Predictive identification and design of potent inhibitors targeting resistance-inducing candidate genes from E. coli whole-genome sequences.

Introduction: This work utilizes predictive modeling in drug discovery to unravel potential candidate genes from Escherichia coli that are implicated in antimicrobial resistance; we subsequently target the gidB, MacB, and KatG genes with some compounds from plants with reported antibacterial potentials. Method: The resistance genes and plasmids were identified from 10 whole-genome sequence datasets of E. coli; forty two plant compounds were selected, and their 3D structures were retrieved and optimized for docking. The 3D crystal structures of KatG, MacB, and gidB were retrieved and prepared for molecular docking, molecular dynamics simulations, and ADMET profiling. Result: Hesperidin showed the least binding energy (kcal/mol) against KatG (-9.3), MacB (-10.7), and gidB (-6.7); additionally, good pharmacokinetic profiles and structure-dynamics integrity with their respective protein complexes were observed. Conclusion: Although these findings suggest hesperidin as a potential inhibitor against MacB, gidB, and KatG in E. coli, further validations through in vitro and in vivo experiments are needed. This research is expected to provide an alternative avenue for addressing existing antimicrobial resistances associated with E. coli's MacB, gidB, and KatG.

Histopathologic Characteristics of Childhood Nephrotic Syndrome in a Tertiary Health Facility in Nigeria.

BACKGROUND: Globally, the predominant histopathologic characteristic of childhood nephrotic syndrome has been minimal change nephropathy (MCN). However, some studies from Africa and Nigeria have revealed otherwise. It is imperative that this pattern is re-examined from time to time given changing disease and environmental dynamics from place to place. OBJECTIVE: This study aimed to determine the histopathological characteristics of childhood nephrotic syndrome in Ilorin, northcentral Nigeria. METHODS: A prospective study of all new patients aged 2-14 years who presented with clinical features of nephrotic syndrome between January 2010 to December 2023 at the University of Ilorin Teaching Hospital, Ilorin was carried out. All eligible patients underwent renal biopsy. RESULTS: A total of 47 children with nephrotic syndrome were biopsied comprising of 21 males and 26 females making an M: F ratio of 1:1.2. The age range of subjects was 2-14 years with a mean of 7.8 ±3.6 years. The most common histological type of nephrotic syndrome was minimal change nephrotic syndrome (MCNS) which occurred in 35(74.5%) children followed by membranoproliferative glomerulonephritis (MPGN) in 5(10.6%) and focal segmental glomerulosclerosis (FSGS) in 2(4.3%). Of the 35 MCNS patients, 31(88.6%) were steroid sensitive while 4(11.4%) were steroid resistant. CONCLUSION: The predominant histopathological characteristic of childhood nephrotic syndrome was minimal change nephrotic syndrome, which was mostly steroid-sensitive.

CONTEXTE: Au niveau mondial, la principale caractéristique histopathologique du syndrome néphrotique de l'enfant a été la néphropathie à lésions minimales (NLM). Cependant, certaines études en Afrique et au Nigeria ont montré des résultats différents. Il est essentiel de réévaluer ce modèle régulièrement en raison de l'évolution des maladies et de l'environnement d'un endroit à l'autre. OBJECTIF: Cette étude visait à déterminer les caractéristiques histopathologiques du syndrome néphrotique de l'enfant à Ilorin, dans le nord-centre du Nigeria. MÉTHODES: Une étude prospective de tous les nouveaux patients âgés de 2 à 14 ans présentant des signes cliniques de syndrome néphrotique entre janvier 2010 et décembre 2023 à l'hôpital universitaire d'Ilorin, à Ilorin, a été réalisée. Tous les patients éligibles ont subi une biopsie rénale. RÉSULTATS: Au total, 47 enfants atteints du syndrome néphrotique ont été biopsiés, dont 21 garçons et 26 filles, soit un ratio H/F de 1/1,2. La tranche d'âge des sujets était de 2 à 14 ans avec une moyenne de 7,8 ± 3,6 ans. Le type histologique le plus fréquent du syndrome néphrotique était la néphropathie à lésions minimales (NLM), obser vée chez 35 (74,5 %) enfants, suivie de la glomérulonéphrite membranoproliférative (GMPN) chez 5 (10,6 %) et du sclérose segmentaire et focale (SSF) chez 2 (4,3 %). Parmi les 35 patients atteints de NLM, 31 (88,6 %) étaient cortico-sensibles et 4 (11,4 %) cortico-résistants. CONCLUSION: La principale caractéristique histopathologique du syndrome néphrotique de l'enfant était la néphropathie à lésions minimales, qui était principalement cortico-sensible. MOTS-CLÉS: Syndrome néphrotique, Enfant, Histopathologie, Nigeria.

Web-based prognostic tools for oral tongue cancer: An analysis of online predictors.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) often presents with aggressive clinical behaviour that may require multimodality treatment based on reliable prognostication. We aimed to evaluate the prognostic ability of five online web-based tools to predict the clinical behaviour of OTSCC resection and biopsy samples. METHODS: A total of 135 OTSCC resection cases and 33 OTSCC biopsies were included to predict recurrence and survival. Area under the receiver operating characteristic curves (AUC), χ2 tests, and calibration plots constructed to estimate the prognostic power of each tool. RESULTS: The tool entitled 'Prediction of risk of Locoregional Recurrences in Early OTSCC' presented an accuracy of 82%. The tool, 'Head & Neck Cancer Outcome Calculator' for 10-year cancer-related mortality had an accuracy 77% and AUC 0.858. The other tool entitled 'Cancer Survival Rates' for 5-year mortality showed an accuracy of 74% and AUC of 0.723. For biopsy samples, 'Cancer Survival Prediction Calculators' predicted the recurrence free survival with an accuracy of 70%. CONCLUSIONS: Web-based tools can aid in clinical decision making of OTSCC. Three of five online web-based tools could predict recurrence risk and cancer-related mortality in resected OTSCC and one tool could help in clinical decision making for biopsy samples.

Oral squamous cell carcinoma: Effect of tobacco and alcohol on cancer location.

INTRODUCTION: The underlying factors of oral squamous cell cancers (OSCC) have been elucidated, but studies have focused little on etiological differences in affected oral cavity sites. The aim of this retrospective study was to clarify the role of carcinogen exposure in OSCC of different oral cavity areas. METHODS: A cross-sectional study of patients with primary OSCC was conducted retrospectively, based on patient records from Helsinki University Hospital, Finland, between January 2016 and December 2020. The patients' self-reported history of tobacco smoking and alcohol use was explained by tumor site, age, sex, tumor size, and lymph node status in a logistic regression model. The information on smoking and alcohol use was compiled from a patient background form. RESULTS: In 519 patients, tumors occurred most often in the tongue (51%), gingiva (21%), or floor of the mouth (FOM; 15%). FOM had 26-fold greater odds for a history of smoking and alcohol use than other tumor sites (OR=25.78; 95% CI: 8.02-82.95; p<0.001). Gingival and buccal sites were associated significantly less with smoking and alcohol use (OR=0.43, 95% CI: 0.28-0.67; p<0.001 and OR=0.47; 95% CI: 0.25-0.92; p<0.026, respectively). Patients of older age were less likely to have a history of smoking and alcohol use (AOR=0.95; 95% CI: 0.94-0.97; p<0.001) than younger patients. Tumor size (T3-4) and FOM increased the odds for history of smoking and alcohol use (AOR=1.73; 95% CI: 1.15-2.60; p=0.009 and AOR=26.15; 95% CI: 8.01-84.84; p<0.001, respectively). CONCLUSIONS: OSCC of oral cavity sites has notable differences in etiology. FOM seems to be related almost exclusively to conventional smoking and heavy alcohol use.

Plasma-based proteomic profiling identifies the distinct regulation of proteins in hyperplasia and endometrial cancer.

BACKGROUND: Among gynaecological malignancies, endometrial cancer (EC) is the most prevalent type of uterine cancer affecting women. This study explored the proteomic profiles of plasma samples obtained from EC patients, those with hyperplasia (Hy), and a control group (CO). A combination of techniques, such as 2D-DIGE, mass spectrometry, and bioinformatics, including pathway analysis, was used to identify proteins with modified expression levels, biomarkers and their associated metabolic pathways in these groups. METHODS: Thirty-four patients, categorized into three groups-10 with EC, 12 with Hy, and 12 CO-between the ages of 46 and 75 years old were included in the study. Untargeted proteomic analysis was carried out using two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: In all three groups, 114 proteins that were significantly (p ≤ 0.05 and fold change ≥ 1.5) altered were successfully identified using peptide mass fingerprints (PMFs). Compared with those in the control group (CO), the EC samples had 85 differentially expressed proteins (39 upregulated and 46 downregulated), and in the Hy group, 81 proteins were dysregulated (40 upregulated and 41 downregulated) compared to those in the CO group, while 33 proteins exhibited differential regulation (12 upregulated and 21 downregulated) in the EC plasma samples compared to those in the Hy group. Vitamin D binding protein and complement C3 distinguished Hy and EC from CO with the greatest changes in expression. Among the differentially expressed proteins identified, enzymes with catalytic activity represented the largest group (42.9%). In terms of biological processes, most of the proteins were involved in cellular processes (28.8%), followed by metabolic processes (16.7%). STRING analysis for protein interactions revealed that the significantly differentially abundant proteins in the three groups are involved in three main biological processes: signalling of complement and coagulation cascades, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), and plasma lipoprotein assembly, remodelling, and clearance. CONCLUSION: The identified plasma protein markers have the potential to serve as biomarkers for differentiating between EC and Hy, as well as for early diagnosis and monitoring of cancer progression.

Proteomics of Penicillium chrysogenum for a Deeper Understanding of Lead (Pb) Metal Bioremediation.

Penicillium chrysogenum (P. chrysogenum), a ubiquitous filamentous fungus, has demonstrated remarkable potential in the bioremediation of lead-contaminated environments. Its inherent tolerance and bioaccumulation capacity for lead (Pb), coupled with its relatively rapid growth rate, make it an attractive candidate for bioremediation applications. This study aims to identify the proteomic changes in P. chrysogenuminduced by Pb metal stress and unravel the roles of identified proteins in molecular mechanisms and cellular responses. Untargeted proteomic analysis was carried out using a two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). This study reported the identification of 43 statistically significant proteins (24 upregulated and 19 downregulated, ANOVA, p ≤ 0.05; fold change ≥1.5) in P. chrysogenum as a consequence of Pb treatment. Proteins were grouped according to their function into 18 groups from which 13 proteins were related to metabolism, 11 were related to cellular process and signaling, and 19 proteins were related to information storage and processing. The current study is considered the first report about the proteomics study of P. chrysogenum under Pb stress conditions, where upregulated proteins could better explain the mechanism of tolerance and Pb toxicity removal. Our research has provided a thorough understanding of the molecular and cellular processes involved in fungal-metal interactions, paving the way for the development of innovative molecular markers for heavy metal myco-remediation. To the best of our knowledge, this study of P. chrysogenum provides valuable insights toward growing research in comprehending the metal-microbe interactions. This will facilitate development of novel molecular markers for metal bioremediation.

PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Evaluation of Stages, Treatment Protocols, and Outcomes of Colorectal Cancer among West Bank Patients.

Background: Colorectal cancer (CRC) is the second most widespread cancer among Palestinian patients. As cancer care improves in hospitals across the West Bank, services like palliative care, targeted therapy, bone marrow transplantation, and individualized therapy are still limited. This study aimed to assess the CRC stages, treatment protocols, and survival rates of patients in the West Bank. Methodology: This retrospective study collected data from the medical records of Al-Najah University Hospital (NUH), which specializes in the care of cancer patients. Patients with confirmed CRC (stages I-IV) undergoing surgical or medical treatment were included in the study. Data collection was standardized by using a data collection form to gather information from the medical records included in the study. All statistical analyses were performed using SPSS (version v27), and survival was assessed using a regression analysis of the number of days from the time of diagnosis to the most recent visit against the type of treatment (e.g., surgery, chemotherapy, radiotherapy). Results: A sample of 252 patients with CRC from NUH was collected, including 143 males and 109 females aged between 27 and 86 years, with the average age being 60.6 ± 11.4 years. The sample included 183 patients (72.6%) diagnosed with colon cancer only, 29 patients (11.5%) diagnosed with rectal cancer only, and 40 patients (15.9%) diagnosed with both. Diagnosis took place at CRC stage I for 3 patients (1.2%), stage II for 33 patients (13.1%), stage III for 57 patients (22.6%), and stage IV for 159 patients (63.1%). Surgery was the most prevailing mode of treatment for 230 patients (91.3%), while 227 patients (90.1%) received chemotherapy treatment, and 38 patients (15.1%) received radiotherapy. Of the 252 patients, 40 patients (15.8%) received FOLFOX (i.e., folinic acid, fluorouracil, oxaliplatin), and 25 patients (9.9%) received FOLFIRI (i.e., folinic acid, fluorouracil, irinotecan), while the 187 remaining patients (74.2%) were treated with capecitabine, oxaliplatin, bevacizumab, cetuximab, regorafenib, cisplatin, etoposide, gemcitabine, or a combination thereof. The sample was categorized into six outcomes: (1) death, (2) cure, (3) disease progression, (4) disease recurrence, (5) under-treatment, and (6) unknown. Mortality was high, with 104 patients (41.3%) dying within a short time after diagnosis, and may have been attributable to delayed diagnosis. Surgical treatment had a positive impact on increasing the survival years, and it was significant (p = 0.033). Conclusions: A high percentage of patients were diagnosed in advanced CRC stages. The treatment modes were adopted from general international guidelines; however, the cure rates were low, and mortality was high. More studies need to be undertaken to investigate the actual application of chemotherapy protocols, and survival would benefit from the involvement of clinical pharmacists in the chemotherapy protocol selection, dosing, frequency, and follow-up. The present study advocates for greater public awareness of CRC and attests to the merits of screening by primary care professionals, which can help to avoid this serious illness and to promote a better prognosis.

Proton Pump Inhibitors and Cancer Risk: A Comprehensive Review of Epidemiological and Mechanistic Evidence.

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.

Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1).

Central and peripheral mechanisms of the endocannabinoid system (ECS) favor energy intake and storage. The ECS, especially cannabidiol (CBD) receptors, controls adipocyte differentiation (hyperplasia) and lipid accumulation (hypertrophy) in adipose tissue. In white adipose tissue, cannabidiol receptor 1 (CB1) stimulation increases lipogenesis and inhibits lipolysis; in brown adipose tissue, it decreases mitochondrial thermogenesis and biogenesis. This study compared the availability of phytocannabinoids [CBD and Δ9-tetrahydrocannabinol (THC)] and polyunsaturated fatty acids [omega 3 (ω3) and omega 6 (ω6)] in different hemp seed oils (HSO). The study also examined the effect of HSO on adipocyte lipid accumulation by suppressing cannabinoid receptors in adipogenesis-stimulated human mesenchymal stem cells (hMSCs). Most importantly, Oil-Red-O' and Nile red tests showed that HSO induced adipogenic hMSC differentiation without differentiation agents. Additionally, HSO-treated cells showed increased peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to controls (hMSC). HSO reduced PPARγ mRNA expression after differentiation media (DM) treatment. After treatment with HSO, DM-hMSCs had significantly lower CB1 mRNA and protein expressions than normal hMSCs. HSO treatment also decreased transient receptor potential vanilloid 1 (TRPV1), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MGL) mRNAs in hMSC and DM-hMSCs. HSO treatment significantly decreased CB1, CB2, TRPV1, and G-protein-coupled receptor 55 (GPCR55) protein levels in DM-hMSC compared to hMSC in western blot analysis. In this study, HSO initiated adipogenic differentiation in hMSC without DM, but it suppressed CB1 gene and protein expression, potentially decreasing adipocyte lipid accumulation and lipogenic enzymes.

Building Synthetic Cells─From the Technology Infrastructure to Cellular Entities.

The de novo construction of a living organism is a compelling vision. Despite the astonishing technologies developed to modify living cells, building a functioning cell "from scratch" has yet to be accomplished. The pursuit of this goal alone has─and will─yield scientific insights affecting fields as diverse as cell biology, biotechnology, medicine, and astrobiology. Multiple approaches have aimed to create biochemical systems manifesting common characteristics of life, such as compartmentalization, metabolism, and replication and the derived features, evolution, responsiveness to stimuli, and directed movement. Significant achievements in synthesizing each of these criteria have been made, individually and in limited combinations. Here, we review these efforts, distinguish different approaches, and highlight bottlenecks in the current research. We look ahead at what work remains to be accomplished and propose a "roadmap" with key milestones to achieve the vision of building cells from molecular parts.

Network Polymer Properties Engineered Through Polymer Backbone Dispersity and Structure.

Dispersity (Ð or Mw/Mn) is an important parameter in material design and as such can significantly impact the properties of polymers. Here, polymer networks with independent control over the molecular weight and dispersity of the linear chains that form the material are developed. Using a RAFT polymerization approach, a library of polymers with dispersity ranging from 1.2-1.9 for backbone chain-length (DP) 100, and 1.4-3.1 for backbone chain-length 200 were developed and transformed to networks through post-polymerization crosslinking to form disulfide linkers. The tensile, swelling, and adhesive properties were explored, finding that both at DP 100 and DP 200 the swelling ratio, tensile strength, and extensibility were superior at intermediate dispersity (1.3-1.5 for DP 100 and 1.6-2.1 for DP 200) compared to materials with either substantially higher or lower dispersity. Furthermore, adhesive properties for materials with chains of intermediate dispersity at DP 200 revealed enhanced performance compared to the very low or high dispersity chains.

Plasma Proteomic Signature of Endometrial Cancer in Patients with Diabetes.

The incidence and mortality of endometrial cancer (EC) have increased in recent years. There is mounting evidence that diabetes may play a role in the greater incidence of EC. The molecular mechanisms of the interaction between type 2 diabetes and EC are not yet clearly understood yet. The present study was undertaken to investigate the plasma proteomics of EC patients with diabetes in comparison to those of EC patients without diabetes. Plasma samples were obtained from age-matched patients (EC diabetic and EC nondiabetic). Untargeted proteomic analysis was carried out using a two-dimensional differential gel electrophoresis coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Of the 33 proteins identified, which significantly differed in the plasma abundance between groups, 17 were upregulated and 16 were downregulated. The majority of the altered proteins are involved in the acute phase reaction, cholesterol metabolism, scavenging of heme from plasma, and plasma lipoprotein assembly and mobilization. α-2-macroglobulin, Ras association domain-containing protein 3, apolipoprotein A-I, α-1B-glycoprotein, and zinc-α-2-glycoprotein were significantly upregulated. The significantly downregulated proteins included haptoglobin, apolipoprotein A-IV, hemopexin, and α-1-antichymotrypsin. The differential expression of proteins found in patients who had EC and diabetes indicated severe disease and a poor prognosis. The protein interaction analysis showed dysregulation of cholesterol metabolism and heme scavenging pathways in these patients.

Alkyl chain functionalised Ir(iii) complexes: synthesis, properties and behaviour as emissive dopants in microemulsions.

Six iridium(iii) complexes of the general form [Ir(C^N)2(N^N)]X (where C^N = cyclometalating ligand; N^N = disubstituted 2,2'-bipyridine), and incorporating alkyl chains of differing lengths (C8, C10, C12), have been synthesised and characterised. The complexes have been characterised using a variety of methods including spectroscopies (NMR, IR, UV-Vis, luminescence) and analytical techniques (high resolution mass spectrometry, cyclic voltammetry, X-ray diffraction). Two dodecyl-functionalised complexes were studied for their behaviour in aqueous solutions. Although the complexes did not possess sufficient solubility to determine their critical micelle concentrations (CMC) in water, they were amenable for use as emissive dopants in a N-methyl C12 substituted imidazolium salt microemulsion carrier system with a CMC = 36.5 mM. The investigation showed that the metal doped microemulsions had increased CMCs of 40.4 and 51.3 mM and luminescent properties characterised by the dopant.

From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy.

Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are often undervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating on exciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions.

Expression Patterns of ER, PR, HER-2/neu and p53 in Association with Nottingham Tumour Grade in Breast Cancer Patients.

Objectives: Recent molecular studies show that breast cancer (BC) is a heterogeneous disease, and several molecular changes may accumulate over time to influence treatment response. As a result, employing reliable molecular biomarkers to monitor these modifications may help deliver personalised treatment. However, this may be unrealistic in the resource-limited parts of the world. Thus, this study aimed to investigate the expression pattern of hormone receptors and p53 tumour suppressor using immunohistochemistry (IHC) in BC compared to the traditional tumour grade. Methods: In total, 205 cases were investigated, and the Modified Bloom-Richardson score system was adopted in grading the tumours. The tissue sections of the cases were stained with specific primary antibodies at dilutions of 1:60 for oestrogen receptors (ER) and progesterone receptors (PR), 1:350 for the human epidermal growth factor (HER-2/neu) and 1:50 for p53. Results: Invasive ductal carcinoma of no-specific type (n = 190, 92.7%) was predominant and grade II tumour (n = 146, 71.2%) was the most frequent. Hormone receptors ER (n = 127) and PR (n = 145) had 62.0% and 70.7% positive cases, respectively; 34.1% (n = 70) were positive for HER-2/neu, while 76.1% (n = 156) were positive for p53. Significant associations between Nottingham grade and expression patterns of ER (P <0.01), PR (P <0.001), HER-2/neu (P <0.001) and p53 (P = 0.001) were observed. Conclusion: Nottingham grade had a high degree of concordance with the patterns of expression of hormone receptors, HER-2/neu and p53, suggesting that it may play an important role in connection with the predictive and prognostic biomarkers for BC.

Health-Related Quality of Life and Its Determinants Among Hypertensive Patients in Rural Southwest Nigeria.

BACKGROUND: The health-related quality of life (HRQOL) of patients with hypertension is of particular concern to stakeholders because hypertension is a chronic disease. OBJECTIVES: To determine the pattern of HRQOL and its determinants among hypertensive patients in rural Southwestern Nigeria. SUBJECTS, MATERIALS AND METHODS: Ahospital-based crosssectional survey was conducted between June and October 2019 on 390 consented adult patients with hypertension on follow-up using systematic sampling technique. Respondents'blood pressure (BP), body mass index (BMI), waist circumference (WC), waist-hip ratio (W-HR) and other measurements were taken. Relevant data on socio-demographics and lifestyle behaviours were collected using an interviewer-administered questionnaire which incorporated validated instrument for assessment of HRQOL score using SF-12 survey. The data were analyzed using SPSS (version 21). Binary logistic regression was used to identify the determinants of HRQOL. RESULTS: The mean physical component summary (42.0 ± 8.44), mental component summary (40.6 ± 8.11), and mean overall quality of life score (41.3 ± 8.17) were all below the normal score of 50 ±10. However, of all the eight domains, the role emotional was the highest (47.61 ± 14.97). The odds of having overall good HRQOL were better with respondents with female gender (AOR=1.99, 95% CI: 1.05-3.88), tertiary education (AOR=3.22, 95% CI: 1.63-7.20), and controlled BP (AOR=3.01,95% CI: 1.04-15.79). CONCLUSION: The mean HRQOLscore of the respondents was below the mean score. The findings of this study would assist stakeholders in decision-making towards improved management of patients with hypertension.

CONTEXTE: La qualité de vie liée à la santé (HRQOL) des patients hypertendus est une préoccupation particulière pour les parties prenantes car l'hypertension est une maladie chronique. OBJECTIFS: Déterminer le modèle de la HRQOL et ses déterminants chez les patients hypertendus en milieu rural du sud-ouest du Nigéria. SUJETS, MATÉRIAUX ET MÉTHODES: Une enquête transversale hospitalière a été menée entre juin et octobre 2019 sur 390 patients adultes atteints d'hypertension en suivi, consentis, en utilisant une technique d'échantillonnage systématique. La pression artérielle (PA), l'indice de masse corporelle (IMC), la circonférence de la taille (CT), le rapport taillehanche (W-HR) et d'autres mesures ont été prises chez les répondants. Les données pertinentes sur les caractéristiques sociodémographiques et les comportements liés au mode de vie ont été collectées à l'aide d'un questionnaire administré par un enquêteur, intégrant un instrument validé pour l'évaluation du score HRQOL à l'aide de l'enquête SF-12. Les données ont été analysées à l'aide de SPSS (version 21). La régression logistique binaire a été utilisée pour identifier les déterminants de la HRQOL. RÉSULTATS: Le résumé de la composante physique (42,0 ± 8,44), la composante mentale (40,6 ± 8,11) et le score moyen de qualité de vie global (41,3 ± 8,17) étaient tous en dessous du score normal de 50 ± 10. Cependant, de tous les huit domaines, le rôle émotionnel était le plus élevé (47,61 ± 14,97). Les chances d'avoir une HRQOL globale satisfaisante étaient meilleures chez les répondants de sexe féminin (AOR=1,99, IC à 95 % : 1,05-3,88), ayant une éducation tertiaire (AOR=3,22, IC à 95 % : 1,63-7,20) et une PAcontrôlée (AOR=3,01, IC à 95 % : 1,04-15,79). CONCLUSION: Le score moyen de HRQOL des répondants était en dessous du score moyen. Les résultats de cette étude aideront les parties prenantes dans la prise de décision en vue d'une meilleure gestion des patients hypertendus. Mots-clés: Qualité de vie globale, Déterminants, Hypertension, Nigéria rural.

Efficient Protocol for Novel Hybrid Pyrimidines Synthesis: Antiproliferative Activity, DFT Analyses, and Molecular Docking Studies.

An efficient, microwave/ultrasound-irradiated synthesis of novel chromenopyrimidines has been established. 2-Amino-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (1) underwent cyclization reactions with various assorted reagents under sustainable conditions to afford a family of fused pyrimidine derivatives. The proposed structures of the designed fused pyrimidines were confirmed by several spectral techniques. Moreover, the targeted pyrimidines were estimated for their in vitro cytotoxic activities toward three carcinoma cell lines: breast (MCF7), hepatocyte (HepG2), and lung (A549) cancer cell lines, as well as one noncancerous cell line (MCF-10A). Structure-activity relationship (SAR) analyses revealed that derivatives 3 and 7 exhibited the highest potency in inhibiting the growth of cancer cells tested in vitro. Particularly, 3-amino-4-imino-5-(thiophen-2-yl)-3,4,5,7,8,9-hexahydro-6H-chromeno[2,3-d]pyrimidin-6-one (3) displayed a robust impact with IC50 values ranging from 2.02 to 1.61 µM. Interestingly, compound 3 was observed to have low cytotoxicity toward noncancerous cell (MCF-10A) compared to the standard drug (Doxorubicin). Further, quantum chemical computations of the designed molecules utilizing density functional theory (DFT) were conducted and shown to be compatible with the observed antiproliferative properties. Thorough docking investigations revealed that the assembled compounds possess exceptionally low binding energies toward our three selected proteins: 4b3z-Lung, HepG2-2JW2, and 6ENV-MCV-7. Based on these intriguing results, compound 3 could be further evaluated for preclinical screening, potentially paving the way for its utilization as a promising cancer treatment.

Controlling primary chain dispersity in network polymers: elucidating the effect of dispersity on degradation.

Although dispersity has been demonstrated to be instrumental in determining many polymer properties, current synthetic strategies predominantly focus on tailoring the dispersity of linear polymers. In contrast, controlling the primary chain dispersity in network polymers is much more challenging, in part due to the complex nature of the reactions, which has limited the exploration of properties and applications. Here, a one-step method to prepare networks with precisely tuned primary chain dispersity is presented. By using an acid-switchable chain transfer agent and a degradable crosslinker in PET-RAFT polymerization, the in situ crosslinking of the propagating polymer chains was achieved in a quantitative manner. The incorporation of a degradable crosslinker, not only enables the accurate quantification of the various primary chain dispersities, post-synthesis, but also allows the investigation and comparison of their respective degradation profiles. Notably, the highest dispersity networks resulted in a 40% increase in degradation time when compared to their lower dispersity analogues, demonstrating that primary chain dispersity has a substantial impact on the network degradation rate. Our experimental findings were further supported by simulations, which emphasized the importance of higher molecular weight polymer chains, found within the high dispersity materials, in extending the lifetime of the network. This methodology presents a new and promising avenue to precisely tune primary chain dispersity within networks and demonstrates that polymer dispersity is an important parameter to consider when designing degradable materials.