Research Roundup: Pancreatic Cancer, Dementia Genes, Molecular Surgery and More
There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.
Possible Immune Therapy for Pancreatic Cancer
Researchers at the University of Pennsylvania School of Medicine used a combination of immunotherapy and chemotherapy on pancreatic cancer. The combination, which included a checkpoint inhibitor to CD40, resulted in the tumors shrinking. The team presented the findings at the American Association for Cancer Research (AACR) 2019 Annual Meeting in Atlanta. The research is conducted in collaboration with the Parker Institute for Cancer Immunotherapy.
“These findings give us clues that this new and innovative combination therapy can be effective against pancreatic cancer,” stated Mark H. O’Hara, assistant professor of Hematology-Oncology at Penn and co-lead author of the study. “Although only time and future research will truly tell, our data are a reason for optimism.”
Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who were previously untreated received a combination of four different therapies. Each patient received gemcitabine and nab-aclitaxel, standard-of-care chemotherapies, in addition to an experimental antibody CD40 called APZ005M. Half the group also received the PD-1 inhibitor Bristol-Myers Squibb’s Opdivo (nivolumab). At the time of the data cutoff for interim analysis, 20 out of 24 patients, or 83 percent, saw their tumors shrink.
Keeping Microglia Young Could Restore Cognition
A lot of work has been done recently on the role of microglia in the aging brain and how it relates to various forms of dementia, like Alzheimer’s disease. Microglia are a type of brain cells that act as the brain’s immune cells and garbage collectors, scooping up cellular debris and protein deposits. But as we age, those cells don’t work as well. Researchers with Stanford University, School of Medicine found that by blocking a specific protein’s activity, it restored cognition in aging mice. The work was published in the journal Nature.
“Many of the genes whose high-risk variants have recently been linked to Alzheimer’s disease are known to be active in the brain only in microglia,” stated Tony Wyss-Coray, professor of neurology and neurological sciences and senior author of the study. “Microglial genes’ activation patterns are abnormal in Alzheimer’s patients, and in other neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. We think we may have discovered a way to get these cells back on track and make them work the way they used to when we were young.”
Wyss-Coray’s team looked at about 3,000 genes encoding proteins they thought could be targeted by drugs or were already being targeted. One at a time, they blocked each gene, to see how it affected microglia in mice from ingesting small bits of fluorescently labeled latex. They also evaluated which of the 3,000 genes were more or less active in microglia from the brains of young mice and old mice. They found that just one gene that affected microglial phagocytosis and that increased in activity as the mice aged. The gene is called CD22 and is found in both mice and humans. When they blocked the activity of the CD22 protein and found that the microglial were better at ingesting the latex—and in additional experiments, were better in ingesting beta-amyloid, the proteins associated with Alzheimer’s disease, and alpha-synuclein, a protein associated with Parkinson’s disease.
Excess Weight Before 50 Linked to Higher Risk of Pancreatic Cancer
Researchers with the American Cancer Society in Atlanta presented research at the AACR Annual meeting showing that excessive body weight before the age of 50 is strongly associated with pancreatic cancer death.
Pancreatic cancer accounts for slightly over 3 percent of all new cancer cases, but the five-year survival rate is only 8.5 percent. “Pancreatic cancer rates have been steadily increasing since the early 2000s,” stated the study’s lead author, Eric J. Jacobs, senior scientific director of Epidemiology Research at the ACS in Atlanta. “We’ve been puzzled by that increase because smoking—a major risk factor for pancreatic cancer—is declining. Increased weight in the U.S. population is a likely suspect, but previous studies have indicated that excess weight is linked with only a relatively small increase in risk, which doesn’t look large enough to fully explain recent increases in pancreatic cancer rates.”
However, in this study, they looked at data from 963,317 U.S. adults with no history of cancer enrolled in the ACS’s Cancer Prevention Study II, a national study of cancer mortality that began in 1982 and followed participants through 2014. Everybody in the study reported their weight and height just once, at the beginning of the study, when some were as young as 30 while others were in their 70s or 80s. They then calculated body mass index (BMI) as an indicator of excess weight.
In the follow-up period, 8,354 people died of pancreatic cancer and higher BMI was linked to increased risk of dying of pancreatic cancer. But the increased risk was highest for people whose BMI was higher at earlier ages.
Two New Dementia Genes Identified
Researchers with the Boston University School of Medicine discovered two rare genes associated with Alzheimer’s disease. One variant is in the NOTCH3 gene and the other is in the TREMN2 gene. The NOTCH3 variant hasn’t been linked to Alzheimer’s before, although mutations in the gene cause a rare type of dementia called CADASIL. Mutations in the TREM2 gene have been linked with Alzheimer’s, and it was also known that people with two copies of the Q33X mutations in the TREM2 gene have a very rare disease called Nasu-Hakola disease, characterized by dementia in midlife and polycystic bone lesions with fractures.
“Our findings indicate that different mutations in the same gene or different number of copies of a particular mutation may lead to very distinct forms of dementia,” stated Lindsay Farrer, chief of the Biomedical Genetics division at Boston University School of Medicine and corresponding author of the study. “Discovery of associations of Alzheimer’s risk with rare genetic variants can lead to new insights about biological pathways involved in AD and strategies for developing novel treatments and biomarkers.”
Molecular Surgery—No Scalpels, No Incisions
Scientists at Occidental College in Los Angeles and the University of California, Irvine (UCI) developed a “molecular surgery” technique that uses minuscule needles, electric current and 3D-printed molds to reshape living tissue without incisions, scarring or recovery time. They presented their findings at the American Chemical Society Spring 2019 National Meeting & Exposition.
“We envision this new technique as a low-cost office procedure done under local anesthesia,” stated Michael Hill, with Occidental College, one of the project’s principal investigators. “The whole process would take about five minutes.”
Hill worked with Brian Wong, at UCI, who is an expert on an alternative technique that utilizes an infrared laser to heat cartilage, which makes it flexible enough to reshape. Hill stated, “The problem is, that technique is expensive, and it’s hard to heat the cartilage enough so that it’s malleable without killing the tissue.”
Hill and Wong passed electrical current through the cartilage to heat it, which allowed them to reshape the tissue, but didn’t warm it. The current converts the water in the cartilage into oxygen and hydrogen ions, which reduces charge density and makes the cartilage more malleable. They initiated the technique on a rabbit whose ears normally stood upright. They used a mold to hold one ear bent over. They inserted microneedle electrodes into the ear where they wanted the ear to bend and pulsed the current through it, which made the cartilage bendable without damaging it.
A Method for Delaying Progression of ALS?
Researchers with the University of South Florida developed a method in laboratory mice of slowing the symptoms of amyotrophic lateral sclerosis (ALS). They transplanted human bone marrow-derived endothelial progenitor cells into the mice, with the result that more motor neurons survived and slowed the disease progressions. It basically repaired damage to the blood-spinal cord barrier. They published their research in the journal Scientific Reports.
Previous research by lead author Svitlana Garbuzova-Davis and her colleagues at the USF Health Morsani College of Medicine’s Center of Excellence for Aging & Brain Repair, showed that human bone marrow-derived stem cells improved motor functions and nervous system conditions in ALS mice. But in the earlier research, the beneficial effect was slowed until several weeks after cell transplant and some severely damaged capillaries were observed even after high-dose treatment. In this most recent study, the researchers tested if human EPCs would provide better BSCB restoration, which it did.
The authors of the paper note, “Neuroinflammation has been implicated in motor neuron degeneration and is considered a significant component in ALS pathogenesis. It has been shown that numerous peripheral factors, including immune/inflammatory cells, readily enter the CNS parenchyma and may exacerbate motor neuron dysfunction. Repair of the BBB/BSCB could block infiltration of detrimental peripheral effectors preventing motor neuron damage and serve as one mechanism for neuroprotection in ALS.”
Fat Hormone Makes Women Less Likely to Develop Liver Cancer
A hormone secreted by fat cells that women have more than men appears to prevent liver cells from becoming cancerous. This explains why hepatocellular carcinoma (HCC) is more common in men. Researchers at the Spanish National Center for Cardiovascular Research (CNIC) in Madrid published their research in the Journal of Experimental Medicine.
“Circulating adiponectin levels have been reported to be higher in women than in men,” stated Guadalupe Sabio, senior author of the study. “However, adiponectin’s role in HCC is controversial and needed further investigation.”
Sabio and colleagues identified increased levels of adiponectin in female mice that seemed to protect them from HCC. They then found that the hormone activates two liver cell proteins, p38alpha and AMPK, which block cell proliferation and impair tumor growth. They also found that testosterone activates a protein in fat cells called JNK1 that inhibits adiponectin production.
Sabio stated, “Our results unravel a clear crosstalk between sex hormones, adipose tissue, and the liver, clarifying the mechanisms underlying gender disparity in liver cancer development.”