Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

Cardiac Magnetic Resonance Imaging for the Investigation of Cardiovascular Disorders. Part 1: Current Applications

Cardiac magnetic resonance imaging is a robust noninvasive technique for investigating cardiovascular disorders. The evolution of cardiac magnetic resonance and its widening span of diagnostic and prognostic applications have generated excitement as well as uncertainty regarding its potential clinical use and its role vis-à-vis conventional imaging techniques. The purpose of this evidence-based review is to discuss some of these issues by highlighting the current (Part 1) and emerging (Part 2) applications of cardiac magnetic resonance. Familiarity with the versatility and usefulness of cardiac magnetic resonance will facilitate its wider clinical acceptance for improving the management of cardiovascular disorders

Endoscopic Nasobiliary Drainage in the Management of Acute Cholangitis: An Experience in 143 Patients

Acute cholangitis is associated with a high mortality and morbidity and often requires drainage of the obstructed biliary system. The purpose of this study was to evaluate the usefulness and safety of endoscopic nasobiliary drainage in the treatment and prevention of acute cholangitis due to diverse etiology. During a 32-month period, 143 patients (67 males, 76 females) with age range of 15 to 84 years underwent urgent fluoroscopy guided endoscopic nasobiliary drainage using a 7 Fr catheter either to treat acute cholangitis not responding to antibiotics (group A, n = 116) or to prevent its development following endoscopic retrograde cholangiography performed in an obstructed biliary system (group B, n = 27). Underlying etiology included bile duct stones (92), malignant biliary obstruction (34), choledochal cyst (4), chronic pancreatitis (4), ruptured hydatid cyst (3), portal hypertensive cholangiopathy (3) and liver abscess (3). Endoscopic nasobiliary drainage was performed successfully in 129 patients (90.2%). Cholangitis improved within 1 to 3 days (in group A) or did not develop (in Group B) in 125 patients (96.7%) with successful endoscopic nasobiliary drainage. Two patients however required additional drainage by percutaneous transhepatic route, while two died inspite of effective endoscopic drainage. Of the 14 patients (9.8%) with failed endoscopic drainage, 9 were managed by surgical decompression or percutaneous transhepatic drainage, 3 died of septicemia. Endoscopic nasobiliary drainage is a safe and effective method to treat patients with acute cholangitis as well as to prevent its development following cholangiography performed in an obstructed biliary system

Role of Endoscopic Retrograde Cholangiography and Nasobiliary Drainage in the Management of Postoperative Biliary Leak

In order to assess the role of endoscopic retrograde cholangiography in evaluating the patients with post-operative biliary leak and of endoscopic nasobiliary drainage in its management, 36 patients with biliary leak seen over a period of 9 years were studied. Thirty-two had biliary leak following cholecystectomy, 3 following repair of liver trauma and 1 following choledochoduodenostomy. Patients presented at an interval of 4 days to 210 days (mean ± SEM, 32.4 ± 6.7 days) following laparotomy. Hyperbilirubinemia was noticed in only 13 patients (36.1%), while abdominal ultrasonogram showed ascites or biloma in 24 (66.7%). Endoscopic retrograde cholangiography showed the leak to involve the common bile duct in 55.6%, cystic duct in 33.3% and intrahepatic biliary radicles in 8.3%. Associated lesions included bile duct obstruction due to stricture or accidental ligature in 20%, bile duct stone in 20% and liver abscess in 2.8%

Cardiac Magnetic Resonance Imaging for the Investigation of Cardiovascular Disorders. Part 2: Emerging Applications

Cardiac magnetic resonance imaging has emerged as a robust noninvasive technique for the investigation of cardiovascular disorders. The coming-of-age of cardiac magnetic resonance—and especially its widening span of applications—has generated both excitement and uncertainty in regard to its potential clinical use and its role vis-à-vis conventional imaging techniques. The purpose of this evidence-based review is to discuss some of these issues by highlighting the current (Part 1, previously published) and emerging (Part 2) applications of cardiac magnetic resonance. Familiarity with the versatile uses of cardiac magnetic resonance will facilitate its wider clinical acceptance for improving the management of patients with cardiovascular disorders

Graphene Oxide-Gallic Acid Nanodelivery System for Cancer Therapy

Despite the technological advancement in the biomedical science, cancer remains a life-threatening disease. In this study, we designed an anticancer nanodelivery system using graphene oxide (GO) as nanocarrier for an active anticancer agent gallic acid (GA). The successful formation nanocomposite (GOGA) was characterized using XRD, FTIR, HRTEM, Raman, and UV/Vis spectroscopy. The release study shows that the release of GA from the designed anticancer nanocomposite (GOGA) occurs in a sustained manner in phosphate-buffered saline (PBS) solution at pH 7.4. In in vitro biological studies, normal fibroblast (3T3) and liver cancer cells (HepG2) were treated with different concentrations of GO, GOGA, and GA for 72 h. The GOGA nanocomposite showed the inhibitory effect to cancer cell growth without affecting normal cell growth. The results of this research are highly encouraging to go further for in vivo studies

Spatial rigid-multi-body systems with lubricated spherical clearance joints : modeling and simulation

The dynamic modeling and simulation of spatial rigid-multi-body systems with lubricated spherical joints is the main purpose of the present work. This issue is of paramount importance in the analysis and design of realistic multibody mechanical systems undergoing spatial motion. When the spherical clearance joint is modeled as dry contact; i.e., when there is no lubricant between the mechanical elements which constitute the joint, a body-to-body (typically metal-to-metal) contact takes place. The joint reaction forces in this case are evaluated through a Hertzian-based contact law. A hysteretic damping factor is included in the dry contact force model to account for the energy dissipation during the contact process. The presence of a fluid lubricant avoids the direct metal-to-metal contact. In this situation, the squeeze film action, due to the relative approaching motion between the mechanical joint elements, is considered utilizing the lubrication theory associated with the spherical bearings. In both cases, the intra-joint reaction forces are evaluated as functions of the geometrical, kinematical and physical characteristics of the spherical joint. These forces are then incorporated into a standard formulation of the system’s governing equations of motion as generalized external forces. A spatial four bar mechanism that includes a spherical clearance joint is considered here as example. The computational simulations are carried out with and without the fluid lubricant, and the results are compared with those obtained when the system is modeled with perfect joints only. From the general results it is observed that the system’s performance with lubricant effect presents fewer peaks in the kinematic and dynamic outputs, when compared with those from the dry contact joint model.Fundação para a Ciência e a Tecnologia (FCT

Bacillus Calmette–Guérin-Induced Human Mast Cell Activation Relies on IL-33 Priming

Bacillus Calmette–Guérin (BCG) vaccine is an attenuated strain of Mycobacterium bovis that provides weak protection against tuberculosis (TB). Mast cells (MCs) are tissue-resident immune cells strategically that serve as the first line of defence against pathogenic threats. In this study, we investigated the response of human MCs (hMCs) to BCG. We found that naïve hMCs exposed to BCG did not secrete cytokines, degranulate, or support the uptake and intracellular growth of bacteria. Since we could show that in hMCs IL-33 promotes the transcription of host-pathogen interaction, cell adhesion and activation genes, we used IL-33 for cell priming. The treatment of hMCs with IL-33, but not IFN-γ, before BCG stimulation increased IL-8, MCP-1 and IL-13 secretion, and induced an enhanced expression of the mycobacteria-binding receptor CD48. These effects were comparable to those caused by the recombinant Mycobacterium tuberculosis (Mtb) 19-KDa lipoprotein. Finally, stimulation of hMCs with IL-33 incremented MC-BCG interactions. Thus, we propose that IL-33 may improve the immunogenicity of BCG vaccine by sensitising hMCs

Facilitators and barriers of heart failure care in Kerala, India: A qualitative analysis of health-care providers and administrators.

OBJECTIVE: Heart failure is a leading cause of death worldwide and in India, yet the qualitative data regarding heart failure care are limited. To fill this gap, we studied the facilitators and barriers of heart failure care in Kerala, India. METHODS AND RESULTS: During January 2018, we conducted a qualitative study using in-depth, semi-structured interviews with 21 health-care providers and quality administrators from 8 hospitals in Kerala to understand the context, facilitators, and barriers of heart failure care. We developed a theoretical framework using iteratively developed codes from these data to identify 6 key themes of heart failure care in Kerala: (1) need for comprehensive patient and family education on heart failure; (2) gaps between guideline-directed clinical care for heart failure and clinical practice; (3) national hospital accreditation contributing to a culture of systematically improving quality and safety of in-hospital care; (4) limited system-level attention toward improving heart failure care compared with other cardiovascular conditions; (5) application of existing personnel and technology to improve heart failure care; and (6) longitudinal and recurrent costs as barriers for optimal heart failure care. CONCLUSIONS: Key themes emerged regarding heart failure care in Kerala in the context of a health system that is increasingly emphasizing health-care quality and safety. Targeted in-hospital quality improvement interventions for heart failure should account for these themes to improve cardiovascular outcomes in the region