Asif Talukder

JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer

ABSTRACT Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration. JAK-STAT inhibitor Ruxolitinib selectively inhibits STAT1 and STAT3 activation and increases CTL infiltration to induce a Tc1/Th1 immune response in the tumor microenvironment in an orthotopic pancreatic cancer mouse model. Ruxilitinib-mediated tumor suppressive efficacy diminishes in T-cell-deficient mice. Pancreatic tumor grows significantly faster in IFNγ-deficient mice. However, neutralizing IFNγ does not alter tumor growth but diminishes Ruxolitinib-induced tumor suppression in vivo, indicating that lymphocytes and IFNγ are essential for Ruxolitinib-induced host antitumor immune response. Both type I and type II interferons upregulate PD-L1 expression through the JAK-STAT signaling pathway in mouse pancreatic tumor cells. Tumor cells respond to activated T cells by activating STAT3. The inhibition of STAT3 downregulates immune suppressive cytokines production by tumor cells, resulting in increased T cell activation and effector function. Consequently, Ruxolitinib significantly improves the efficacy of anti-PD-1 immunotherapy. Our data demonstrate that Ruxolitinib is effective in the inhibition of systemic inflammation in the tumor microenvironment and therefore upregulates CTL infiltration and activation to overcome pancreatic cancer resistance to anti-PD-1 immunotherapy.

Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets

Background:Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets.Methods:Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules – HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models.Results:In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial–mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression.Conclusions:This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.

Demographic and clinical factors associated with suicide in gastric cancer in the United States

While increased suicidal tendencies among cancer patients have been well documented, there has been no specific examination of suicide and gastric cancer. The purpose of this study is to characterize suicide incidence among patients diagnosed with gastric cancer from 1973 to 2013 and identify variables associated with higher suicide rates. Patients with gastric cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The study included clinical and demographic data from 1973 to 2013. Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated. Comparisons with the general US population were based on mortality data collected by the Centers for Disease Control and Preventions National Center for Injury Prevention and Control using the Web-based Injury Statistics Query and Reporting System. Multivariable logistic regression models generated odds ratios (ORs) to assess factors associated with increased suicide in gastric malignancy. There were 210 suicides for patients with gastric cancer (SMR, 3.21; 95% CI: 2.80-3.67). Female gender (SMR 8.54), White race (SMR 4.08), age ≤39 years (SMR 3.06), and age 70-79 years (SMR 2.90), were found to be significant for an increased incidence of suicide compared with the general population. There was not a statistically significant relationship between suicide and marital status, income, mode of radiation therapy, and the role of surgical intervention. Approximately 77% of deaths by suicide occurred within the first year following diagnosis. Female gender, White race, age ≤39 years, and age 70-79 years are factors associated with increased risk of suicide in patients with gastric cancer. These results, coupled with further studies and analyses, will be used to formulate a comprehensive suicide risk factor scoring system for screening all cancer patients.

A case report of a patient with gallbladder agenesis resulting in a common bile duct injury

Highlights • Gallbladder agenesis can present with symptoms of biliary colic or cholecystitis.• Imaging studies of a patient with gallbladder agenesis can be inconclusive.• If operated on, the surgeon will be unable to visualize the gallbladder.• In such cases, the procedure should be aborted, and further diagnostic testing should be done.

Molecular Characterization of Renal Cell Carcinoma: A Potential three microRNA Prognostic Signature

Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach. Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (n = 241). Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2–4-fold) and miR-192 and miR-194 as downregulated (3–60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75–0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58–0.23). Conclusions: The interconnected discovery–validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients. Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464–72. ©2018 AACR.

Gallbladder Dysfunction: Cholecystitis, Choledocholithiasis, Cholangitis, and Biliary Dyskinesia

The prevalence of gallstones is 10% to 15% in adults. Individuals with acute cholecystitis present with right upper quadrant pain, fever, and leukocytosis. Management includes supportive care and cholecystectomy. The prevalence of choledocholithiasis is 10% to 20%, and serious complications include cholangitis and gallstone pancreatitis. The goal of management in individuals with choledocholithiasis consists of clearing common bile duct stones. Acute ascending cholangitis is a life-threatening condition involving acute inflammation and infection of the common bile duct. Treatment includes intravenous fluids, analgesia, intravenous antibiotics, and biliary drainage and decompression. Biliary dyskinesia includes motility disorders resulting in biliary colic in the absence of gallstones.