Regulation of Tumor Progression by Programmed Necrosis

Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose) deprivation, which occurs because of insufficient blood supply. This results in necrotic cell death in the core region of solid tumors. Necrotic cells release their cellular cytoplasmic contents into the extracellular space, such as high mobility group box 1 (HMGB1), which is a nonhistone nuclear protein, but acts as a proinflammatory and tumor-promoting cytokine when released by necrotic cells. These released molecules recruit immune and inflammatory cells, which exert tumor-promoting activity by inducing angiogenesis, proliferation, and invasion. Development of a necrotic core in cancer patients is also associated with poor prognosis. Conventionally, necrosis has been thought of as an unregulated process, unlike programmed cell death processes like apoptosis and autophagy. Recently, necrosis has been recognized as a programmed cell death, encompassing processes such as oncosis, necroptosis, and others. Metabolic stress-induced necrosis and its regulatory mechanisms have been poorly investigated until recently. Snail and Dlx-2, EMT-inducing transcription factors, are responsible for metabolic stress-induced necrosis in tumors. Snail and Dlx-2 contribute to tumor progression by promoting necrosis and inducing EMT and oncogenic metabolism. Oncogenic metabolism has been shown to play a role(s) in initiating necrosis. Here, we discuss the molecular mechanisms underlying metabolic stress-induced programmed necrosis that promote tumor progression and aggressiveness

Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth

BackgroundMicroenvironmental factors, including microbe-induced inflammation and immune-checkpoint proteins that modulate immune cells have been associated with both cervical insufficiency and preterm delivery. These factors are incompletely understood. This study aimed to explore and compare interactions among microbiome and inflammatory factors, such as cytokines and immune-checkpoint proteins, in patients with cervical insufficiency and preterm birth. In particular, factors related to predicting preterm birth were identified and the performance of the combination of these factors was evaluated.MethodsA total of 220 swab samples from 110 pregnant women, prospectively recruited at the High-Risk Maternal Neonatal Intensive Care Center, were collected between February 2020 and March 2021. This study included 63 patients with cervical insufficiency receiving cerclage and 47 control participants. Endo- and exocervical swabs and fluids were collected simultaneously. Shotgun metagenomic sequencing for the microbiome and the measurement of 34 immune-checkpoint proteins and inflammatory cytokines were performed.ResultsFirst, we demonstrated that immune-checkpoint proteins, the key immune-regulatory molecules, could be measured in endocervical and exocervical samples. Secondly, we identified significantly different microenvironments in cervical insufficiency and preterm birth, with precise cervical locations, to provide information about practically useful cervical locations in clinical settings. Finally, the presence of Moraxella osloensis (odds ratio = 14.785; P = 0.037) and chemokine CC motif ligand 2 levels higher than 73 pg/mL (odds ratio = 40.049; P = 0.005) in endocervical samples were associated with preterm birth. Combining M. osloensis and chemokine CC motif ligand 2 yielded excellent performance for predicting preterm birth (area under the receiver operating characteristic curve = 0.846, 95% confidence interval = 0.733-0.925).ConclusionMultiple relationships between microbiomes, immune-checkpoint proteins, and inflammatory cytokines in the cervical microenvironment were identified. We focus on these factors to aid in the comprehensive understanding and therapeutic modulation of local microbial and immunologic compositions for the management of cervical insufficiency and preterm birth

The Effect of Composite Pig Islet-Human Endothelial Cell Grafts on the Instant Blood-Mediated Inflammatory Reaction

Instant blood-mediated inflammatory reaction (IBMIR) causes rapid islet loss in portal vein islet transplantation. Endothelial cells are known to protect against complement-mediated lysis and activation of coagulation. We tested composite pig islet-human endothelial cell grafts as a strategy to overcome IBMIR. Porcine islets were cocultured with human endothelial cells in specially modified culture medium composed of M199 and M200 for 1-9 days. A positive control group, negative control group, and the endothelial cell-coated group were examined with an in vitro tubing loop assay using human blood. The endothelial cell-coated group was subdivided and analyzed by degree of surface coverage by endothelial cells (50%) or coculture time (= 5 days). Platelet consumption and complement and coagulation activation were assessed by platelet count, C3a, and thrombin-antithrombin complex (TAT), respectively. After 60-min incubation in human blood, the endothelial cell-coated group showed platelet consumption inhibition and low C3a and TAT assay results compared to uncoated controls. When the endothelial cell-coated group was subdivided by degree of surface coverage, the <= 50% coated group showed less platelet consumption and less activation of complement and coagulation compared with the positive control (uncoated) group. On analysis by coculture time, only the subgroup cocultured for <5 days showed the same protective effect. Human endothelial cell-coated pig islets, especially the partially coated and short-term cocultured pig islet-human endothelial cell composites, reduced all components of IBMIR. If the optimal endothelial cell-islet coculture method could be identified, human endothelial cell coating of pig islets would offer new strategies to improve xenogenic islet transplantation outcomes.McGuigan AP, 2007, BIOMATERIALS, V28, P2547, DOI 10.1016/j.biomaterials.2007.01.039Kim JH, 2007, XENOTRANSPLANTATION, V14, P60, DOI 10.1111/j.1399-3089.2006.00364.xCowan PJ, 2007, XENOTRANSPLANTATION, V14, P7, DOI 10.1111/j.1399-3089.2006.00368.xJones GL, 2007, CELL TRANSPLANT, V16, P505Johansson U, 2005, AM J TRANSPLANT, V5, P2632, DOI 10.1111/j.1600-6143.2005.01076.xKorsgren O, 2005, TRANSPLANTATION, V79, P1289, DOI 10.1097/01.TP.0000157273.60147.7CVenturini M, 2005, RADIOLOGY, V234, P617, DOI 10.1148/radiol.2342031356Goto M, 2004, TRANSPLANTATION, V77, P741, DOI 10.1097/01.TP.0000114872.26990.4FSzmitko PE, 2003, CIRCULATION, V107, P3093, DOI 10.1161/01.CIR.0000074242.66719.4ALinn T, 2003, FASEB J, V17, P881, DOI 10.1096/fj.02-0615fjeOzmen L, 2002, DIABETES, V51, P1779Buhler L, 2002, XENOTRANSPLANTATION, V9, P3Bennet W, 2001, TRANSPLANTATION, V72, P312Bennet W, 2000, TRANSPLANTATION, V69, P711Bennet W, 1999, DIABETES, V48, P1907ANTONOV AS, 1992, THROMB RES, V67, P135SPEISER W, 1987, BLOOD, V69, P964KUMAR S, 1987, DIFFERENTIATION, V36, P57MADRI JA, 1983, J CELL BIOL, V97, P153

Korea HIV/AIDS Cohort Study: study design and baseline characteristics

The number of persons infected by HIV/AIDS has consistently increased in Korea since the first case of HIV/AIDS infection in 1985 and reached 15,208 by 2016. About 1,100 new patients with HIV/ AIDS infections have emerged every year since 2013. In Korea, the Korea HIV/AIDS Cohort Study was established for the evidenced-based prevention, treatment, and effective management of patients infected with human immunodeficiency virus (HIV) in December 2006. This study monitored 1,438 patients, who accounted for about 10% of all patients with HIV/AIDS in Korea, for 10 years with the following aims: (1) to develop an administrative system for the establishment of a HIV/AIDS cohort-based study; (2) to standardize methodologies and the case report forms; and (3) to standardize multi-cohort data and develop a data cleaning method. This study aims to monitor at least 1,000 patients (excluding those for whom investigation had been completed) per year (estimated number of patients who can be monitored by January 2018: 939). By December 2016, the sex distribution was 93.3% for men, and 6.7% for women (gender ratio, 13.9:1.0), and 98.9% of all participants were Korean. More than 50.0% of the participants were confirmed as HIV positive after 2006. This study reports competitive, long-term research that aimed to develop policies for the prevention of chronic infectious diseases for patients with HIV. The data collected over the last decade will be used to develop indices for HIV treatment and health promotion

Outer Membrane Vesicles Derived from Escherichia coli Induce Systemic Inflammatory Response Syndrome

Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-α and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI