Citations

Abstract Aims Chronic kidney disease (CKD) is prevalent and is associated with increased cardiovascular morbidity and mortality. The interaction between diastolic dysfunction (DD) and CKD in subjects with preserved systolic function is not well defined. This study sought to determine the association between renal function and DD in subjects with preserved ejection fraction. Methods and results Through the Rochester Epidemiology Project, subjects who underwent echocardiography over 2 years with EF ≥50% were identified and the clinical data were obtained. Glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease equation. Linear regression was used to test for association of GFR and DD. DD was defined as follows: Grade 2 or pseudonormal pattern (0.75 < E/A ≤ 1.5, E/e′ ≥ 10, DT > 140 ms, ΔE/A ≥ 0.5, and PV S < D) or Grade 3+ or restrictive pattern (E/A > 1.5, E/e′ ≥ 10, DT < 140 ms, and PV S < D). Cox regression was used to assess correlation of GFR and DD with time-to-event outcomes. A total of 2056 patients were identified. There was significant correlation between worsening GFR and degree of DD assessed by echo Doppler E/e′ ratio (P = 0.005), left ventricular mass index (P = 0.004), and right ventricular systolic pressure (P = 0.01). Worsening GFR was associated with increased mortality, development of heart failure, and hospitalization (P < 0.001). Within each GFR group, abnormal DD was associated with a higher risk of the clinical outcomes. No interaction between GFR and DD was noted, suggesting an increased risk of events associated with abnormal DD across ranges of GFR. Conclusions Worsening GFR was associated with a greater degree of diastolic dysfunction and adverse clinical outcomes. Within each GFR group, the presence of DD was associated with increased morbidity and mortality. Further studies are warranted to determine if improving DD in patients with CKD will benefit clinical outcomes.

AbstractMotivationNext generation sequencing technologies have enabled the study of the human microbiome through direct sequencing of microbial DNA, resulting in an enormous amount of microbiome sequencing data. One unique characteristic of microbiome data is the phylogenetic tree that relates all the bacterial species. Closely related bacterial species have a tendency to exhibit a similar relationship with the environment or disease. Thus, incorporating the phylogenetic tree information can potentially improve the detection power for microbiome-wide association studies, where hundreds or thousands of tests are conducted simultaneously to identify bacterial species associated with a phenotype of interest. Despite much progress in multiple testing procedures such as false discovery rate (FDR) control, methods that take into account the phylogenetic tree are largely limited.ResultsWe propose a new FDR control procedure that incorporates the prior structure information and apply it to microbiome data. The proposed procedure is based on a hierarchical model, where a structure-based prior distribution is designed to utilize the phylogenetic tree. By borrowing information from neighboring bacterial species, we are able to improve the statistical power of detecting associated bacterial species while controlling the FDR at desired levels. When the phylogenetic tree is mis-specified or non-informative, our procedure achieves a similar power as traditional procedures that do not take into account the tree structure. We demonstrate the performance of our method through extensive simulations and real microbiome datasets. We identified far more alcohol-drinking associated bacterial species than traditional methods.Availability and implementationR package StructFDR is available from CRAN.Supplementary informationSupplementary data are available at Bioinformatics online.

Abstract A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR–DOCK180–RAC1–MLK3–JNK signaling axis that drives glioblastoma cell migration and dissemination. Implications: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. Mol Cancer Res; 15(8); 1085–95. ©2017 AACR.

Abstract Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. Because of the inflammatory display in endometrial cancer, we set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. We undertook a pilot study of the microbiome in 238 samples taken from different locations along the entire female reproductive tract in hysterectomy patients with endometrial cancer (n=17), patients with endometrial hyperplasia (n=4) and patients afflicted with a benign uterine condition (n=10). Samples were collected aseptically both in the operating room and the pathology laboratory. Following DNA extraction, the 16S rDNA (V3-V5 region) microbial gene was amplified and sequenced to identify the microbiota present. The microbiome sequencing revealed a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p=0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1-68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99% match to P.somerae) were found to be predictive of the disease status (sensitivity 73-93%; specificity 67-90%, AUC 0.918). Sensitivity is increased to 100% if combined with a high vaginal pH (>4.5), although specificity is decreased to 60%. Although our numbers are low, the microbiome signature of hyperplasia was even more distinct from benign disease than endometrial cancer itself. This is suggestive of an early microbiome role in the disease. Given the pathogenic profile of the identified microorganisms these findings raise the possibility of a microbiome role in the etiology or progression of endometrial cancer that should be further investigated. Citation Format: Marina Walther-Antonio, Jun Chen, Francesco Multinu, Alexis Hokenstad, Tammy Distad, Heidi Cheek, Gary Keeney, Douglas Creedon, Heidi Nelson, Andrea Mariani, Nicholas Chia. Endometrial cancer microbiome signature and its implications for carcinogenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B45.

Introduction A retrospective chart review was conducted of visual analog scale (VAS) scores completed before and after trigger point injections (TPIs) for pelvic floor myofascial spasm to evaluate response. Methods Sixty-eight female patients who underwent TPIs from October 9, 2007 to March 12, 2015 were included. The primary end point was the difference between scores. Secondary analyses were conducted for patients who needed repeat TPIs. Descriptive and paired t test analyses were used. Results The key result was an improvement in VAS scores for 65% (44/68) of patients (p<0.0001). The median pre-injection VAS score was 7 (1 to 10), (mean 6.3). The median post-injection VAS score was 4 (0 to 9), (mean 4.3). The median difference between scores in patients who improved was 3 (1 to 8), (mean 3.6). Seventeen of 68 (25%) patients needed repeat TPI, and the median time between injections was 1.5 months (1 to 7 months), (mean 2.2 months). When analyzing pre-injection VAS scores in patients who underwent subsequent repeat injection when compared to patients who did not require repeat injection, there was no difference (p = 0.32). In addition, the differences between pre- and post-injection VAS scores in the patients who underwent repeat injection and those who did not was not significant (p = 0.26). Conclusions We report on 68 women who underwent TPIs, with an improvement in VAS pain scores in 65%. It appears that TPIs for pelvic floor myofascial spasm are successful in reducing pain scores for patients who are refractory to primary therapy.

Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our previous article reported that small molecule YM155 induced apoptosis in pancreatic cancer cells via activation of death receptor 5. In this study, we aim to continuously address death receptor 5–mediated apoptosis in chemo-resistant pancreatic carcinoma. We found that in comparison to paired pancreatic cancer tissues and adjacent normal tissues, five of the six cancer tissues had downregulated death receptor 5 and upregulated Bcl-xL. Mono treatment with lexatumumab was not sufficient to induce apoptosis in pancreatic cancer cells, whereas focal adhesion kinase inhibitor PF573228 significantly sensitized lexatumumab-induced apoptosis. Western blotting analysis revealed that lexatumumab and PF573228 combination treatment increased death receptor 5 but decreased Bcl-xL expression. Interestingly, pre-treatment with Bcl-xL inhibitor ABT263 reversed the insensitivity of panc-1 cells to lexatumumab or PF573228-induced apoptosis. Specific small interfering RNA-mediated gene silencing of Bcl-xL effectively sensitized pancreatic cancer cells to lexatumumab or PF573228-induced apoptosis. Furthermore, lexatumumab and PF573228 combination was shown to exhibit significant xenograft pancreatic tumor growth inhibition in SCID mice. Our data provide fundamental evidence to support the notion that lexatumumab and PF573228 co-treatment could be a potentially effective regime for patients with pancreatic cancer.

Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (Cmax) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavgof tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38Cmaxand diarrhea with tIRICmax. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2(free‐base; equivalent to 80 mg/m2salt base) Q2W over 100 mg/m2Q3W.

Serum response factor (SRF) was found to be involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD), but the exact mechanism remains unclear. SRF regulates microRNAs (miRNAs) that contain the SRF-binding consensus (CArG) element in the promoter region. Therefore, we investigated whether the miR-199a/214 gene cluster, which contains a CArG element in its promoter, is directly regulated by SRF. High-glucose (HG) treatment significantly unregulated the expression of the miR-199a-5p/214–3p gene cluster in human peritoneal mesothelial cells (HPMCs). By chromatin immunoprecipitation and reporter assays, we found that SRF binds to the miR-199a-5p/214–3p gene cluster promoter after HG stimulation. In vitro , in HPMCs, silencing of miR-199a-5p or miR-214–3p inhibited the HG-induced phenotypic transition and cell migration but enhanced cell adhesion, whereas ectopic expression of mimic oligonucleotides had the opposite effects. Both miR-199a-5p and miR-214–3p targeted claudin-2 and E-cadherin mRNAs. In a PD rat model, treatment with an SRF inhibitor silenced miR-199a-5p and miR-214–3p and alleviated HG-PD fluid–induced damage and fibrosis. Overall, this study reveals a novel SRF–miR-199a/miR-214–E-cadherin/claudin-2 axis that mediates damage and fibrosis in PD.