Vrishketan Sethi

“Heat shock protein 70 in pancreatic diseases: Friend or foe”

The heat shock response in pancreatitis that is activated via HSP70 protects acinar cells through multiple simultaneous mechanisms. It inhibits trypsinogen activation and modulates NF‐κB signaling to limit acinar cell injury. On the other hand, HSP70 is overexpressed in pancreatic cancer and is hijacked by the cellular machinery to inhibit apoptosis. Inhibition of HSP70 in pancreatic cancer by a novel compound, Minnelide, has shown considerable clinical promise.

Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response

We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.

Insights into the Pathogenesis of Pancreatic Cystic Neoplasms

With the current epidemic of diagnosed pancreatic cystic neoplasms on the rise, a substantial amount of work has been done to unravel their biology, thus leading to implications on clinical decision making. Recent genetic profiling of resected human specimens has identified alterations in signaling pathways involving KRAS and GNAS signaling as early events in the pathogenesis of intraductal pancreatic mucinous neoplasms. Progressively, mutations in genes such as TP53, SMAD4, RNF43, and others are thought to characterize invasive and advanced lesions. The role of inflammation in fueling the growth and transformation of these cysts has also begun to be studied with greater interest. A number of promising clinical studies have attempted to integrate these genetic insights into classifying these cysts and treating patients. We have reviewed existing literature on similar lines besides commenting on some useful animal models that recapitulate molecular and phenotypic progression of these cysts.

Genetics of pancreatic cyst-cancer progression: Standing on the shoulders of giants

Purpose of review Pancreatic cancer, despite years of study and some progress, presents with a grim prognosis in almost all cases. In the current review, we have discussed recent studies that have attempted to decipher the genetic makeup of pancreatic ductal adenocarcinoma and preneoplastic pancreatic cystic neoplasms. Recent findings With the advent of high throughput sequencing, the genetic code of pancreatic cancer is beginning to unravel and this new-found information heralds an era of precision cancer care where treatment will be guided by the genetic code of the neoplasm. Results from these studies have pointed towards the complexity and heterogeneity of the pancreatic cancer genome, provided avenues to “tailor therapy” based as well as shed light on progression of preneoplastic pancreatic neoplasms into full blown invasive pancreatic ductal adenocarcinoma. Summary While this progress has made us closer to the model of precision medicine, significant obstacles need to be overcome to use this new-found information to change the way we manage patients with pancreatic cancer.