A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction.

Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-ß/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.

Vaccination Rates Among Patients Age 65 Years and Older Who Require Interpreter Services in the State of Minnesota.

In the United States, the growing population of older adults with limited English language proficiency (LEP) faces profound health care disparities. Previous research on vaccination of older adults has been based on self-reported data, without clinical verification. We compared pneumococcal vaccination rates between a patient group with LEP and a group of English speakers in an older community-dwelling population. A population-nested matched cohort of participants age 65 years and older was identified in Minnesota. Patients with LEP were identified through an electronic alert within the electronic health record, designed to determine the need for an interpreter. Patients were matched 1 to 1 for age, sex, and Charlson comorbidity index. We used conditional logistic regression for the final analysis. In total, 24,052 patients were identified as older patients (mean [SD] age, 74 [7] years). Of them, 617 patients (2.6%) had LEP. The most common primary languages were Somali (24%), Vietnamese (15%), and Spanish (13%). We found lower rates of vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) in the LEP group compared with English speakers [62% vs 77%; odds ratio (OR) (95% CI) 2.07 (1.61-2.66); P < 0.001]. Results were similar for 23-valent pneumococcal polysaccharide vaccine (PPSV23) [60% vs 75%; OR (95% CI) 1.97 91.54-2.51); P < 0.001]. These data are suggestive that older adults who required a language interpreter during health care encounters were less likely to be vaccinated with PCV13 and PPSV23 than older adults who did not require an interpreter. Effectiveness studies are needed to determine which interventions can help improve vaccination rates in the LEP population of elderly patients.

Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts.

Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades. In the current review, we briefly summarize these advances, including the generation of high-quality liver extracellular matrix scaffolds, evaluation criteria for quality control, modification of matrix for enhanced properties, and reseeding strategies. These efforts to optimize the methods of decellularization and recellularization lay the groundwork towards generating a transplantable, human-sized liver graft for the treatment of patients with severe liver disease.

Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts.

Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades. In the current review, we briefly summarize these advances, including the generation of high-quality liver extracellular matrix scaffolds, evaluation criteria for quality control, modification of matrix for enhanced properties, and reseeding strategies. These efforts to optimize the methods of decellularization and recellularization lay the groundwork towards generating a transplantable, human-sized liver graft for the treatment of patients with severe liver disease.

The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells.

Poly(ADP-ribose) polymerase 1 (PARP1) is an important component of the base excision repair (BER) pathway as well as a regulator of homologous recombination (HR) and non-homologous end-joining (NHEJ). Previous studies have demonstrated that treatment of HR-deficient cells with PARP inhibitors results in stalled and collapsed replication forks. Consequently, HR-deficient cells are extremely sensitive to PARP inhibitors. Several explanations have been advanced to explain this so-called synthetic lethality between HR deficiency and PARP inhibition: (i) reduction of BER activity leading to enhanced DNA double-strand breaks, which accumulate in the absence of HR; (ii) trapping of inhibited PARP1 at sites of DNA damage, which prevents access of other repair proteins; (iii) failure to initiate HR by poly(ADP-ribose) polymer-dependent BRCA1 recruitment; and (iv) activation of the NHEJ pathway, which selectively induces error-prone repair in HR-deficient cells. Here we review evidence regarding these various explanations for the ability of PARP inhibitors to selectively kill HR-deficient cancer cells and discuss their potential implications.

Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro.

PURPOSE: Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib. EXPERIMENTAL DESIGN: The abilities of iniparib, olaparib, and veliparib to (i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, (ii) selectively sensitize HR-proficient cells to topoisomerase I poisons, and (iii) inhibit formation of poly(ADP-ribose) polymer (pADPr) in intact cells were compared. RESULTS: Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel. CONCLUSIONS: While iniparib kills normal and neoplastic cells at high (>40 µmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.