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Environmental toxic pollutants and pathogens that enter the ecosystem are major global issues. Detection of these toxic chemicals/pollutants and the diagnosis of a disease is a first step in efficiently controlling their contamination and spread, respectively. Various analytical techniques are available to detect and determine toxic chemicals/pathogens, including liquid chromatography, HPLC, mass spectroscopy, and enzyme-linked immunosorbent assays. However, these sensing strategies have some drawbacks such as tedious sample pretreatment and preparation, the requirement for skilled technicians, and dependence on large laboratory-based instruments. Alternatively, biosensors, especially paper-based sensors, could be used extensively and are a cost-effective alternative to conventional laboratory testing. They can improve accessibility to testing to identify chemicals and pollutants, especially in developing countries. Due to its low cost, abundance, easy disposal (by incineration, for example) and biocompatible nature, paper is considered a versatile material for the development of environmentally friendly electrochemical/optical (bio) sensor devices. This review presents an overview of sensing platforms constructed from paper, pointing out the main merits and demerits of paper-based sensing systems, their fabrication techniques, and the different optical/electrochemical detection techniques that they exploit.

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses. Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies. Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards. Results: Younger (

ObjectivePatients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.DesignWe conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).ResultsOverall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.ConclusionsNaproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.Trial registration numbergov Identifier: NCT02052908.

Abstract Background The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer and development, at present not much is known about the functional domains of BMI1 oncoprotein. In the present study, we carried out a deletion analysis of BMI1 to identify its negative regulatory domain. Results We report that deletion of the C-terminal domain of BMI1, which is rich in proline-serine (PS) residues and previously described as PEST-like domain, increased the stability of BMI1, and promoted its pro-oncogenic activities in human mammary epithelial cells (HMECs). Specifically, overexpression of a PS region deleted mutant of BMI1 increased proliferation of HMECs and promoted an epithelial-mesenchymal transition (EMT) phenotype in the HMECs. Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts. Conclusions In summary, our data suggest that the PS domain of BMI1 is involved in its stability and that it negatively regulates function of BMI1 oncoprotein. Our results also suggest that the PS domain of BMI1 could be targeted for the treatment of proliferative disorders such as cancer and aging.

Summary: Endothelial cell (EC) metabolism has emerged as a driver of angiogenesis. While hypoxia inactivates the oxygen sensors prolyl-4 hydroxylase domain-containing proteins 1–3 (PHD1-3) and stimulates angiogenesis, the effects of PHDs on EC functions remain poorly defined. Here, we investigated the impact of chemical PHD inhibition by dimethyloxalylglycine (DMOG) on angiogenic competence and metabolism of human vascular ECs. DMOG reduced EC proliferation, migration, and tube formation capacities, responses that were associated with an unfavorable metabolic reprogramming. While glycolytic genes were induced, multiple genes encoding sub-units of mitochondrial complex I were suppressed with concurrent decline in nicotinamide adenine dinucleotide (NAD+) levels. Importantly, the DMOG-induced defects in EC migration could be partially rescued by augmenting NAD+ levels through nicotinamide riboside or citrate supplementation. In summary, by integrating functional assays, transcriptomics, and metabolomics, we provide insights into the effects of PHD inhibition on angiogenic competence and metabolism of human vascular ECs.

Introduction: The Men who have Sex with Men (MSM) are a vulnerable population and need special attention in fight against the HIV/AIDS. The HIV trend has been an increasing trend among MSM. Study was done to determine the factors influencing sexual practice, perception of HIV/AIDS and Health seeking behavior among MSM in Hyderabad. Methodology: This was a facility based cross sectional study undertaken in the Targeted Intervention sites in Hyderabad, Telangana. A total of 300 Men who have Sex with Men who are above 18 years of age and registered were included. All the MSM visiting the TI centres during the study period were interviewed personally in their local language by using a pre-designed, pre-tested, semi structured and pre-coded proforma. Results: Mean age was 27.68 years. Majority of participants 119(39.66%) had their first sexual encounter at the age of 15-17 years. 130 (43.33%) visited the Target Intervention centres 1-2 times during the last month. About half of the participants i.e, 141(47.00%) belongs to Kothi Group and most of the MSM i.e, 198(66.00%) used condom during the sex with male last time. Conclusions: Stigma and cultural intolerance of same-sex relations are often largely to blame for rising epidemics, and until these issues are addressed it will be difficult to make headway in reducing HIV infection levels among MSM - which, in turn, will hinder the wider global efforts to manage HIV and AIDS.

Environmental toxic pollutants and pathogens that enter the ecosystem are major global issues. Detection of these toxic chemicals/pollutants and the diagnosis of a disease is a first step in efficiently controlling their contamination and spread, respectively. Various analytical techniques are available to detect and determine toxic chemicals/pathogens, including liquid chromatography, HPLC, mass spectroscopy, and enzyme-linked immunosorbent assays. However, these sensing strategies have some drawbacks such as tedious sample pretreatment and preparation, the requirement for skilled technicians, and dependence on large laboratory-based instruments. Alternatively, biosensors, especially paper-based sensors, could be used extensively and are a cost-effective alternative to conventional laboratory testing. They can improve accessibility to testing to identify chemicals and pollutants, especially in developing countries. Due to its low cost, abundance, easy disposal (by incineration, for example) and biocompatible nature, paper is considered a versatile material for the development of environmentally friendly electrochemical/optical (bio) sensor devices. This review presents an overview of sensing platforms constructed from paper, pointing out the main merits and demerits of paper-based sensing systems, their fabrication techniques, and the different optical/electrochemical detection techniques that they exploit.

Cancer is one of the major public health issues in the world. It has become the second leading cause of death, with approximately 75% of cancer deaths transpiring in low- or middle-income countries. It causes a heavy global economic cost estimated at more than a trillion dollars per year. The most common cancers are breast, colon, rectum, prostate, and lung cancers. Many of these cancers can be treated effectively and cured if detected at the primary stage. Nowadays, around 50% of cancers are detected at late stages, leading to serious health complications and death. Early diagnosis of cancer diseases substantially increases the efficient treatment and high chances of survival. Biosensors are one of the potential screening methodologies useful in the early screening of cancer biomarkers. This review summarizes the recent findings about novel cancer biomarkers and their advantages over traditional biomarkers, and novel biosensing and diagnostic methods for them; thus, this review may be helpful in the early recognition and monitoring of treatment response of various human cancers.

In this present paper, the machine learning approach is used to optimize, model, and predict the factors during drilling Nimonic C263 under dry mode. Nimonic C263 is tough to machine aero alloys, and it is required to find a predictive model and to optimize the factors in drilling this alloy before the actual machining process. It helps to avoid the actual machining cost and material cost. Experimental trails are planned based on Taguchi analysis, and L27 orthogonal array was chosen. Speed, feed, and approach angle of drill were considered as controlling factors, and cutting force and surface roughness were considered as responses. The feed forward neural network (FFNN) was used to develop a predictive model. The prediction capability was validated with a predictive model developed by Taguchi analysis. Furthermore, ANOVA (analysis of variance) analysis was done to find out the most influence factor on the responses.

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

Design and application of novel Rhodamine B amide derivatives achieved especially with simple secondary amines, and furthermore exhibiting fluorescence property and anticancer activity is not reported elsewhere. Further functionalization of rhodamine B at the carboxylic acid group with selected secondary amines generated amides, avoiding cyclization and simultaneously sustaining fluorescence. Currently, we have designed and developed three well defined novel rhodamine B amide derivatives by reacting rhodamine B (RHB) with thiomorpholine, bis-(2-chloroethyl) amine and morpholine (the side chains of several anticancer drugs) via rhodamine B acid chloride which resulted in fluorophores namely rhodamine B thiomorpholine amide (1), rhodamine B bis(2-chloroethyl)amine amide (2) and rhodamine B morpholine amide (3). All the three RHB amides were thoroughly characterized using analytical techniques like FT-IR, Mass, 1H NMR, 13C NMR spectroscopy and HPLC. Obtained compounds displayed molecular material attributes as well as anticancer activity. The wavelength of maximum absorption and emission of solutions occurred at ~560 nm and ~583 nm. Quantum yields (Φf = 0.40) and average fluorescence decay (~1.60 ns) of amides was comparable to RHB (1.72 ns). Optical bandgap of solids revealed semiconducting property (~ 2.9 eV). Acquired rhodamine B amides were found to be insensitive over a wide range of pH i.e. from 2 to 10 suggesting their plausible utility in biological labeling, moreover, showed potential anticancer activity against B16F10 (murine melanoma cells), MDA-MB231 (human breast cancer cells), A549 (human lung cancer cells) while they displayed less toxicity to normal HEK 293 (human embryonic kidney) cells. Interestingly, the cellular uptake study manifested that more quantity of the compound were taken up by the cancer cells compared to normal cells which indicate that these amides might become potential candidates to be developed as theranostic agents.

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme.

School tracking is usually criticised as a mechanism for social and cultural reproduction. Evidence from the literature shows a significant effect of early tracking on social inequality. Some studies also show that early tracking has a negative effect on the probability of completing higher education. This study uses PISA 2009 data and the propensity score matching technique to compare the effect of academic and vocational tracks on students' educational expectations and whether the effect varies across different socio-economic status in Austria, a country with an early tracking system, and Italy, a country with a later tracking system. The results show that students in Italy have significantly higher educational expectations for academic tertiary degrees than students in Austria. However, the findings do not show any evidence that the effect of tracking on expectations varies by students' socio-economic status in either country. The findings suggest that a later tracking system is associated with higher probabilities of having academic educational expectations; however, this finding should be interpreted with caution as the higher education and vocational education systems are different between the two countries, as well as the valuation of tertiary degrees in the labour market.

Mobile devices are highly portable, easily distributable, substantially affordable, and have the potential to be pedagogically complementary resources in education. This study, incorporating mixed method analyses, discusses the implications of a mobile learning technology-based learning model in two public primary schools near the Mexico-USA border in the state of Baja California, Mexico. One school was located in an urban slum and the other in a rural village community. Empirical and ethnographic data were collected through a series of achievement tests, observations, surveys, and interviews involving 160 grade school children recruited by convenience sampling. The general technology infrastructure, distinctive features of mobile learning to supplement literacy development, profound contextual phenomena arising from the two uniquely underserved communities, and social factors possibly influencing the educational experiences are discussed. The findings suggest that students in the rural village, seriously lacking educational resources and technology exposure, may have benefited substantially more from mobile technologies than urban school students possibly due to their relatively higher socio-economic status and higher parental involvement and interest in education. In contrast, there was no evidence of interaction with parental education levels, the experience of teachers or school principals, or the teacher's perception or preparation of the technology. Overall, the mobile learning technology adoption was rapid, seamless, and actively driven by the students rather than the teacher. The challenges of the phenomenal migratory nature of most families in this unique geographical region are also discussed to benefit future studies.

Background: Late‐Onset Alzheimer Disease (LOAD) is the most common neurodegenerative disease. Its heritability is estimated to be 40‐80%, yet the numerous genome‐wide studies (GWAS) conducted to date have identified risk variants that explain only ∼8% phenotypic variance. Method: To improve understanding of the functional genetic etiology of LOAD, we used 39 GWAS datasets including 58,713 cases and controls from the Alzheimer's Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer's Project (IGAP). For the 31 ADGC datasets, high quality variants were used to impute gene expression with PrediXcan, an approach that infers the genetically‐regulated portion of gene expression (GReX) from common expression quantitative trait loci. GReX was modeled using models from 50 different tissue types including 48 tissues from Genotype‐Tissue Expression Project, whole blood samples from the Depression Genes and Networks dataset, and dorsolateral prefrontal cortex samples from the CommonMind Consortium. Also, a multi‐tissues model was applied principal components analysis to extract the common expression pattern across all tissues. In addition, the summary GWAS statistics from the 8 IGAP studies were used to evaluate the GReX‐phenotype associations through S‐PrediXcan with the same 50 diverse tissue models. Result: Meta‐analysis across all studies identified 225 unique genes reaching Benjamini‐Hochberg (BH)‐corrected genome‐wide significance (BH‐adjusted p < 0.05) across all tissue‐specific models, including 26 with no previously‐reported GWAS associations with LOAD. Top hits included BLOC1S3 (p = 2.95 × 10−273), CD3EAP (p = 7.19 × 10−239), and RELB (p = 1.52 × 10−167). In a multi‐tissues model, 33 genes had significant effect, including BLOC1S3 (p = 1.21 × 10−64), APOC1 (p = 2.94 × 10−61), and CD3EAP (p = 1.10 × 10−56). Conditional analysis of previously reported loci using prior LOAD GWAS risk variants identified 8 genes reaching genome‐wide significance independent of known signals, including SLC39A13, SDHD, and MTCH2. Further independent validation of identified genes was performed in ∼23,000 individuals in a large, electronic health record‐linked DNA databank. In a phenome‐wide enrichment analysis with a million times permutation, our identified genes were enriched for associations with insomnia (p < 1 × 10−5) and degenerative disease of the spinal cord (p = 1 × 10−5). Conclusion: In conclusion, leveraging genotype‐based GReX in ∼60,000 individuals illustrates the utility of gene regulatory models in the discovery of new loci and function‐based fine mapping of known regions for LOAD and highlights other potential clinical consequences of disrupted regulation at LOAD‐associated genes. [ABSTRACT FROM AUTHOR]

Background: Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pharmacologics used to treat depressive-like symptoms, the efficacy and overall benefit(s) are not well-characterized in older adult patients with cancer. The objective of this investigation was to review what is known about the efficacy of pharmacologic treatment for older adults with depression and cancer. Methods: PubMed (Medline) and EMBASE (Elsevier) databases were analyzed for relevant literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: 1,919 unique studies were identified for title and abstract screening. Forty-eight publications were retrieved for full review. None of the identified studies evaluated the potential for benefit after pharmacological treatment among older adults with cancer and depression. Twenty-seven publications met all study criteria except for an analysis focused on older patients. Conclusion: We discovered a universal absence of literature with a relevance to pharmacologic antidepressant treatment effects in older adult patients with cancer. This included a lack of evaluation in patients with brain tumors who have an unusually high predilection for developing depression. Our findings suggest that new research is critically needed for understanding optimal clinical management strategies in older adults with cancer and depression who are treated with antidepressants.

Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.

Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan., Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy., Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice., Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM., (©2023 The Authors; Published by the American Association for Cancer Research.)

Bmi1 is a polycomb group proto-oncogene that has been implicated in multiple tumor types. However, its role in hepatocellular carcinoma (HCC) development has not been well studied. In this article, we report that Bmi1 is overexpressed in human HCC samples. When Bmi1 expression is knocked down in human HCC cell lines, it significantly inhibits cell proliferation and perturbs cell cycle regulation. To investigate the role of Bmi1 in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or an activated form of Ras (RasV12) in mouse liver. We found that while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, coexpression of Bmi1 and RasV12 promotes HCC formation in mice. Tumors induced by Bmi1/RasV12 resemble human HCC by deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. Intriguingly, we found no evidence that Bmi1 regulates Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development. In summary, our study shows that Bmi1 can cooperate with other oncogenic signals to promote hepatic carcinogenesis in vivo. Yet Bmi1 functions independent of Ink4A/Arf repression in liver cancer development.

Elevated expression of Bmi-1 is associated with many cancers, including breast cancer. Here, we examined the oncogenic potential of Bmi-1 in MCF10A cells, a spontaneously immortalized, nontransformed strain of human mammary epithelial cells (HMEC). Bmi-1 overexpression alone in MCF10A cells did not result in oncogenic transformation. However, Bmi-1 co-overexpression with activated H-Ras (RasG12V) resulted in efficient transformation of MCF10A cells in vitro. Although early-passage H-Ras-expressing MCF10A cells were not transformed, late-passage H-Ras-expressing cells exhibited features of transformation in vitro. Early- and late-passage H-Ras-expressing cells also differed in levels of expression of H-Ras and Ki-67, a marker of proliferation. Subsets of early-passage H-Ras-expressing cells exhibited high Ras expression and were negative for Ki-67, whereas most late-passage H-Ras-expressing cells expressed low levels of Ras and were Ki-67 positive. Injection of late-passage H-Ras-expressing cells in severe combined immunodeficient mice formed carcinomas with leiomatous, hemangiomatous, and mast cell components; these tumors were quite distinct from those induced by late-passage cells co-overexpressing Bmi-1 and H-Ras, which formed poorly differentiated carcinomas with spindle cell features. Bmi-1 and H-Ras co-overexpression in MCF10A cells also induced features of epithelial-to-mesenchymal transition. Importantly, Bmi-1 inhibited senescence and permitted proliferation of cells expressing high levels of Ras. Examination of various growth-regulatory pathways suggested that Bmi-1 overexpression together with H-Ras promotes HMEC transformation and breast oncogenesis by deregulation of multiple growth-regulatory pathways by p16(INK4a)-independent mechanisms.