Targeting lung cancer in never-smokers
Lung cancer is the leading cause of cancer-related deaths worldwide, and between 10 percent and 15 percent of new cases arise in never-smokers. Never-smokers – as well as individuals of East-Asian ethnicity and those with adenocarcinoma tumors – appear more likely to respond to certain targeted therapies.
William Pao, M.D., Ph.D., and colleagues at Fudan University in Shanghai, China have taken a closer look at the genetic factors that may underlie these responses in lung adenocarcinomas from 52 Chinese patients classified as never-smokers. In these tumors, the investigators analyzed major known “driver mutations” – mutations in genes involved in cell proliferation and survival (e.g., EGFR, HER2, KRAS, BRAF, PI3KCA, and EML4-ALK).
They found that 88 percent of tumors harbored well-known mutations in EGFR, HER2 or ALK – all of which have corresponding targeted therapies now available. The results in the Oct. 20 issue of the Journal of Clinical Oncology indicate that prospective genetic testing in these patients would allow for the selection of an appropriate targeted therapy in the majority of cases.
— Melissa Marino
Seizure-linked receptor gloms together
An inherited genetic mutation that alters part of GABAA receptors – a family of receptors that normally inhibit neuronal activity – can cause a spectrum of epilepsy types, from relatively mild fever-induced seizures to more severe seizures and cognitive impairment.
Jing-Qiong Kang, M.D., Ph.D., and colleagues had previously demonstrated that this mutation (γ2 Q351X) reduced cell surface levels of functional GABAA receptors. Now, in the Oct. 13 Journal of Neuroscience, they show that the γ2 Q351X mutant protein has additional impairments. It is degraded more slowly than wild-type γ2 protein, and it clumps together into aggregates in multiple cell types, including neurons. Protein aggregation is a hallmark of neurodegenerative diseases such as Parkinson’s and Huntington’s disease, and the presence of mutant γ2 aggregates may be toxic to cells over a lifelong disease course.
The findings suggest that a mutation such as γ2 Q351X may not only impair GABA signaling and neuronal inhibition, but may also have pathological actions related to protein aggregation.
— Leigh MacMillan
Stomach bug’s cancer-causing ways
Helicobacter pylori – a bacterial species found in the stomachs of more than half of all humans – is the strongest known risk factor for gastric adenocarcinoma, but only a fraction of infected persons will develop cancer.
Alexander Zaika, Ph.D., and colleagues investigated the regulation of p53, a tumor suppressor that might counteract oncogenic signaling pathways, in H. pylori-infected Mongolian gerbils and gastric epithelial cells co-cultured with the bacterium. They found that H. pylori decreases p53 levels by increasing ubiquitination (a modification that targets p53 for destruction) and proteasomal degradation in a pathway involving the proteins AKT1 and HDM2. The H. pylori virulence factor CagA mediated these effects, and the reduced levels of p53 increased the survival of cells with DNA damage.
The findings, reported in the October issue of Gastroenterology, suggest that H. pylori-induced dysregulation of p53 may be a mechanism by which the bug increases the risk of gastric cancer in infected individuals.
— Leigh MacMillan
Therapy extinguishes fires of diabetes
A novel anti-inflammatory therapy halted the destruction of insulin-producing beta cells in a mouse model of type 1 (“juvenile”) diabetes, a team of investigators led by Jacek Hawiger, M.D., Ph.D., reports in the October issue of PLoS ONE.
Type 1 diabetes results from the autoimmune destruction of beta cells in pancreatic islets. The researchers tested a first-of-its-kind therapeutic: a protein fragment (peptide) that works by blocking the nuclear import of proteins that control inflammatory gene expression. They found that a 2-day course of treatment with the “nuclear import inhibitor” protected islets and rendered the mice diabetes-free for one year, without apparent toxicity. The inhibitor reduced accumulation of islet-destructive autoimmune cells and enhanced their death. It also reduced production of pro-inflammatory molecules in immune cells.
The findings support further study of this novel anti-inflammatory therapy in type 1 diabetes. The research team included Daniel Moore, Jozef Zienkiewicz, Peggy Kendall, Danya Liu, Xueyan Liu, Ruth Ann Veach, and Robert Collins.
— Leigh MacMillan
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