Conservation laws for systems of extended bodies in the first post-Newtonian approximation.

The general form of the global conservation laws for $N$-body systems in the first post-Newtonian approximation of general relativity is considered. Our approach applies to the motion of an isolated system of $N$ arbitrarily composed and shaped, weakly self-gravitating, rotating, deformable bodies and uses a framework recently introduced by Damour, Soffel and Xu (DSX). We succeed in showing that seven of the first integrals of the system (total mass-energy, total dipole mass moment and total linear momentum) can be broken up into a sum of contributions which can be entirely expressed in terms of the basic quantities entering the DSX framework: namely, the relativistic individual multipole moments of the bodies, the relativistic tidal moments experienced by each body, and the positions and orientations with respect to the global coordinate system of the local reference frames attached to each body. On the other hand, the total angular momentum of the system does not seem to be expressible in such a form due to the unavoidable presence of irreducible nonlinear gravitational effects.Comment: 18 pages, Revte

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-jB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expandedpotential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GB

High Rates of Readmission in Necrotizing Pancreatitis: Natural History or Opportunity for Improvement?

Background Necrotizing pancreatitis (NP) is a complex and heterogeneous disease with a protracted disease course. Hospital readmission is extremely common; however, few data exist regarding the cause of readmission in NP. Methods A retrospective review of NP patients treated between 2005 and 2017 identified patients readmitted both locally and to our hospital. All patients with unplanned hospital readmissions were evaluated to determine the cause for readmission. Clinical and demographic factors of all patients were recorded. As appropriate, two independent group t tests and Pearson’s correlation or Fisher’s exact tests were performed to analyze the relationship between index admission clinical factors and readmission. p values of < 0.05 were accepted as statistically significant. Results Six hundred one NP patients were reviewed. Median age was 52 years (13–96). Median index admission length of stay was 19 days (2–176). The most common etiology was biliary (49.9%) followed by alcohol (20.0%). Unplanned readmission occurred in 432 patients (72%) accounting for a total of 971 unique readmissions (mean readmissions/patient, 2.3). The most common readmission indications were symptomatic necrosis requiring supportive care and/or intervention (31.2%), infected necrosis requiring antibiotics and/or intervention (26.6%), failure to thrive (9.7%), and non-necrosis infection (6.6%). Patients requiring readmission had increased incidence of index admission renal failure (21.3% vs. 14.2%, p = 0.05) and cardiovascular failure (12.5% vs. 4.7%, p = 0.01). Discussion Readmission in NP is extremely common. Significant portions of readmissions are a result of the disease natural history; however, a percentage of readmissions appear to be preventable. Patients with organ failure are at increased risk for unplanned readmission and will benefit from close follow-up

Novel Murine Glioblastoma Models That Reflect the Immunotherapy Resistance Profile of a Human Disease

BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. RESULTS: QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. CONCLUSIONS: These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM

Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan–Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14ARF, p16INK4A and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making

Designing Clinical Trials for Combination Immunotherapy: A Framework for GlioblastomaCombining Immunotherapy for Glioblastoma

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents

Analyzing the Decision to get Flu Shot: An Empirical Study

Influenza vaccination has been shown to be cost effective in reducing morbidity and mortality and in decreasing work absenteeism and use of health-care resources. The purpose of this study was to identify predictors and beliefs regarding people's vaccination decision against the influenza. It was hypothesized that Health Belief Model (HBM) categories, such as severity of illness, vaccine effectiveness and side effects of the vaccine, affect the decision to get flu shot. In addition, we examined psychological effects, such as time preference, subjective probability of flu, and attitude toward risk. A questionnaire surveys was conducted in the USA, in 2004. The questions included HBM categories and the psychological effects. The results indicate that the main predictors of past immunization against influenza are: the estimated effectiveness of the vaccination, periodic blood test, perceived severity of flu illness, side effects of vaccine (negative effect), having health anxieties, and subjective probability of being infected. Based upon these results, it is recommended to enlarging people's knowledge regarding the influenza illness, its potential risks, and the potential benefits of the vaccine

Visceral artery pseudoaneurysm in necrotizing pancreatitis: incidence and outcomes

Background: Visceral artery pseudoaneurysms (VA-PSA) occur in necrotizing pancreatitis; however, little is known about their natural history. This study sought to evaluate the incidence and outcomes of VA-PSA in a large cohort of patients with necrotizing pancreatitis. Methods: Data for patients with necrotizing pancreatitis who were treated between 2005 and 2017 at Indiana University Health University Hospital and who developed a VA-PSA were reviewed to assess incidence, presentation, treatment and outcomes. Results: Twenty-eight of 647 patients with necrotizing pancreatitis (4.3%) developed a VA-PSA between 2005 and 2017. The artery most commonly involved was the splenic artery (36%), followed by the gastroduodenal artery (24%). The most common presenting symptom was bloody drain output (32%), followed by incidental computed tomographic findings (21%). The median time from onset of necrotizing pancreatitis to diagnosis of a VA-PSA was 63.5 days (range 1-957 d). Twenty-five of the 28 patients who developed VA-PSA (89%) were successfully treated with percutaneous angioembolization. Three patients (11%) required surgery: 1 patient rebled following embolization and required operative management, and 2 underwent upfront operative management. The mortality rate attributable to hemorrhage from a VA-PSA in the setting of necrotizing pancreatitis was 14% (4 of 28 patients). Conclusion: In this study, VA-PSA occurred in 4.3% of patients with necrotizing pancreatitis. Percutaneous angioembolization effectively treated most cases; however, mortality from VA-PSA was high (14%). A high degree of clinical suspicion remains critical for early diagnosis of this potentially fatal problem

A miR-200b/200c/429-Binding Site Polymorphism in the 3′ Untranslated Region of the AP-2α Gene Is Associated with Cisplatin Resistance

The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3′ untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3′ UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3′ UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3′ UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3′ UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment