Intergovernmental Science/Engr/Tech Advisory Panel (ISETAP): Overview

Major constraints to the utilization of LANDSAT by state governments are identified. Six recommendations are made: (1) commitment by the federal government to assure LANDSAT data continuity and compatibility; (2) federal support of LANDSAT system; (3) federal agency responsibility should be clearly defined; (4) commitment by the federal government to prior consultation with the state in LANDSAT decisions; (5) commitment by the federal government to systematic and ongoing technology transfer programs; and (6) improvement of the data processing and delivery system. The transfer of technology from NOAA to the private sector and its impact on the state governments utilizing LANDSAT are also discussed

Primary Caregivers of Children with Williams Syndrome: Posttraumatic Growth and Related Health Outcomes

Background: Current literature on caregivers of children with chronic illnesses and developmental disabilities primarily focuses on negative aspects of adjustment, with maternal stress and depression as common outcome variables (Duvdevany & Abboud, 2003; Shin and Crittenden, 2003). While these pediatric caregivers have been shown to struggle more than caregivers of typically developing children, the possibility of positive psychological outcomes from such an experience is only beginning to be explored (Kim, Greenberg, Seltzer & Krauss, 2003; Scallan, Senior & Reilly, 2010). One such positive outcome is the idea of Posttraumatic Growth (PTG), a construct for which a widely accepted theoretical model exists (Tedeschi & Calhoun, 2004). This model has yet to be empirically validated and fails to provide an exhaustive picture of PTG. The current study aims to document this phenomenon among caregivers of children with Williams, empirically evaluate a portion of the proposed theoretical model, and explore possible extensions of the model in the form of health behaviors. Methods: Participants included 104 primary caregivers of children with Williams syndrome who were recruited through the Williams Syndrome Association List serve. Caregivers completed an online survey through SurveyMonkey software that included the posttraumatic growth inventory, the deliberate rumination scale, the MOS social support survey, and the taking care of yourself questionnaire. Results: The vast majority of caregivers reported some degree of growth following a diagnosis of Williams syndrome (M =55.91, SD =22.63), consistent with reports of other pediatric caregivers (Polantinsky & Esprey, 2000). Further, perceived social support was found to predict posttraumatic growth, F(2,73) = 2.488, p=.029, consistent with model predictions. However, perceived social support was not predictive of an increase in deliberate rumination, F(2,72) = 0.143, p=.867, failing to support the mediational model. Finally, posttraumatic growth was not found to predict health behaviors, although those caregivers who reported more posttraumatic growth also reported being less bothered by sleep-related caregiving burdens. Conclusion: Posttraumatic growth is prevalent among Williams syndrome caregivers, indicating the need for future research in facilitating this process among pediatric caregivers and patients alike. Further, a better understanding of the cognitive constructs involved in the posttraumatic growth process is essential. This improved understanding will facilitate more accurate measurement tools for evaluating these cognitive processes along with additional clarity with regards to the theoretical model. Finally, the identification of health behaviors and health belief constructs that are impacted by posttraumatic growth would improve the depth of the theoretical model and improve overall understanding of the construct

AAPT Diagnostic Criteria for Chronic Cancer Pain Conditions

Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative worked to develop the characteristics of an optimal diagnostic system.59, 65 Following the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (i.e., bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (i.e., chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability and validity and extension to other cancer-related pain syndromes

Biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death[1]. Despite this, there are currently only 3 FDA approved pharmacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances

Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1

Differences in age-related effects on brain volume in Down syndrome as compared to Williams syndrome and typical development

BACKGROUND: Individuals with Down Syndrome (DS) are reported to experience early onset of brain aging. However, it is not well understood how pre-existing neurodevelopmental effects versus neurodegenerative processes might be contributing to the observed pattern of brain atrophy in younger adults with DS. The aims of the current study were to: (1) to confirm previous findings of age-related changes in DS compared to adults with typical development (TD), (2) to test for an effect of these age-related changes in a second neurodevelopmental disorder, Williams syndrome (WS), and (3) to identify a pattern of regional age-related effects that are unique to DS. METHODS: High-resolution T1-weighted MRI of the brains of subjects with DS, WS, and TD controls were segmented, and estimates of regional brain volume were derived using FreeSurfer. A general linear model was employed to test for age-related effects on volume between groups. Secondary analyses in the DS group explored the relationship between brain volume and neuropsychological tests and APOE. RESULTS: Consistent with previous findings, the DS group showed significantly greater age-related effects relative to TD controls in total gray matter and in regions of the orbitofrontal cortex and the parietal cortex. Individuals with DS also showed significantly greater age-related effects on volume of the left and right inferior lateral ventricles (LILV and RILV, respectively). There were no significant differences in age-related effects on volume when comparing the WS and TD groups. In the DS group, cognitive tests scores measuring signs of dementia and APOE ϵ4 carrier status were associated with LILV and RILV volume. CONCLUSIONS: Individuals with DS demonstrated a unique pattern of age-related effects on gray matter and ventricular volume, the latter of which was associated with dementia rating scores in the DS group. Results may indicate that early onset of brain aging in DS is primarily due to DS-specific neurodegenerative processes, as opposed to general atypical neurodevelopment

COVID-19 Severity and Cardiovascular Outcomes in SARS-CoV-2-Infected Patients With Cancer and Cardiovascular Disease

BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)

MONOCLONAL ANTIBODY PRODUCTION FOR CANCER IMMUNOTHERAPY

The goal of the proposed plant is to produce 8760 g of bevacizumab at a concentration of 25 mg/mL which yields 349 L of product per year. Bevacizumab is a monoclonal antibody that is used to treat six different types of cancer. It acts by binding to the growth factor which essentially starves the cancerous tumor. To mass produce the antibody, recombinant Chinese Hamster Ovary cells that produce the desired humanized antibody are grown in a cascade of bioreactors. The cell solution then goes through a series of purification steps to isolate the desired antibody. A centrifuge is used to remove cell mass and chromatography columns are used to rid the solution of the undesired proteins. Filtration removes the buffer salts and then the final product is freeze dried. While the startup cost of the proposed plant is high, the pharmaceutical market is very lucrative and the facility is expected to make a profit within the first year. After seven years the investment has an estimated net present value of over $120 million. Due to the high economic return, the proposed plant design should move on to further development and implementation

Targeting the Cystine/Glutamate Antiporter System xc⁻ in Cancer-Induced Bone Pain

Many common cancers, including breast, prostate and lung cancers, have a propensity to metastasize to bone. Although these cancers go undetected in their native tissues, bone metastases often produce excruciating pain, the etiology of which is poorly understood. Cancer-induced bone pain (CIBP) is not well-controlled with existing medications, severely compromising patient quality of life. While CIBP is multifaceted, increased level of the excitatory neurotransmitter glutamate in the bone-tumor microenvironment may contribute to the pain state. Here, we demonstrate for the first time a relationship between reactive oxygen/nitrogen species, glutamate in the bone-tumor microenvironment and pain behaviors. The murine mammary adenocarcinoma cell line 66.1 is found to release glutamate via the cystine/glutamate antiporter system xc⁻. In a syngeneic model of breast CIBP in which 66.1 cells are inoculated into the femur intramedullary space, administration of sulfasalazine, an established system xc⁻ inhibitor and anti-inflammatory agent, reduces femur glutamate level and attenuates CIBP-related behaviors. Peroxynitrite, a reactive nitrogen species known to be generated in breast tumors, is shown to drive 66.1 system xc⁻ functional expression and tumor cell glutamate release. The elimination of peroxynitrite with the redox modulators FeTMPyP or SRI10 not only modulates tumor cell system xc⁻ functional expression in vitro and in vivo, significantly altering glutamate levels, but also assuages CIBP. In sum, we demonstrate that pharmacological inhibition of system xc⁻ transport attenuates CIBP-related behaviors. These data support a role for tumor-derived glutamate in CIBP and validate system xc⁻ an analgesic target in this pain state.Release 01-Aug-201