Quantitative assessment of preanalytic variables on clinical evaluation of PI3/AKT/mTOR signaling activity in diffuse glioma.

Biomarker-driven therapeutic clinical trials require implementation of standardized, evidence-based practices for sample collection. In diffuse glioma, phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR (PI3/AKT/mTOR) signaling is an attractive therapeutic target for which window of opportunity clinical trials could facilitate identification of promising new agents. Yet, the relevant preanalytic variables and optimal tumor sampling methods necessary to measure pathway activity are unknown. To address this, we used a murine model for IDH-wildtype glioblastoma (GBM) and human tumor tissue, including IDH-wildtype GBM and IDH-mutant diffuse glioma. First, we determined the impact of delayed time-to-formalin fixation, or cold ischemia time (CIT), on the quantitative assessment of cellular expression of six phosphoproteins that are readouts of PI3K/AK/mTOR activity (phosphorylated -proline-rich Akt substrate of 40 kDa (p-PRAS40, T246), -mechanistic target of rapamycin (p-mTOR; S2448); -AKT (p-AKT, S473); -ribosomal protein S6 (p-RPS6, S240/244 and S235/236), and -eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1, T37/46). With CITs ≥2 hours, typical of routine clinical handling, all had reduced or altered expression with p-RPS6 (S240/244) exhibiting relatively greater stability. A similar pattern was observed using patient tumor samples from the operating room with p-4EBP1 more sensitive to delayed fixation than p-RPS6 (S240/244). Many clinical trials utilize unstained slides for biomarker evaluation. Thus, we evaluated the impact of slide storage conditions on the detection of p-RPS6 (S240/244), p-4EBP1, and p-AKT. After 5 months, storage at -80ºC was required to preserve the expression of p-4EBP1 and p-AKT while p-RPS6 (240/244) expression was not stable regardless of storage temperature. Biomarker heterogeneity impacts optimal tumor sampling. Quantification of p-RPS6 (240/244) expression in multiple regionally distinct human tumor samples from eight patients revealed significant intratumoral heterogeneity. Thus, the accurate assessment of PI3K/AKT/mTOR signaling in diffuse glioma must overcome intratumoral heterogeneity and multiple preanalytic factors, including time-to-formalin fixation, slide storage conditions, and phosphoprotein of interest.

Antiplasmodial potential of phytochemicals from Citrus aurantifolia peels: a comprehensive in vitro and in silico study.

Phytochemical investigation of Key lime (Citrus aurantifolia L., F. Rutaceae) peels afforded six metabolites, known as methyl isolimonate acetate (1), limonin (2), luteolin (3), 3`-hydroxygenkwanin (4), myricetin (5), and europetin (6). The structures of the isolated compounds were assigned by 1D NMR. In the case of limonin (2), further 1- and 2D NMR experiments were done to further confirm the structure of this most active metabolite. The antiplasmodial properties of the obtained compounds against the pathogenic NF54 strain of Plasmodium falciparum were assessed in vitro. According to antiplasmodial screening, only limonin (2), luteolin (3), and myricetin (5) were effective (IC50 values of 0.2, 3.4, and 5.9 µM, respectively). We explored the antiplasmodial potential of phytochemicals from C. aurantifolia peels using a stepwise in silico-based analysis. We first identified the unique proteins of P. falciparum that have no homolog in the human proteome, and then performed inverse docking, ΔGBinding calculation, and molecular dynamics simulation to predict the binding affinity and stability of the isolated compounds with these proteins. We found that limonin (2), luteolin (3), and myricetin (5) could interact with 20S a proteasome, choline kinase, and phosphocholine cytidylyltransferase, respectively, which are important enzymes for the survival and growth of the parasite. According to our findings, phytochemicals from C. aurantifolia peels can be considered as potential leads for the development of new safe and effective antiplasmodial agents.

Dual action of epigallocatechin-3-gallate in virus-induced cell Injury.

BACKGROUND: Viral infections cause damage and long-term injury to infected human tissues, demanding therapy with antiviral and wound healing medications. Consequently, safe phytochemical molecules that may control viral infections with an ability to provide wound healing to viral-induced tissue injuries, either topically or systemically, are advantageous. Herein, we hypothesized that epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, might be effective as a wound healing, antiviral, and antifibrotic therapy. RESULTS: The antiviral activities of EGCG against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Herpes simplex virus type 2 (HSV-2) as well as its wound healing activities against different monolayer tissue (continuous and primary) systems were investigated. Consider its possible wound-healing advantages as well. To determine the safe concentrations of EGCG in green monkey kidney (Vero) and Vero-E6 cell lines, MTT assay was performed and showed high CC50 values of 405.1 and 322.9 µM, respectively. The antiviral activities of EGCG against SARS-CoV-2 and HSV-2, measured as half-maximal concentration 50 (IC50) concentrations, were 36.28 and 59.88 µM, respectively. These results confirm that the EGCG has remarkable viral inhibitory activities and could successfully suppress the replication of SARS-CoV-2 and HSV-2 in vitro with acceptable selectivity indices (SI) of 11.16 and 5.39, respectively. In parallel, the EGCG exhibits significant and dose/time-dependent anti-migration effects in human breast cancer cells (MCF-7), its resistant variation (MCF-7adr), and human skin fibroblast (HSF) indicating their potential to heal injuries in different internal and topical mammalian systems. CONCLUSIONS: The EGCG has proven to be an efficient antiviral against SARS-CoV-2 and HSV-2, as well as a wound-healing phytochemical. We assume that EGCG may be a promising option for slowing the course of acute cellular damage induced by systemic (Coronavirus Disease 2019 (COVID-19)) or topical (HSV-2) viral infections.

Nutritional Composition and Anti-Type 2 Diabetes Mellitus Potential of Femur Bone Extracts from Bovine, Chicken, Sheep, and Goat: Phytochemical and In Vivo Studies.

Nutritional deficits in one's diet have been established as the key risk factor for T2DM in recent years. Nutritional therapy has been demonstrated to be useful in treating T2DM. The current study was carried out to assess the nutritional composition of bovine (12 months), chicken (4 months), sheep (13 months), and goat (9 months) femur bone extracts, as well as their potential therapeutic effects on T2DM regression in a Wistar albino rat model (500 mg/kg b.wt.). The proximate composition of the different extracts, their fatty acid composition, their amino acids, and their mineral contents were identified. In vivo data indicated considerably improved T2DM rats, as seen by lower serum levels of TL, TG, TC, ALT, AST, ALP, bilirubin, creatinine, urea, IL-6, TNF-α, sICAM-1, sVCAM-1, and MDA. Low levels of HDL-C, GSH, and total proteins were restored during this study. Histological investigations of liver and pancreatic tissue revealed that the distribution of collagen fibers was nearly normal. The bovine extract, on the other hand, was the most active, followed by the sheep, goat, and finally chicken extract. This research could result in the creation of a simple, noninvasive, low-cost, and reliable method for T2DM control, paving the way for potential early therapeutic applications in T2DM control.

Anti-Alzheimer Potential of a New (+)-Pinitol Glycoside Isolated from Tamarindus indica Pulp: In Vivo and In Silico Evaluations.

Tamarindus indica Linn (tamarind, F. Leguminosae) is one of the most widely consumed edible fruits in the world. Phytochemical investigation of tamarind pulp n-butanol fraction yielded one new (+)-pinitol glycoside compound 1 (25% w/w), and 1D, 2D NMR, and HRESIMS investigation were used to confirm the new compound's structure. (+)-Pinitol glycoside showed anti-Alzheimer potential that was confirmed in prophylactic and treatment groups by decreasing time for the T-maze test; decreased TAO, brain and serum AChE, MDA, tau protein levels, and ß amyloid peptide protein levels; and increasing GPX, SOD levels, and in vivo regression of the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. The reported molecular targets for human Alzheimer's disease were then used in a network pharmacology investigation to examine their complex interactions and identify the key targets in the disease pathogenesis. An in silico-based analysis (molecular docking, binding free energy calculation (ΔGBinding), and molecular dynamics simulation) was performed to identify the potential targets for compound 1. The findings of this study may lead to the development of dietary supplements for the treatment of Alzheimer's disease.

Postoperative risk of IDH-mutant glioma-associated seizures and their potential management with IDH-mutant inhibitors.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Assessment of incidence of cerebral vascular diseases and prediction of stroke risk in chronic obstructive pulmonary disease patients using multimodal biomarkers.

BACKGROUND: Early assessment of cerebrovascular disease in chronic obstructive pulmonary disease (COPD) patients is an important issue for a favorable influence on the quality of life. METHODOLOGY: This cross-sectional case-control study was conducted on 38 eligible COPD patients (mean age 55.5 ± 11.5, 25 males, and 13 females) and 26 age-/sex-matched healthy controls. All participants were subjected to stroke risk screening instruments that included the Stroke Riskometer™, the Framingham 10-Year Risk Score, the stroke risk screening tool (the Department of Disease Control of Thailand), the My Risk Stroke Calculator, and Q Stroke. Radiologically, diffusion tensor imaging (DTI) and echo-gradient MRI (T2 star) T2 star imaging were done. Color-coded duplex sonography was done. Laboratory investigations included C-reactive protein (CRP), serum amyloid A, plasma fibrinogen level, serum IL6, 8-Isoprostane, vWF and urinary albumin creatinine ratio. RESULTS: Stroke risk screening instruments revealed a significant increase in COPD patients. DTI showed a significant bilateral reduction in fractional isotropy and a significant bilateral increase in mean diffusivity of white matter through many areas in COPD patients. Patients also had a significant increase of intima-media thickness, presence of atherosclerotic focal thicknesses or plaques on duplex sonography. There was a significant elevation of CRP, serum amyloid A, plasma fibrinogen level, serum IL6, 8-isoprostane, von Willebrand factor (vWF), and urinary albumin creatinine ratio in COPD patients. CONCLUSION: COPD patients had an increased risk for stroke that could be assessed on stroke risk screening instruments, DTI, T2 star, duplex sonography, and laboratory investigation and could be correlated with the severity of the disease.

Effect of substituting hydroponic barley forage with or without enzymes on performance of growing rabbits.

This study aims to evaluate the effect of hydroponic barley (HB) by substituting control diet with 25% HB with or without enzymes on rabbit performance, nutrient digestibility, and economic efficiency. A total number of 60 growing male HyPlus rabbits (average body weight 669 ± 12 g, 30 days of age) were utilized in the present study. The rabbits were randomly assigned to three groups (n = 20 rabbits per group). The first group served as a control (C). The other two groups were fed the control diet substituted with 25% hydroponic barley HB (group CHB), and the control diet substituted with 25% HB added with 0.5 g/kg enzymes (CHBE). The experiment lasted for 56 days. The results revealed that daily body weight gain improved (P < 0.05) by 18.64% and 23.94%, and feed conversion ratio improved by 3.74% and 17.91% than control, respectively, during 30-86 days of age in CHB and CHBE groups. The economic efficiency was improved (P < 0.05) by 32.17% and 39.60% in CHB and CHBE diets, respectively, compared to control; and nutrient digestibility, and mineral retention of growing rabbits were also improved (P < 0.05) by substituting HB with or without enzymes compared to control diet. Overall, the best rabbit performances were observed in both CHB and CHBE groups. In conclusion, these results suggest that substituting 25% of concentrated control diet by hydroponic barley with or without enzymes have positive effects in a sustainable way on growth performance, nutrient digestibility, and economic efficiency of growing rabbits.

Effects of aflatoxin B1 on human breast cancer (MCF-7) cells: cytotoxicity, oxidative damage, metabolic, and immune-modulatory transcriptomic changes.

Aflatoxin B1 (AFB1) is a potent mycotoxin that is commonly produced by molds such as Aspergillus (A.) flavus and A. parasiticus. AFB1 is associated with several health adverse effects in humans including mutagenesis and carcinogenesis. Aflatoxin is commonly secreted in the milk leading to deleterious effects on breast tissue and potential nursing infants. However, the effects of aflatoxins, particularly AFB1, on the breast cells are less investigated. In this study, AFB1-associated effects on human breast cancer cell lines (MCF-7) were investigated. AFB1 caused significant cytotoxicity on MCF-7 cells. Such cytotoxicity had a positive correlation with the induction of oxidative stress. In addition, AFB1 caused significant transcriptomic alterations in xenobiotics and drug-metabolizing enzymes, transporters, and antioxidant enzymes. Besides, AFB1 upregulated pro-inflammatory markers such as tumor necrosis factor-α and cyclooxygenase-2 with a significant reduction of mRNA expressions of the immunity-related genes including interleukins 8 and 10.

Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNß-1a Biologics.

Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNß-1a) or pegylated-IFNß-1a (pegIFNß-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNß-1a and pegIFNß-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change ≥ 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNß1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers.

Application of Lyophilized Gene-Delivery Formulations to Dental Implant Surfaces: Non-Cariogenic Lyoprotectant Preserves Transfection Activity of Polyplexes Long-Term.

Titanium is the metal of choice for dental implants because of its biocompatibility and ability to merge with human bone tissue. Despite the great success rate of dental implants, early and late complications occur. Coating titanium dental implant surfaces with polyethyleneimine (PEI)-plasmid DNA (pDNA) polyplexes improve osseointegration by generating therapeutic protein expression at the implantation site. Lyophilization is an approach for stabilizing polyplexes and extending their shelf life; however, most lyoprotectants are sugars that can aid bacterial growth in the peri-implant environment. In our research, we coated titanium surfaces with polyplex solutions containing varying amounts of lyoprotectants. We used two common lyoprotectants (sucrose and polyvinylpyrrolidone K30) and showed for the first time that sucralose (a sucrose derivative used as an artificial sweetener) might act as a lyoprotectant for polyplex solutions. Human embryonic kidney (HEK) 293T cells were used to quantify the transfection efficiency and cytotoxicity of the polyplex/lyoprotectant formulations coating titanium surfaces. Polyplexes that were lyophilized in the presence of a lyoprotectant displayed both preserved particle size and high transfection efficiencies. Polyplexes lyophilized in 2% sucralose have maintained transfection efficacy for three years. These findings suggest that modifying dental implants with lyophilized polyplexes might improve their success rate in the clinic.

Carbapenem-Resistant Gram-Negative Bacilli Causing Ventilator Associated Pneumonia: Study of MASTDISCS Combi Carba Plus for Detection of Carbapenemase Producing Enterobacterales.

Background: Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant gram-negative bacteria has been proven to be an escalating public health challenge in Egypt owing to its high mortality rate and raised health care costs. Purpose: Detection of carbapenem-resistant gram-negative bacilli among VAP patients, genotypic identification of carbapenemase genes in the isolated strains with evaluation of their impact on patient outcome and detection of carbapenemase-producing enterobacterales by MASTDISCS combi Carba plus disc system. Methods: Broncho-alveolar lavage fluid (BALF) and endotracheal aspirate were collected aseptically from clinically suspected VAP patients. Pathogen identification and antibiotic sensitivity testing were done. Carbapenemase-encoding genes (bla KPC, bla NDM, and bla OXA-48) were tested by PCR in all carbapenem-resistant gram-negative isolates. Performance of MASTDISCS combi Carba plus in isolated Enterobacterales was assessed in relation to the PCR results. Results: Eighty-three carbapenem-resistant gram-negative isolates were detected. The most frequent pathogens were Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa representing 34.9%, 20.5% and 18.1%, respectively. bla KPC was the predominant gene. Patients with persistent mechanical ventilation less than 15 days and Pseudomonas aeruginosa infection were significantly associated with a higher death rate. MAST-Carba plus had the highest sensitivity, specificity, positive and negative predictive values for detecting OXA-48 carbapenemases representing 81.8%, 92.5%, 75% and 94.9%, respectively. Conclusion: Worse outcome in VAP patients was associated with carbapenem-resistant gram-negative bacilli. MASTDISCS combi Carba plus is an efficient simple method for identification of different carbapenemases among enterobacterales.

A Novel CNN pooling layer for breast cancer segmentation and classification from thermograms.

Breast cancer is the second most frequent cancer worldwide, following lung cancer and the fifth leading cause of cancer death and a major cause of cancer death among women. In recent years, convolutional neural networks (CNNs) have been successfully applied for the diagnosis of breast cancer using different imaging modalities. Pooling is a main data processing step in CNN that decreases the feature maps' dimensionality without losing major patterns. However, the effect of pooling layer was not studied efficiently in literature. In this paper, we propose a novel design for the pooling layer called vector pooling block (VPB) for the CCN algorithm. The proposed VPB consists of two data pathways, which focus on extracting features along horizontal and vertical orientations. The VPB makes the CNNs able to collect both global and local features by including long and narrow pooling kernels, which is different from the traditional pooling layer, that gathers features from a fixed square kernel. Based on the novel VPB, we proposed a new pooling module called AVG-MAX VPB. It can collect informative features by using two types of pooling techniques, maximum and average pooling. The VPB and the AVG-MAX VPB are plugged into the backbone CNNs networks, such as U-Net, AlexNet, ResNet18 and GoogleNet, to show the advantages in segmentation and classification tasks associated with breast cancer diagnosis from thermograms. The proposed pooling layer was evaluated using a benchmark thermogram database (DMR-IR) and its results compared with U-Net results which was used as base results. The U-Net results were as follows: global accuracy = 96.6%, mean accuracy = 96.5%, mean IoU = 92.07%, and mean BF score = 78.34%. The VBP-based results were as follows: global accuracy = 98.3%, mean accuracy = 97.9%, mean IoU = 95.87%, and mean BF score = 88.68% while the AVG-MAX VPB-based results were as follows: global accuracy = 99.2%, mean accuracy = 98.97%, mean IoU = 98.03%, and mean BF score = 94.29%. Other network architectures also demonstrate superior improvement considering the use of VPB and AVG-MAX VPB.

Anti-Inflammatory and Antioxidant Properties of Malapterurus electricus Skin Fish Methanolic Extract in Arthritic Rats: Therapeutic and Protective Effects.

The protective and therapeutic anti-inflammatory and antioxidant potency of Malapterurus electricus (F. Malapteruridae) skin fish methanolic extract (FE) (300 mg/kg.b.wt/day for 7 days, orally) was tested in monosodium urate(MSU)-induced arthritic Wistar albino male rats' joints. Serum uric acid, TNF-α, IL-1ß, NF-𝜅B, MDA, GSH, catalase, SOD, and glutathione reductase levels were all measured. According to the findings, FE significantly reduced uric acid levels and ankle swelling in both protective and therapeutic groups. Furthermore, it has anti-inflammatory effects by downregulating inflammatory cytokines, primarily through decreased oxidative stress and increased antioxidant status. All the aforementioned lesions were significantly improved in protected and treated rats with FE, according to histopathological findings. iNOS immunostaining revealed that protected and treated arthritic rats with FE had weak positive immune-reactive cells. Phytochemical analysis revealed that FE was high in fatty and amino acids. The most abundant compounds were vaccenic (24.52%), 9-octadecenoic (11.66%), palmitic (34.66%), stearic acids (14.63%), glycine (0.813 mg/100 mg), and alanine (1.645 mg/100 mg). Extensive molecular modelling and dynamics simulation experiments revealed that compound 4 has the potential to target and inhibit COX isoforms with a higher affinity for COX-2. As a result, we contend that FE could be a promising protective and therapeutic option for arthritis, aiding in the prevention and progression of this chronic inflammatory disease.

CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma.

PURPOSE: The immunosuppressive tumor microenvironment present in the majority of diffuse glioma limits therapeutic response to immunotherapy. As the determinants of the glioma-associated immune response are relatively poorly understood, the study of glioma with more robust tumor-associated immune responses may be particularly useful to identify novel immunomodulatory factors that can promote T-cell effector function in glioma. EXPERIMENTAL DESIGN: We used multiplex immune-profiling, proteomic profiling, and gene expression analysis to define the tumor-associated immune response in two molecular subtypes of glioma and identify factors that may modulate this response. We then used patient-derived glioma cultures and an immunocompetent murine model for malignant glioma to analyze the ability of tumor-intrinsic factors to promote a CD8+ T-cell response. RESULTS: As compared with isocitrate dehydrogenase (IDH)-mutant astrocytoma, MAPK-activated pleomorphic xanthoastrocytoma (PXA) harbored increased numbers of activated cytotoxic CD8+ T cells and Iba1+ microglia/macrophages, increased MHC class I expression, enrichment of genes associated with antigen presentation and processing, and increased tumor cell secretion of the chemokine CXCL14. CXCL14 promoted activated CD8+ T-cell chemotaxis in vitro, recruited tumor-infiltrating CD8+ T cells in vivo, and prolonged overall survival in a cytotoxic T-cell-dependent manner. The immunomodulatory molecule B7-H3 was also highly expressed in PXA. CONCLUSIONS: We identify the MAPK-activated lower grade astrocytoma PXA as having an immune-rich tumor microenvironment and suggest this tumor may be particularly vulnerable to immunotherapeutic modulation. We also identify CXCL14 as an important determinant of the glioma-associated immune microenvironment, sufficient to promote an antitumor CD8+ T-cell response.

PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications.

BACKGROUND: IDH-mutant diffuse gliomas are heterogeneous, and improved methods for optimal patient therapeutic stratification are needed. PI3K/AKT/mTOR signaling activity can drive disease progression and potential therapeutic inhibitors of the pathway are available. Yet, the prevalence of PI3K/AKT/mTOR signaling pathway activity in IDH-mutant glioma is unclear and few robust strategies to assess activity in clinical samples exist. METHODS: PI3K/AKT/mTOR signaling pathway activity was evaluated in a retrospective cohort of 132 IDH-mutant diffuse glioma (91 astrocytoma and 41 oligodendroglioma, 1p/19q-codeleted) through quantitative multiplex immunoprofiling using phospho-specific antibodies for PI3K/AKT/mTOR pathway members, PRAS40, RPS6, and 4EBP1, and tumor-specific anti-IDH1 R132H. Expression levels were correlated with genomic evaluation of pathway intrinsic genes and univariate and multivariate Cox proportional hazard regression models were used to evaluate the relationship with outcome. RESULTS: Tumor-specific expression of p-PRAS40, p-RPS6, and p-4EBP1 was common in IDH-mutant diffuse glioma and increased with CNS WHO grade from 2 to 3. Genomic analysis predicted pathway activity in 21.7% (13/60) while protein evaluation identified active PI3K/AKT/mTOR signaling in 56.6% (34/60). Comparison of expression in male versus female patients suggested sexual dimorphism. Of particular interest, when adjusting for clinical prognostic factors, the level of phosphorylation of RPS6 was strongly associated with PFS (P < .005). Phosphorylation levels of both PRAS40 and RPS6 showed an association with PFS in univariate analysis. CONCLUSIONS: Our study emphasizes the value of proteomic assessment of signaling pathway activity in tumors as a means to identify relevant oncogenic pathways and potentially as a biomarker for identifying aggressive disease.

Deep learning model for fully automated breast cancer detection system from thermograms.

Breast cancer is one of the most common diseases among women worldwide. It is considered one of the leading causes of death among women. Therefore, early detection is necessary to save lives. Thermography imaging is an effective diagnostic technique which is used for breast cancer detection with the help of infrared technology. In this paper, we propose a fully automatic breast cancer detection system. First, U-Net network is used to automatically extract and isolate the breast area from the rest of the body which behaves as noise during the breast cancer detection model. Second, we propose a two-class deep learning model, which is trained from scratch for the classification of normal and abnormal breast tissues from thermal images. Also, it is used to extract more characteristics from the dataset that is helpful in training the network and improve the efficiency of the classification process. The proposed system is evaluated using real data (A benchmark, database (DMR-IR)) and achieved accuracy = 99.33%, sensitivity = 100% and specificity = 98.67%. The proposed system is expected to be a helpful tool for physicians in clinical use.

Towards a unifying basis of auditory thresholds: Thresholds for multicomponent stimuli.

Sounds consisting of multiple simultaneous or consecutive components can be detected by listeners when the stimulus levels of the components are lower than those needed to detect the individual components alone. The mechanisms underlying such spectral, spectrotemporal, temporal, or across-ear integration are not completely understood. Here, we report threshold measurements from human subjects for multicomponent stimuli (tone complexes, tone sequences, diotic or dichotic tones) and for their individual sinusoidal components in quiet. We examine whether the data are compatible with the detection model developed by Heil, Matysiak, and Neubauer (HMN model) to account for temporal integration (Heil et al. 2017), and we compare its performance to that of the statistical summation model (Green 1958), the model commonly used to account for spectral and spectrotemporal integration. In addition, we compare the performance of both models with respect to previously published thresholds for sequences of identical tones and for diotic tones. The HMN model is similar to the statistical summation model but is based on the assumption that the decision variable is a number of sensory events generated by the components via independent Poisson point processes. The rate of events is low without stimulation and increases with stimulation. The increase is proportional to the time-varying amplitude envelope of the bandpass-filtered component(s) raised to an exponent of 3. For an ideal observer, the decision variable is the sum of the events from all channels carrying information, for as long as they carry information. We find that the HMN model provides a better account of the thresholds for multicomponent stimuli than the statistical summation model, and it offers a unifying account of spectral, spectrotemporal, temporal, and across-ear integration at threshold.

Effect of Humic Acid Addition on Buffering Capacity and Nutrient Storage Capacity of Soilless Substrates.

Excessive application of fertilizers has become a major issue in croplands of intensive agricultural systems in China, resulting in severe non-point source pollution; thus, reduction in the use of chemical fertilizers has received significant attention. Improving the nutrient storage capacity of soils or substrates is an effective approach for solving this problem. Humic acids (HA) are excellent soil conditioners. Thus, in the present study, their ability to improve the physico-chemical properties of three substrates with different textures was evaluated. HA treatments included 1% HA root application in three different types of substrates, including pure sand, pure cocopeat, and a mixture of sand:cocopeat (1:1, v/v) and their relative controls. We examined the morphological parameters of cucumber seedlings as well as pH buffering capacity (pHBC), total organic carbon (TOC), organic matter (OM), cation exchange capacity (CEC), and nutrient storage capacity of the three substrates. The results show that HA application improved the morphological parameters of cucumber seedlings (plant height, stem diameter, and biomass) in pure cocopeat and cocopeat-sand mixture treatments. On the contrary, HA addition had harmful effects on the cucumber seedlings cultivated in sand due to the low pHBC of sand. The seedlings cultivated in pure cocopeat showed the best morphological parameter performances among the seedlings grown in the three substrates. Furthermore, pHBC, TOC, OM, and CEC were enhanced by HA application. Incorporation of HA improved ammonium (NH4 +) and potassium (K+) storage capacity while decreasing phosphorus (P) storage. Pure cocopeat had the highest pHBC, TOC, OM, CEC, and nutrient storage capacity among the three substrates. In conclusion, mixing 1% HA into substrates promoted cucumber growth, improved substrate properties, and enhanced fertilizer use efficiency. Pure cocopeat is a suitable substrate for cucumber cultivation, and mixing cocopeat with sand amends the substrate properties and consequently improves plant growth.

Endogenous and exogenous opioid effects on oligodendrocyte biology and developmental brain myelination.

The elevated presence of opioid receptors and their ligands throughout the developing brain points to the existence of maturational functions of the endogenous opioid system that still remain poorly understood. The alarmingly increasing rates of opioid use and abuse underscore the urgent need for clear identification of those functions and the cellular bases and molecular mechanisms underlying their physiological roles under normal and pathological conditions. This review is focused on current knowledge on the direct and indirect regulatory roles that opioids may have on oligodendrocyte development and their generation of myelin, a complex insulating membrane that not only facilitates rapid impulse conduction but also participates in mechanisms of brain plasticity and adaptation. Information is examined in relation to the importance of endogenous opioid function, as well as direct and indirect effects of opioid analogues, which like methadone and buprenorphine are used in medication-assisted therapies for opioid addiction during pregnancy and pharmacotherapy in neonatal abstinence syndrome. Potential opioid effects are also discussed regarding late myelination of the brain prefrontal cortex in adolescents and young adults. Such knowledge is fundamental for the design of safer pharmacological interventions for opioid abuse, minimizing deleterious effects in the developing nervous system.