Citations

AbstractThe Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFRβ and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co‐activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX). PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line. siRNA silencing of PDGFR‐β similarly downregulated YAP target genes. YAP activation (nuclear localization and target gene expression) was regulated by Src family kinases (SFKs) downstream of PDGFR. SFK activity resulted in phosphorylation of YAP on tyrosine357 (YAPY357). The importance of YAPY357 phosphorylation in regulating YAP activation was confirmed utilizing the SB‐1 cell line, a mouse cell line expressing YAP S127A precluding canonical serine phosphorylation. PDGFR inhibition decreased cellular abundance of the survival protein Mcl‐1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo. These preclinical data demonstrate that a PDGFR‐SFK cascade regulates YAP activation via tyrosine phosphorylation in CCA. Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy.

BACKGROUNDPrior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists.METHODSThe authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan‐Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM‐specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses.RESULTSA total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65‐0.99) but not HM‐specific mortality (HR, 0.77 [95% CI, 0.53‐1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70‐1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59‐1.01) and 0.46 (95% CI, 0.24‐0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation.CONCLUSIONSThe current post hoc analysis of data from a large and well‐executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168–4177. © 2017 American Cancer Society.

Summary This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma ( DLBCL ) after failure of front line anthracycline‐based immunochemotherapy ( IC ). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource ( MER ) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B‐cell lymphoma ( PMBL ) patients treated with front‐line anthracycline‐based IC were followed for relapse. Patients with relapse on follow‐up and subsequently retreated were included in this analysis. 1039 patients received anthracycline‐based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years ( OS 4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (auto HCT ) with OS 4 from auto HCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS 4 of 47% but those with a transient or no response to initial therapy had OS 4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo auto HCT . The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL .

Abstract Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits. Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10−6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer. Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors. Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427–35. ©2017 AACR.

Background: Strict glycemic control is known to be a vital key in the management of diabetes mellitus (DM). However, traditional methods face limitations in their efficacy due to the pain and invasiveness of needle pricking which often discourages DM patients from performing the required number of tests per day. Saliva glucose (SG) sensing has long been considered a noninvasive alternative to blood glucose monitoring for diabetes management, however the sample preparation and sensor detection limit have been deemed as challenges to overcome. Herein, we describe a preliminary clinical validation of a disposable SG sensor without any requirement for sample preparation. Methods: The sensor utilizes glucose dehydrogenase flavine-adenine dinucleotide (GDH-FAD) in conjunction with disposable screen printed electrodes to measure glucose levels in saliva collected directly from 9 healthy subjects. Cyclic voltammetry and amperometric-time (Amp-it) assays were used to develop calibration curves and test subjects. Sensor calibration was performed using simulated saliva at 6.5 pH and 37ºC. Results: The lower limit of detection was determined to be 0.11 mg/dL. A lag time of 15 minutes with a positive correlation between SG and BG levels was found, which agrees with literature results. The detected SG ranges from 2.38 to 3.40 mg/dL over a BG range of 90 to 143 mg/dL. Conclusion: This is the first reported use of measuring SG with GDH-FAD without prior sample preparation. Upon optimization, the sensor has the potential to serve as a supplement to blood glucose monitoring.

Objective: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT). Background: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce. Methods: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients. Results: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort. Conclusions: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories.

Abstract Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive. Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders. Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90–0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56–0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94–1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95–1.05). Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer. Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225–32. ©2017 AACR.