Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade.

While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

Differential expression of metallothionein-1 and cytochrome p450-2a5 (cyp2a5) in mice in response to lead acetate exposure and industrial effluents in Ibadan, Nigeria.

Metallothionein-1 ( MT-1), cytochrome P450-2A ( CYP2a) and other genes are involved in the detoxification of xenobiotics such as heavy metals and toxins. Changes in their expression precede overt toxic effects and can serve as a marker for exposure to pollutants. We used a mouse experimental system and quantitative reverse transcription polymerase chain reaction to determine changes in gene expression and the direction of change, in response to exposure to lead acetate (LA) and waste water (WW) from an industrial area in Ibadan. MT-1 and CYP2a5 genes were quickly and highly induced at different exposure periods and concentrations. MT-1 was mostly downregulated by the LA exposure, but upregulated by several folds on exposure to WW. CYP2a5 expression was mostly downregulated with LA exposure. The optimum expression of MT-1 and CYP2a5 genes induced by both LA and WW was at 48 h. We conclude that rapid assays to determine the direction of change in the expression of MT-1 and CYP2a5 could be a fast and reliable method in developing countries for screening humans exposed to pollutants from industrial waste.

Kidney injury, fluid, electrolyte and acid-base abnormalities in alcoholics.

In the 21(st) century, alcoholism and the consequences of ethyl alcohol abuse are major public health concerns in the United States, affecting approximately 14 million people. Pertinent to the global impact of alcoholism is the World Health Organisation estimate that 140 million people worldwide suffer from alcohol dependence. Alcoholism and alcohol abuse are the third leading causes of preventable death in the United States. Alcohol dependence and alcohol abuse cost the United State an estimated US$220 billion in 2005, eclipsing the expense associated with cancer (US$196 billion) or obesity (US$133 billion). Orally ingested ethyl alcohol is absorbed rapidly without chemical change from the stomach and intestine, reaching maximum blood concentration in about an hour. Alcohol crosses capillary membranes by simple diffusion, affecting almost every organ system in the body by impacting a wide range of cellular functions. Alcohol causes metabolic derangements either directly, via its chemical by-product or secondarily through alcohol-induced disorders. Many of these alcohol-related metabolic disturbances are increased in severity by the malnutrition that is common in those with chronic alcoholism. This review focuses on the acute and chronic injurious consequences of alcohol ingestion on the kidney, as well as the fluid, electrolyte and acid-base abnormalities associated with acute and chronic ingestion of alcohol.