research was supported by the Australian National Health and Medical Research Council, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, the Conrad R. Hilton Foundation, the Sol Goldman Charitable Trust, John Templeton Foundation, National Institutes of Health (CA62924, CA009071, GM136577, CA06973) and the Eastern Health Research Foundation Linda Williams Memorial Grant.

Bert Vogelstein, Kenneth Kinzler and Nickolas Papadopoulos are founders of and hold equity in Thrive Earlier Detection, an Exact Sciences Company. Kenneth Kinzler and Nickolas Papadopoulos are consultants to Thrive Earlier Detection, an Exact Sciences Company. Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos and Joshua Cohen are consultants to and own equity in Haystack Oncology. Nickolas Papadopoulos and Kenneth Kinzler are on the board of directors of Haystack Oncology. The companies named above have licensed previously described technologies related to the work described in this paper from The Johns Hopkins University. Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos and Joshua Cohen are inventors on some of these technologies. Licenses to these technologies are or will be associated with royalty payments to the inventors as well as to The Johns Hopkins University.