Biopharmaceuticals, medium- and high-molecular weight biologically active macromolecules, are not easily absorbed by the small intestine, the main organ responsible for gastrointestinal absorption, resulting in a bottleneck for oral administration type biopharmaceutical development. Now, researchers have found a new small intestine permeable peptide that can facilitate digestive tract absorption of biopharmaceutical products. The discovery should make it possible for oral administration of drugs that were previously only available by injection.
Respiratory tract infections in young children are linked to an increased risk of asthma and worse lung function in later life, according to new research.
Based on a new molecular study of tissues biopsied from various parts of the upper digestive tract, researchers at Georgetown Lombardi Comprehensive Cancer Center have identified significant, if subtle, differences in gene mutations and other factors that could help in developing more tailored treatment options for cancer patients. This finding is notable because as the digestive tract winds its way down from the mouth to the rectum, a continuum of cancers can arise, each of which may be amenable to precision treatment.
In this study, the researchers focused primarily on small bowel adenocarcinomas (SBAs) and compared them with parts of the upper digestive tract that precede it and follow it — the gastroesophageal area and right-sided colon cancers, respectively. Each section of the gastrointestinal, or GI, tract plays a role in digestion of food and hence has distinct structural as well as molecular differences. The finding will be presented June 30, 2017, at the European Society for Medical Oncology gastrointestinal meeting in Barcelona, Spain.
“Our study was undertaken primarily because SBAs are greatly understudied, as well as increasing in incidence nationwide, and we wanted to determine what may make them unique,” says Mohamed E. Salem, MD, assistant professor of medicine at Georgetown Lombardi, and principal investigator for the study. “We really didn’t have good data on SBAs so we’ve been treating the tumors as if they were colon cancers and we really need to start treating them based on their unique properties.”
The investigators looked at 4,278 tumor samples from a tissue repository of patients with GI tract cancers. The researchers were able to clearly identify 531 SBAs; 2,674 gastroesophageal cancers; and 1,073 ride-sided colon cancers. Using a variety of genetic sequencing techniques, they ascertained how well the genes were expressed, or “turned on” to make proteins. They also calculated what is called the tumor mutational load, or TML, which can be a marker for how responsive a tumor is to immunotherapy — which, paradoxically, could indicate that immunotherapy more effective when a higher TML is found.
The researchers found a set of frequently mutated genes in SBAs that could be helpful to clinicians when they are looking to use targeted therapies that work best in cancers with specifics mutations. In this case, KRAS, BRAF, BRCA2 and a few other genes were identified in SBAs. Mutations to these genes can affect the choice of therapy as well as how to better target the mutations.
Next, the investigators compared the SBA mutations with mutations in the two other parts of the GI tract and found higher and lower mutation frequencies across a wide array of genes. They were able to discern that SBAs were more like colon than gastric cancers.
More importantly, though, they found about a two-fold higher PD-L1 expression level for gastroesophageal cancers compared to right-side colon cancers but did not find such a marked difference between those tumors and SBAs. PD-L1 is often used as a marker to indicate if a cancer might be responsive to immunotherapy, and usually the higher the PD-L1 level, the more responsive a cancer would be to certain immunotherapies.
“With this study we now have what I think is one of the biggest datasets on SBAs,” says Salem. “Previously, investigators studying the colon found very unique differences between the left and ride sides, and our study therefore took advantage of those findings by exploring the differences between ride-sided colon cancers and SBAs. We now see a continuum of molecular changes that occur as these regions of the digestive tract transition from one area to the other.”
The next step, says Salem, will be to try to correlate these findings with patient treatment outcomes, initially as a retrospective, or backward looking study, and then hopefully design a forward looking clinical trial to determine which treatments may be best for patients with SBAs.
Acute and chronic infections in a person’s upper gastrointestinal tract appear to be linked to Parkinson’s disease, say scientists at Georgetown University Medical Center and their collaborators at the National Institutes of Health and other institutions.
Their study, published in the Journal of Innate Immunity, finds that alpha-Synuclein (αS), the protein implicated in Parkinson’s disease and other forms of neurodegenerative diseases, is released when an infection occurs in the upper GI tract (the esophagus, stomach and duodenum) inducing an immune response as part of the body’s innate immune system. The researchers say that these findings suggest that frequent or chronic upper GI infections could overwhelm the body’s capacity to clear αS, leading to disease.
This largely federally-funded study helps clarify the function of αS, which is poorly understood, says the study’s senior investigator, Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine and scientific director of the MedStar Georgetown Transplant Institute.
This research builds upon prior studies that showed in autopsied material from individuals at very early as well as later stages of Parkinson’s, that the buildup of αS actually begins in the enteric nervous system (nerves in the GI tract). Animal studies have further shown that microbes in the GI tract can induce formation of toxic aggregates in the enteric nervous system, which can then travel up to the brain.
Zasloff and his colleagues studied biopsy samples, collected at the University of Oklahoma Health Sciences Center, from 42 children with upper GI distress. They also looked at another population of 14 MedStar Georgetown University Hospital patients who received an intestinal transplant. This second group had documented cases of infection by Norovirus, a common cause of upper GI infection.
The biopsies showed that expression of αS in enteric nerves of the upper GI tract in these children positively correlated with the degree of acute and chronic inflammation in the intestinal wall. Some highly monitored transplant patients expressed αS as Norovirus was infecting them.
Researchers also showed that human αS could potently attract human immune cells such as macrophages and neutrophils and could “turn on” dendritic cells to alert the immune system of the specific pathogen encountered.
As Zasloff explains, “When expressed in normal amounts following an infection of the upper GI tract, αS is a good molecule. It is protective. The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing αS. αS then attracts white blood cells to the site where it has been released. In addition, αS produced in one nerve can spread to others with which it communicates thereby protecting a large field. By this means, the nervous system can protect both itself as well as the GI tract as a whole in the setting of an infection.”
He adds, “It is well known from animal studies that αS produced in the enteric nervous system can use the nerves connecting the GI tract to the brainstem as an escalator, trafficking αS from the gut to the brain and spreading to centers within the central nervous system.
“But too much αS — such as from multiple or chronic infections — becomes toxic because the system that disposes of αS is overwhelmed, nerves are damaged by the toxic aggregates that form and chronic inflammation ensues. Damage occurs both within the nervous system of the GI tract and the brain.”
Zasloff says the new findings “make sense” of observations made in Parkinson’s disease patients, such as the presence of chronic constipation from damage to the enteric nervous system that develops decades before brain symptoms become apparent and that chronic upper GI distress is relatively common in people who develop Parkinson’s.
Zasloff adds that the publication of this study coincides with the start of a clinical trial targeting the accumulation of αS in the enteric nervous system. The phase 1/2a study is examining the safety, tolerability, pharmacokinetics, and pharmacodynamics of an oral drug, ENT-01, a synthetic version of squalamine, a natural steroid made by the dogfish shark, to relieve constipation associated with Parkinson’s disease. Research recently published by Zasloff and collaborators demonstrated that squalamine both reduced the formation of toxic αS clumps and their toxicity, in animal experiments. The clinical trial, being conducted in the US, is sponsored by Enterin, Inc.