Transcriptional Upregulation of NLRC5 by Radiation Drives STING- and Interferon-Independent MHC-I Expression on Cancer Cells and T Cell Cytotoxicity.

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to generate a large population of tumor antigen specific T cells but found that the presence of cells with cytotoxic capacity was unable to replicate the efficacy of radiation with combination checkpoint blockade. Instead, we demonstrated that a major role of radiation was to increase the susceptibility of surviving cancer cells to CD8+ T cell-mediated control through enhanced MHC-I expression. We observed a novel mechanism of genetic induction of MHC-I in cancer cells through upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation of tumors by radiation to improve tumor control with combination immunotherapy

Patterns of Childhood Trauma and Psychological Distress among Injecting Heroin Users in China

Background: Childhood trauma has been reported as a possible cause of future substance abuse in some countries. This study reports the prevalence of childhood trauma and examines its association with psychological distress among injecting drug users from mainland China. Methodology: The study was conducted in three government-operated drug rehabilitation facilities in Shanghai, China in 2007. The Early Trauma Inventory Self Report-Short Form (ETISR-SF) was used to evaluate 4 types (general, emotional, physical and sexual) and severity of childhood trauma, and the Symptom Checklist-90-Revised (SCL-90-R) to evaluate psychological distress. Principal Findings: Among 341 injecting drug users who completed the study, about 80 % reported one or more types o

Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6

BACKGROUND: AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation. METHODS: Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3. RESULTS: Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1. CONCLUSION: These studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3

Anxiety Levels in Children with Autism Spectrum Disorder:A Meta-Analysis

The aim of the current study was to meta-analytically examine whether anxiety levels in children with autism spectrum disorders (ASD) are elevated. A total of 83 articles were selected from a systematic literature search and were included in the meta-analyses. Results demonstrated that children with ASD had higher anxiety levels compared to typically developing children, and this difference increased with IQ. Youth with ASD also tended to have higher anxiety levels compared to clinically referred children, and this difference increased with age. Children with ASD had higher anxiety levels compared to youth with externalizing or developmental problems, but not when compared to youth with internalizing problems. The study findings highlight the importance of more research in order to fully understand the nature and development of anxiety in children with ASD. More specifically, the results suggest that especially high-functioning adolescents with ASD may be at risk for developing anxiety disorders. Therefore, it seems important to carefully follow and monitor children with ASD transcending to adolescenc

The NANOGrav 15 yr Data Set: Search for Transverse Polarization Modes in the Gravitational-wave Background

\ua9 2024. The Author(s). Published by the American Astronomical Society.Recently we found compelling evidence for a gravitational-wave background with Hellings and Downs (HD) correlations in our 15 yr data set. These correlations describe gravitational waves as predicted by general relativity, which has two transverse polarization modes. However, more general metric theories of gravity can have additional polarization modes, which produce different interpulsar correlations. In this work, we search the NANOGrav 15 yr data set for evidence of a gravitational-wave background with quadrupolar HD and scalar-transverse (ST) correlations. We find that HD correlations are the best fit to the data and no significant evidence in favor of ST correlations. While Bayes factors show strong evidence for a correlated signal, the data does not strongly prefer either correlation signature, with Bayes factors ∼2 when comparing HD to ST correlations, and ∼1 for HD plus ST correlations to HD correlations alone. However, when modeled alongside HD correlations, the amplitude and spectral index posteriors for ST correlations are uninformative, with the HD process accounting for the vast majority of the total signal. Using the optimal statistic, a frequentist technique that focuses on the pulsar-pair cross-correlations, we find median signal-to-noise ratios of 5.0 for HD and 4.6 for ST correlations when fit for separately, and median signal-to-noise ratios of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While the signal-to-noise ratios for each of the correlations are comparable, the estimated amplitude and spectral index for HD are a significantly better fit to the total signal, in agreement with our Bayesian analysis

The NANOGrav 15 yr Data Set: Search for Gravitational-wave Memory

\ua9 2025. The Author(s). Published by the American Astronomical Society.We present the results of a search for nonlinear gravitational-wave (GW) memory in the NANOGrav 15 yr data set. We find no significant evidence for memory signals in the data set, with a maximum Bayes factor of 3.1 in favor of a model including memory. We therefore place upper limits on the strain of potential GW memory events as a function of sky location and observing epoch. We find upper limits that are not always more constraining than previous NANOGrav results. We show that it is likely due to the increase in common red noise between the 12.5 and 15 yr NANOGrav data sets

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era