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Immune checkpoint inhibitors (ICIs) have led recent advances in the field of cancer immunotherapy improving overall survival in multiple malignancies with abysmal prognoses prior to their introduction. The remarkable efficacy of ICIs is however limited by their potential for systemic and organ specific immunerelated adverse events (irAEs), most of which present with mild to moderate symptoms that can resolve spontaneously, with discontinuation of therapy or glucocorticoid therapy. Cardiac irAEs however are potentially fatal. The understanding of autoimmune cardiotoxicity remains limited due to its rareness. In this paper, we provide an updated review of the literature on the pathologic mechanisms, diagnosis, and management of autoimmune cardiotoxicity resulting from ICIs and their combinations and provide perspective on potential strategies and ongoing research developments to prevent and mitigate their occurrence. [ABSTRACT FROM AUTHOR]

A study on metabolism of concentration and catecholamines using anesthetized swine reveals important role of mesenteric organs in the production of dopamine and norepinephrine metabolism. Production of mesenteric organs does not exceed removal of dihydroxyphenylacetic acid and the concentration of homovanillic acid by the liver. This results in more hepatic than renal elimination of the metabolites of the body, besides implying an underestimation of dopamine production by mesenteric organs.

Summary Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis. [ABSTRACT FROM AUTHOR]

Rabies virus (RABV) induces encephalomyelitis in humans and animals. One of the major problems with rabies is that the infected individuals most often do not develop virus neutralizing antibodies (VNA). In this study we have investigated the host immune response to RABV infection in dogs, using a live-attenuated (TriGAS) or a wild-type (wt) (DRV-NG11) RABV isolated from a rabid dog. Methodology/Principal Findings: The experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS. Conclusions/Significance: IM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs. [ABSTRACT FROM AUTHOR]

Opinion. Offers solutions to meet the core criteria of training counsellors in Europe. Clustering of people with limited training around a high-standard professional counsellor; Growth of counselling and psychotherapy in the continent; Purpose of training and educating cousellors; Production of high-standard, professionallly capable counsellor; Retainment on the core value of counselling.

The article discusses the change, which has been observed in many communities in Intermountain West. The late 1960s and most of the 1970s were times of great change for many communities in the Intermountain West. In most cases, the impetus for this change was the development of energy resources in or near these communities. The energy development projects were varied, and included surface and underground coal mining, uranium mining and milling, the exploration, production, and refining of oil and natural gas, power plant construction, and synthetic fuel plant construction. The communities most affected by these developments tended to be small, relatively isolated, and historically dependent upon agriculture. Most had little recent experience with growth; population and employment had typically been stagnant or declining for a number of years. Various case studies illustrate that many community development problems face an energy-impacted community. Because of the size of the project and the small population base in the impact area, a substantial work force has to be imported. Accompanying the influx of workers will be families and numerous support personnel, along with large numbers of other persons seeking employment. The newcomers will almost immediately put great pressure on the community and its infrastructure, including housing, public safety, education, recreation, medical and health care, sewer and water systems. Revenues needed to upgrade existing services and to provide new ones will typically lag well behind the time when they are needed.

There are two hypotheses concerning how rapid growth affects women in rural communities: (1) women are more adversely affected than men, and (2) growth liberates women from their traditional sex roles. We used a specific subgroup of the female population-single, never- married females of marriageable age-to examine these two hypotheses. This paper focuses on how a male marriage-market squeeze caused by the influx of a large number of single, never-married males of marriageable age affects these females. The hypotheses, combined with proposals drawn from the demographic literature on marriage markets, are tested using data from counties in Montana and Utah impacted by energy development in the mid- and late 1970s. The measures used are changes in nuptiality rates and age patterns of first marriages. Our results do not allow us to fully accept or reject either hypothesis. Rather, changes in age patterns of marriage indicate that sorting out the local effects from the more pervasive social effects is problematic. [ABSTRACT FROM AUTHOR]

Personal construct theory and repertory grid methodology were applied to a study of psychological change experienced by a sample of ten neurotic depressives and their matched controls during short-term hospitalization. All subjects completed a repertory grid and the Zung depression scale on admission to hospital. Depressives were characterized by lower self-esteem, more negative social perception and higher scores on the Zung scale. Both measures were repeated at the time of discharge from hospital. Depressives showed a significant reduction in depressive mood, more positive social perception, and a change in th construing of the self; controls showed no changes. It is argued that the use of a quantitative assessment technique reinforced by a theoretical framework results in a more refined understanding of psychological change. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the differences in both verbal and nonverbal modes of communication between patients with depressive and other neurotic disorders and their spouses. The study employed 10 depressed patients and their spouses and 11 surgical patients and their spouses selected according to the diagnosis by a hospital psychiatrist from a psychiatric unit in a general hospital. It was found that there are several differences in both verbal and nonverbal modes of communication between psychiatric patients and their spouses and surgical patients and their spouses.

The article presents information on the views expressed by various speakers at the American Association of Textile Chemists and Colorists (AATCC) symposium held in New York City, regarding knit shrinkage. Thomas P. Scott Junior of William Carter Co. said that technology of home care and the increased use of tumble dryers make it necessary to achieve greater accuracy in measurement of shrinkage. Daniel Powderly of Celanese Corp. cited basic conditions that contribute to knit fabric shrinkage.

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that is widely employed as an animal model of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE we assessed the incidence of EAE and these parameters in mice lacking nuclear factor-kappa B, tumor necrosis factor alpha, interferon alpha beta receptors, interferon gamma receptors, and inducible nitric oxide synthase. Increased MOG-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity. The loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. Disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity appears to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators. This research was supported by a grant from the National Multiple Sclerosis Society. [ABSTRACT FROM AUTHOR]

The mitochondrial citrate–malate exchanger (CIC), a known target of acetylation, is up-regulated in activated immune cells and plays a key role in the production of inflammatory mediators. However, the role of acetylation in CIC activity is elusive. We show that CIC is acetylated in activated primary human macrophages and U937 cells and the level of acetylation is higher in glucose-deprived compared to normal glucose medium. Acetylation enhances CIC transport activity, leading to a higher citrate efflux from mitochondria in exchange with malate. Cytosolic citrate levels do not increase upon activation of cells grown in deprived compared to normal glucose media, indicating that citrate, transported from mitochondria at higher rates from acetylated CIC, is consumed at higher rates. Malate levels in the cytosol are lower in activated cells grown in glucose-deprived compared to normal glucose medium, indicating that this TCA intermediate is rapidly recycled back into the cytosol where it is used by the malic enzyme. Additionally, in activated cells CIC inhibition increases the NADP + /NADPH ratio in glucose-deprived cells; this ratio is unchanged in glucose-rich grown cells due to the activity of the pentose phosphate pathway. Consistently, the NADPH-producing isocitrate dehydrogenase level is higher in activated glucose-deprived as compared to glucose rich cells. These results demonstrate that, in the absence of glucose, activated macrophages increase CIC acetylation to enhance citrate efflux from mitochondria not only to produce inflammatory mediators but also to meet the NADPH demand through the actions of isocitrate dehydrogenase and malic enzyme. [ABSTRACT FROM AUTHOR]

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1 Stroma ) in vivo , enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1 Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80 + and CD11b + macrophages and increasing angiogenesis. Cyclin D1 Stroma induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1 Stroma resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1 Stroma drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflict of interest.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.