Rapamycin Reduces Carcinogenesis and Enhances Survival in Mice when Administered after Nonlethal Total-Body Irradiation.

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure.

Multiomic-Based Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention.

Treatments involving radiation and chemotherapy alone or in combination have improved patient survival and quality of life. However, cancers frequently evade these therapies due to adaptation and tumor evolution. Given the complexity of predicting response based solely on the initial genetic profile of a patient, a predetermined treatment course may miss critical adaptation that can cause resistance or induce new targets for drug and immunotherapy.

Stimulus-Induced Relief of Intentionally Incorporated Frustration Drives Refolding of a Water-Soluble Biomimetic Foldamer.

Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein's ability to display responsive behavior such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here, we report the design, synthesis, characterization, and molecular dynamics simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to an intercalated columnar structure.

The folk psychiatry model: Developing a measure of lay perceptions of PTSD.

Whereas existing data verify the importance of support networks in facilitating resilience following trauma, the sociocultural perceptions of posttrauma difficulties that provide context for these interactions remain largely unexplored. Folk psychiatry models propose that lay explanations of mental illness can be quantified along distinct moralizing, medicalizing, and psychologizing dimensions. The current project aimed to develop a trauma-specific measure capturing lay explanations of posttraumatic stress disorder (PTSD) based on this framework.

Trauma cognitions as intervening variables in the relation of chronic child abuse and thwarted interpersonal needs.

Objective: Chronic childhood trauma is consistently linked to negative mental health outcomes in adulthood, but research exploring specific paths of risk remains limited. The aims of the current study were to examine trauma cognitions as intervening variables in the relation of chronic victimization with perceived burdensomeness and thwarted belongingness, variables implicated in transdiagnostic risk for psychopathology.

Method: Semistructured interviews were used to identify university students reporting exposure to systematic physical and/or sexual violence prior to age 18 ( = 101) versus those experiencing other Criterion-A events ( = 254).

Advances in Antimicrobial Peptide Discovery via Machine Learning and Delivery via Nanotechnology.

Antimicrobial peptides (AMPs) have been investigated for their potential use as an alternative to antibiotics due to the increased demand for new antimicrobial agents. AMPs, widely found in nature and obtained from microorganisms, have a broad range of antimicrobial protection, allowing them to be applied in the treatment of infections caused by various pathogenic microorganisms. Since these peptides are primarily cationic, they prefer anionic bacterial membranes due to electrostatic interactions.

Case Report of Malignant Hyperthermia in the Emergency Department.

Introduction: Malignant hyperthermia (MH) is a rare but deadly condition that may be encountered in the emergency department (ED). This report highlights a case of a patient who initially presented for acute agitation with hypertension and tachycardia and provides explanation for how to manage MH.

Case Report: A 44-year-old male presented to the ED with altered mental status, eventually requiring intubation with etomidate and succinylcholine.

Inhibition of USP14 promotes TNFα-induced cell death in head and neck squamous cell carcinoma (HNSCC).

TNFα is a key mediator of immune, chemotherapy and radiotherapy-induced cytotoxicity, but several cancers, including head and neck squamous cell carcinomas (HNSCC), display resistance to TNFα due to activation of the canonical NFκB pro-survival pathway. However, direct targeting of this pathway is associated with significant toxicity; thus, it is vital to identify novel mechanism(s) contributing to NFκB activation and TNFα resistance in cancer cells. Here, we demonstrate that the expression of proteasome-associated deubiquitinase USP14 is significantly increased in HNSCC and correlates with worse progression free survival in Human Papillomavirus (HPV)- HNSCC.

Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK-NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo.

Public beliefs about trauma and its consequences: Profiles and correlates of stigma.

Public stereotypes about trauma exposure and its likely consequences have the potential to influence levels of support extended to survivors in the larger community. The current project sought to examine unique profiles of stereotype endorsement both within and across participants sampled from distinct populations. Trauma-related stereotypes involving symptom course, dangerousness, employability, social functioning, predictability, character, and treatment need were examined in undergraduate ( = 404; = 502) and MTurk ( = 364) samples.

Development and Validation of the Disclosure Expectancy Scale.

Although the disclosure of traumatic experiences is believed to influence trajectories of post-trauma recovery, less is known about individual differences that affect survivors' motivation to share. The current project describes the development and evaluation of the Disclosure Expectancy Scale (DExS), a novel instrument intended to assess survivors' expectations about the potential risks and benefits of disclosure. Items targeting both positive and negative expectancies were generated based on existing research and the authors' clinical experience with various survivor populations.

The effect of modulation of gut microbiome profile on radiation-induced carcinogenesis and survival.

Non-lethal doses of ionizing radiation (IR) delivered to humans because of terrorist events, nuclear accidents or radiotherapy can result in carcinogenesis. Means of protecting against carcinogenesis are lacking. We questioned the role of the gut microbiome in IR-induced carcinogenesis.

Cure of syngeneic carcinomas with targeted IL-12 through obligate reprogramming of lymphoid and myeloid immunity.

Therapeutic IL-12 has demonstrated the ability to reduce local immune suppression in preclinical models, but clinical development has been limited by severe inflammation-related adverse events with systemic administration. Here, we show that potent immunologic tumor control of established syngeneic carcinomas can be achieved by i.t.

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet.

The nitroxide, Tempol, prevents obesity related changes in mice fed a high fat diet (HFD). The purpose of this study was to gain insight into the mechanisms that result in such changes by Tempol in female C3H mice. Microarray methodology, Western blotting, bile acid analyses, and gut microbiome sequencing were used to identify multiple genes, proteins, bile acids, and bacteria that are regulated by Tempol in female C3H mice on HFD.

Pharmacological Inhibition of HSP90 Radiosensitizes Head and Neck Squamous Cell Carcinoma Xenograft by Inhibition of DNA Damage Repair, Nucleotide Metabolism, and Radiation-Induced Tumor Vasculogenesis.

Purpose: Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity.

The influence of legacy contamination on the transport and bioaccumulation of mercury within the Mobile River Basin.

Past industrial use and subsequent release of mercury (Hg) into the environment have resulted in severe cases of legacy contamination that still influence contemporary Hg levels in biota. While the bioaccumulation of legacy Hg is commonly assessed via concentration measurements within fish tissue, this practice becomes difficult in regions of high productivity and methylmercury (MeHg) production, like the Mobile River Basin, Alabama in the southeastern United States. This study applied Hg stable isotope tracers to distinguish legacy Hg from regional deposition sources in sediments, waters, and fish within the Mobile River.

Mortality and Cholinesterase Inhibition in Butterflies Following Aerial Naled Applications for Mosquito Control on the National Key Deer Refuge.

Natural resource managers are concerned about the impacts of aerial ultra-low volume spray (ULV) of insecticides for mosquito control (i.e., mosquito adulticides) and seek science-driven management recommendations that reduce risk but allow vector control for nearby human populations.

Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non-Small Cell Lung Cancer and .

To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non-small cell lung cancer (NSCLC) cells and IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer.

Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine.

Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug dose that protects against TBI lethality, for potential protection against radiation-induced late effects such as a shortened lifespan and cancer. Three groups of mice were studied: 0 Gy control; 10.

Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model.

Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF.

SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.

Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation.

Mass Spectrometry-Based Metabolomics Identifies Longitudinal Urinary Metabolite Profiles Predictive of Radiation-Induced Cancer.

Nonlethal exposure to ionizing radiation (IR) is a public concern due to its known carcinogenic effects. Although latency periods for IR-induced neoplasms are relatively long, the ability to detect cancer as early as possible is highly advantageous for effective therapeutic intervention. Therefore, we hypothesized that metabolites in the urine from mice exposed to total body radiation (TBI) would predict for the presence of cancer before a palpable mass was detected.

NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay.

Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation.

The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE-/- mice.

Objective: The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE-/- mice fed a high fat diet (HFD).

Methods: ApoE-/- mice were fed for 12 weeks on standard chow diet or a high-fat diet.