Validation of p53 Immunohistochemistry (PAb240 Clone) in Canine Tumors with Next-Generation Sequencing (NGS) Analysis

In human medicine, p53 immunohistochemistry (IHC) is a common method that is used for the identification of tumors with TP53 mutations. In veterinary medicine, several studies have performed IHC for p53 in canine tumors, but it is not known how well it actually predicts the mutation. The aim of this study was to estimate the accuracy of the IHC method for p53 (clone PAb240) using a lab-developed NGS panel to analyze TP53 mutations in a subset of malignant tumors in dogs. A total of 176 tumors were analyzed with IHC and then 41 were subjected to NGS analysis; among them, 15 were IHC positive and 26 were negative, and 16 out of 41 (39%) were found to be inadequate for NGS analysis. Excluding the non-evaluable cases at NGS, of the remaining eight IHC-positive cases, six were mutants and two were wild-type. Among the 17 IHC-negative cases, 13 were wild type, and 4 were mutants. The sensitivity was 60%, specificity was 86.7%, and the accuracy was 76%. These results suggest that when using IHC for p53 with this specific antibody to predict mutation, up to 25% wrong predictions can be expected

HIV-associated neurocognitive impairment in the modern ART era : are we close to discovering reliable biomarkers in the setting of virological suppression?

The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA

Canine smooth muscle tumors: A clinicopathological study

Canine smooth muscle tumors (SMTs) commonly develop in the alimentary and female genital tracts and less frequently in soft tissue. The definition of histological criteria of malignancy is less detailed for SMTs in dogs than in humans. This study evaluated the clinicopathologic features of canine SMTs and compared the veterinary and human medical criteria of malignancy. A total of 105 canine SMTs were evaluated histologically and classified according to both veterinary and human criteria. The Ki67 labeling index was assessed in all SMTs. Estrogen receptor (ER) and progesterone receptor (PR) expression was evaluated for soft tissue SMTs. Follow-up data were available in 25 cases. SMTs were diagnosed in the female genital tract (42%), alimentary tract (22%), and soft tissue (20%). Soft tissue SMTs frequently arose in the perigenital area, pelvic cavity, and retroperitoneum. A subset of soft tissue SMTs expressed ER and/or PR, resembling the gynecologic type of soft tissue SMT in humans. SMTs were less frequently malignant when assessed with human criteria than with veterinary criteria, better reflecting their benign behavior, especially in the genital tract where human criteria tolerate a higher mitotic count for leiomyoma. Decreased differentiation was correlated with increased proliferation, necrosis, and reduced desmin expression. Mitotic count, Ki67 labeling index, and necrosis were correlated with metastases and tumor-related death. Further prognostic studies are warranted to confirm the better performance of the human criteria when assessing SMT malignancy, especially genital cases, to confirm their usefulness in ER/PR-expressing soft tissue SMTs, and to better define the most useful prognostic parameters for canine SMTs

Mars Atmospheric Conversion to Methane and Water: An Engineering Model of the Sabatier Reactor with Characterization of Ru/Al2O3 for Long Duration Use on Mars

The Atmospheric Processing Module (APM) is a Mars In-Situ Resource Utilization (ISRU) technology designed to demonstrate conversion of the Martian atmosphere into methane and water. The Martian atmosphere consists of approximately 95 carbon dioxide (CO2) and residual argon and nitrogen. APM utilizes cryocoolers for CO2 acquisition from a simulated Martian atmosphere and pressure. The captured CO2 is sublimated and pressurized as a feedstock into the Sabatier reactor, which converts CO2 and hydrogen to methane and water. The Sabatier reaction occurs over a packed bed reactor filled with Ru/Al2O3 pellets. The long duration use of the APM system and catalyst was investigated for future scaling and failure limits. Failure of the catalyst was detected by gas chromatography and temperature sensors on the system. Following this, characterization and experimentation with the catalyst was carried out with analysis including x-ray photoelectron spectroscopy and scanning electron microscopy with elemental dispersive spectroscopy. This paper will discuss results of the catalyst performance, the overall APM Sabatier approach, as well as intrinsic catalyst considerations of the Sabatier reactor performance incorporated into a chemical model

HER2 Overexpression and Cytogenetical Patterns in Canine Mammary Carcinomas

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that promotes tumor cell growth and is implicated in the pathogenesis of human breast cancer. The role of HER2 in canine mammary carcinomas (CMCs) is not clear. Therefore, this study aimed to examine the protein expression and cytogenetic changes of HER2 and their correlation with other clinical-pathological parameters in CMC. We retrospectively selected 112 CMCs. HER2, ER, and Ki67 were assessed by immunohistochemistry. HER2 antibody validation was investigated by immunoblot on mammary tumor cell lines. Fluorescence in situ hybridization (FISH) was performed with probes for HER2 and CRYBA1 (control gene present on CFA9). HER2 protein overexpression was detected in 15 carcinomas (13.5%). A total of 90 carcinomas were considered technically adequate by FISH, and 8 out of 90 CMC (10%) were HER2 amplified, 3 of which showed a cluster-type pattern. HER2 overexpression was correlated with an increased number of HER2 gene copies (p = 0.01; R = 0.24) and overall survival (p = 0.03), but no correlation with ER, Ki67, grade, metastases, and tumor-specific survival was found. Surprisingly, co-amplification or polysomy was identified in three tumors, characterized by an increased copy number of both HER2 and CRYBA1. A morphological translocation-fusion pattern was recognized in 20 carcinomas (22%), with a co-localized signal of HER2 and CRYBA1. HER2 is not associated with clinical-pathological parameters of increased malignancy in canine mammary tumors, but it is suitable for studying different amplification patterns

P-Glycoprotein and Breast Cancer Resistance Protein in Canine Inflammatory and Noninflammatory Grade III Mammary Carcinomas

P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) expression are frequently related to multidrug resistance (MDR) in neoplastic cells. Canine inflammatory and grade III noninflammatory mammary carcinomas (IMC and non-IMC) are aggressive tumors that could benefit from chemotherapy. This study describes the immunohistochemical detection of P-gp and BCRP in 20 IMCs and 18 non-IMCs from dogs that had not received chemotherapy. Our aim was to determine if P-gp and BCRP expression was related to the \u201cinflammatory\u201d phenotype, to establish a basis for future studies analyzing the response to chemotherapy in dogs with highly malignant mammary cancer. Immunolabeling was primarily membranous for P-gp with a more intense labeling in emboli, and immunolabeling was membranous and cytoplasmic for BCRP. P-gp was expressed in 17 of 20 (85%) IMCs compared to 7 of 18 (39%) non-IMCs (P = 0.006). BCRP was expressed within emboli in 15 of 19 (79%) emboli in IMC, 12 of 15 (80%) primary IMCs, and 12 of 18 (67%) non-IMCs, without statistically significant differences (P >.05). All IMCs and 67% of non-IMCs expressed at least 1 of the 2 transporters, and 63% (12/19) of IMCs and 39% (7/18) of non-IMCs expressed both P-gp and BCRP. P-gp and BCRP evaluation might help select patients for chemotherapy. P-gp, expressed in a significantly higher percentage of IMCs vs non-IMCs, might play a specific role in the chemoresistance of IMC

Mars ISRU for Production of Mission Critical Consumables - Options, Recent Studies, and Current State of the Art

In 1978, a ground breaking paper titled, "Feasibility of Rocket Propellant Production on Mars" by Ash, Dowler, and Varsi discussed how ascent propellants could be manufactured on the Mars surface from carbon dioxide collected from the atmosphere to reduce launch mass. Since then, the concept of making mission critical consumables such as propellants, fuel cell reactants, and life support consumables from local resources, commonly known as In-Situ Resource Utilization (ISRU), for robotic and human missions to Mars has been studied many times. In the late 1990's, NASA initiated a series of Mars Human Design Reference Missions (DRMs), the first of which was released in 1997. These studies primarily focused on evaluating the impact of making propellants on Mars for crew ascent to Mars orbit, but creating large caches of life support consumables (water & oxygen) as a backup for regenerative life support systems for long-duration surface stays (>500 days) was also considered in Mars DRM 3.0. Until science data from the Mars Odyssey orbiter and subsequent robotic missions revealed that water may be widely accessable across the surface of Mars, prior Mars ISRU studies were limited to processing Mars atmospheric resources (carbon dioxide, nitrogen, argon, oxygen, and water vapor). In December 2007, NASA completed the Mars Human Design Reference Architecture (DRA) 5.0 study which considered water on Mars as a potential resource for the first time in a human mission architecture. While knowledge of both water resources on Mars and the hardware required to excavate and extract the water were very preliminary, the study concluded that a significant reduction in mass and significant enhancements to the mission architecture were possible if Mars water resources were utilized. Two subsequent Mars ISRU studies aimed at reexamining ISRU technologies, processing options, and advancements in the state-of-the-art since 2007 and to better understand the volume and packaging associated with Mars ISRU systems further substantiated the preliminary results from the Mars DRA 5.0 study. This paper will provide an overview of Mars ISRU consumable production options, the analyses, results, and conclusions from the Mars DRA 5.0 (2007), Mars Collaborative (2013), and Mars ISRU Payload for the Supersonic Retro Propulsion (2014) mission studies, and the current state-of-the-art of Mars ISRU technologies and systems. The paper will also briefly discuss the mission architectural implications associated with Mars resource and ISRU processing options