Mechanisms that regulate localization of a DNA double-strand break to the nuclear periphery

DNA double-strand breaks (DSBs) are among the most deleterious forms of DNA lesions in cells. Here we induced site-specific DSBs in yeast cells and monitored chromatin dynamics surrounding the DSB using Chromosome Conformation Capture (3C). We find that formation of a DSB within G1 cells is not sufficient to alter chromosome dynamics. However, DSBs formed within an asynchronous cell population result in large decreases in both intra- and interchromosomal interactions. Using live cell microscopy, we find that changes in chromosome dynamics correlate with relocalization of the DSB to the nuclear periphery. Sequestration to the periphery requires the nuclear envelope protein, Mps3p, and Mps3p-dependent tethering delays recombinational repair of a DSB and enhances gross chromosomal rearrangements. Furthermore, we show that components of the telomerase machinery are recruited to a DSB and that telomerase recruitment is required for its peripheral localization. Based on these findings, we propose that sequestration of unrepaired or slowly repaired DSBs to the nuclear periphery reflects a competition between alternative repair pathways.     

Adenosine triphosphate depletion by cyanide results in a Na-dependent Mg extrusion from liver cells

Addition of NaCN to isolated hepatocytes results in a marked and rapid decrease in cellular adenosine triphosphate (ATP) content, and in the extrusion of a sizable amount of cellular Mg²⁺. This extrusion starts after a 10-minute lag phase and reaches a maximum of 35 to 40 nmol Mg²⁺ per milligram protein within 60 minutes from the addition of CN⁻. A quantitatively similar Mg²⁺ extrusion is also observed after the addition of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone but not that of the glycolysis inhibitor iodoacetate. The Mg²⁺ extrusion is completely inhibited by the removal of extracellular Na⁺ or the addition of imipramine, quinidine, or glibenclamide, whereas it persists after the removal of extracellular Ca²⁺ or K⁺, or the addition of amiloride. An acidic extracellular pH or the removal of extracellular HCO₃⁻ inhibits the cyanide-induced Mg²⁺ extrusion by at least 80%. Taken together, these data suggest that the decrease in cellular adenosine triphosphate content removes a major Mg²⁺ complexing agent from the hepatocyte and results in an extrusion of hepatic Mg²⁺ exclusively through a Na⁺-dependent exchange mechanism modulated by acidic changes in extracellular pH.     

Dialysis disequilibrium syndrome: a narrative review

Dialysis Disequilibrium Syndrome (DDS) is characterized by neurological symptoms caused by rapid removal of urea during hemodialysis. It develops primarily from an osmotic gradient that develops between the brain and the plasma as a result of rapid hemodialysis. This results in brain edema that manifests as neurological symptoms such as headache, nausea, vomiting, muscle cramps, tremors, disturbed consciousness, and convulsions. In severe cases, patients can die from advanced cerebral edema. Recent advancements in cell biology implicate the role of urea disequilibrium (with a smaller contribution from organic osmolytes) as the pathophysiological mechanism responsible for this syndrome. In this review, we discuss the pathogenesis, clinical features and prevention of DDS.     

Clinical role of additional adjuvant chemotherapy in patients with locally advanced urothelial carcinoma following neoadjuvant chemotherapy and cystectomy

Purpose

Neoadjuvant chemotherapy (NAC) can downstage invasive bladder cancers prior to radical cystectomy (RC) and improve overall survival. However, the optimal management in patients with persistent non-organ confined disease (pT3–T4 and/or pN+) following RC has not been completely defined. The aim of this study was to describe outcomes associated with the use of adjuvant chemotherapy (AC) in patients with residual non-organ confined cancer at RC following NAC.

Materials and methods

Using data from a high-volume referral institution, pT3–T4 and/or pN+ patients who received NAC and then also RC were identified. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with Kaplan–Meier analysis.

Results

From 2001 to 2013, 161 patients received NAC and then RC. Eighty-eight pT3–T4 and/or pN+ patients were identified. Twenty-nine (33 %) received AC. Adjuvant chemotherapy in the majority of patients was carboplatin-based (16), followed by cisplatin (8) and other, mainly taxane-containing regimens (5). The median RFS was 17.5 months in the AC and 13.7 months in the non-AC group (p = 0.78). AC remained an insignificant predictor for RFS after adjusting for pT, pN and margin status (HR 0.89, 95 % CI 0.48–1.68]). CSS was 23 and 22 months (p = 0.65) and remained insignificant after adjusting for pathologic confounders.

Conclusions

In our current study population, adjuvant conventional cytotoxic chemotherapy was not associated with significant improvements in RFS or CSS. The choice of AC regimens, and incorporation of newer treatments, may be the key for improving outcomes in this high-risk patient group.

     

Devices for heart failure: the future is now

Despite impressive strides in pharmacologic therapy for heart failure (HF), cumulative evidence from epidemiologic studies suggests that there has been no improvement in the prognosis for this condition over the past 40 years. Several aspects of the pathophysiology of HF are not influenced by drug therapy. Hospitalizations for acute decompensated HF have continued to increase in recent years despite the use of complex and costly drug regimens. Cardiac assist devices offer a promising approach to the management of this challenging problem. The authors review the ways in which these devices are being used to manage HF in different settings and highlight the latest advances in this rapidly evolving field.     

Comparative Evaluation of Stress Distribution in Experimentally Designed Nickel-titanium Rotary Files with Varying Cross Sections: A Finite Element Analysis

Introduction

Single cross-sectional nickel-titanium (NiTi) rotary instruments during continuous rotations are subjected to constant and variable stresses depending on the canal anatomy. This study was intended to create 2 new experimental, theoretic single-file designs with combinations of triple U (TU), triangle (TR), and convex triangle (CT) cross sections and to compare their bending stresses in simulated root canals with a single cross-sectional instrument using finite element analysis.