Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.

Glioblastoma multiforme is a universally lethal brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness and heterogeneity of these tumors has made it challenging to develop effective therapies. Therapeutic oligonucleotides-antisense oligonucleotides and small-interfering RNAs-are chemically modified nucleic acids that can silence gene expression in the brain. However, activity of these oligonucleotides in brain tumors remains inadequately characterized. In this study, we developed a quantitative method to differentiate oligonucleotide-induced gene silencing in orthotopic GBM xenografts from gene silencing in normal brain tissue, and used this method to test the differential silencing activity of a chemically diverse panel of oligonucleotides. We show that oligonucleotides chemically optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. We then survey multiple advanced oligonucleotide chemistries for their activity in GBM xenografts. Attaching lipid conjugates to oligonucleotides improves silencing in GBM cells across several different lipid classes. Highly hydrophobic lipid conjugates cholesterol and docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic, unsaturated fatty acid and amphiphilic lipid conjugates still improve activity without compromising safety. These oligonucleotide conjugates show promise for treating glioblastoma.

Identification of mitogen-activated protein kinase 7 inhibitors from natural products: Combined virtual screening and dynamic simulation studies.

Mitogen-activated protein kinase 7 (MAPK7) is a serine/threonine protein kinase that belongs to the MAPK family and plays a vital role in various cellular processes such as cell proliferation, differentiation, gene transcription, apoptosis, metabolism, and cell survival. The elevated expression of MAPK7 has been associated with the onset and progression of multiple aggressive tumors in humans, underscoring the potential of targeting MAPK7 pathways in therapeutic research. This pursuit holds promise for the advancement of anticancer drug development by developing potential MAPK7 inhibitors. To look for potential MAPK7 inhibitors, we exploited structure-based virtual screening of natural products from the ZINC database. First, the Lipinski rule of five criteria was used to filter a large library of ~90,000 natural compounds, followed by ADMET and pan-assay interference compounds (PAINS) filters. Then, top hits were chosen based on their strong binding affinity as determined by molecular docking. Further, interaction analysis was performed to find effective and specific compounds that can precisely bind to the binding pocket of MAPK7. Consequently, two compounds, ZINC12296700 and ZINC02123081, exhibited significant binding affinity and demonstrated excellent drug-like properties. All-atom molecular dynamics simulations for 200 ns confirmed the stability of MAPK7-ZINC12296700 and MAPK7-ZINC02123081 docked complexes. According to the molecular mechanics Poisson-Boltzmann surface area investigation, the binding affinities of both complexes were considerable. Overall, the result suggests that ZINC12296700 and ZINC02123081 might be used as promising leads to develop novel MAPK7 inhibitors. Since these compounds would interfere with the kinase activity of MAPK7, therefore, may be implemented to control cell growth and proliferation in cancer after required validations.

Applying the structural equation model approach to study the simultaneous relationship between women's empowerment and mental disorder in Egypt.

PURPOSE: The main purpose of this paper is to examine whether women's empowerment and mental disorder affect each other in a one-way or two-way simultaneous relationship. Accordingly, the study fills a gap in the literature since it is the first attempt to examine the simultaneous relationship between women's empowerment and mental disorder in Egypt. To achieve this, the study aims to examine the most important dimensions of women's empowerment and mental disorder that affect each other simultaneously, and the most important determinants affecting women's empowerment and mental disorder. DESIGN/METHODOLOGY/APPROACH: The study depends on the cross-sectional data from the "Survey of Young People in Egypt" implemented in 2014. Married women aged 14-35 are included in the analysis (N = 3052). Recursive and nonrecursive structural equation models are used to examine the simultaneous relationship between women's empowerment and mental disorder using AMOS, which stands for Analysis of Moment Structures (Version 22). RESULTS: Women's education has a positive significant impact on women's empowerment and mental health. Violence has a positive significant impact on mental disorder, while it has a negative impact on women's empowerment. Sexual harassment has a negative impact on treatment with spouse dimension. Regarding the one-way relationship, the results show that the more empowered the woman, the better her mental health is. Considering the two-way simultaneous relationship, the findings show that there is a partial two-way simultaneous relationship. CONCLUSION: There is a relationship between women's empowerment and mental health, indicating that they affect each other simultaneously. Awareness of the importance of psychological counselling and treatment for mental disorders in women is needed.

Impact of allergic rhinitis on quality of life in patients with chronic rhinosinusitis.

OBJECTIVES: To evaluate the impact of allergic rhinitis (AR) on the quality of life (QoL) in patients with chronic rhinosinusitis (CRS). METHODS: Retrospective cross-sectional study of adult patients with CRS presenting to our clinic between August 2020 and February 2023 was performed. AR was diagnosed based on a positive skin or blood allergy test. Patients' characteristics, AR status, comorbidities, endoscopy scores, and SNOT-22 scores were collected. RESULTS: A total of 514 CRS patients were included, with 265 (51.6 %) patients with AR. CRS patients with AR were younger (p = 0.004), more likely to be female (p < 0.001), and more likely to have asthma (p < 0.001). Polyp status and endoscopy scores did not differ between patients with and without AR. Baseline SNOT-22 scores were slightly worse in the AR cohort (43.6 vs 38.7, p = 0.007), which was mainly secondary to rhinologic (p = 0.002), extrarhinologic (p = 0.007), and ear/facial (p = 0.007) subdomains. Worse rhinologic and extrarhinologic scores were associated with the presence of AR after adjusting for confounding variables (Coef = 1.55, p = 0.011; and Coef = 0.83, p = 0.021 respectively). CONCLUSION: The impact of allergic rhinitis on QoL is mainly on the nasal symptoms. Further studies should look at the role of AR on the QoL of different CRS endotypes; and at the role of AR-specific treatment, such as immunotherapy, on the QoL of patients with CRS.

Association of autoimmune disorders with chronic rhinosinusitis in adults.

INTRODUCTION: Increasing evidence suggests that autoimmune disorders and their immunomodulating medications may increase the risk of rhinosinusitis compared to rhinitis. GOAL: To investigate the association between autoimmune disorders and rhinosinusitis. METHODS: We performed a case-control study of patients referred to West Virginia University from August 2020 to October 2022 for rhinologic complaints. Rhinosinusitis patients were diagnosed with either chronic rhinosinusitis (CRS) or recurrent acute rhinosinusitis (RARS). These patients were compared to non-rhinosinusitis patients. Patients' characteristics, comorbidities, and type of treatment of autoimmune disorders were reviewed. RESULTS: The sample consisted of 527 rhinosinusitis [184 CRS without nasal polyps (CRSsNP), 263 CRS with nasal polyps (CRSwNP) and 80 RARS patients] patients and 564 non-rhinosinusitis patients. Patients with rhinosinusitis were more likely to be older, males, have asthma, and have current and past smoking history (all with p-value < 0.05). Autoimmune disorders, primary antibody deficiency, and immunomodulator agents were more common in rhinosinusitis patients (16.5 % vs 9.4 %, OR = 1.9, p < 0.001; 5.1 % vs 0.5 %, OR = 10.1, p < 0.001; and 3.8 % vs 1.1 %, OR = 3.7, p = 0.003 respectively). Multivariate logistic regression adjusting for confounders showed that autoimmune disorders were strongly associated with rhinosinusitis [OR = 1.6, 95 % CI = 1.10-2.48], whereas the immunomodulators did not reach statistical significance [OR = 2.4, 95 % CI = 0.87-6.47]. Subgroup analysis showed the autoimmune disorders did not significantly differ between CRS and RARS groups [OR = 1.0, 95 % CI = 0.5-2.1], or between the CRSsNP and CRSwNP groups [OR = 0.9, 95 % CI = 0.5-1.7]. CONCLUSION: Autoimmune disorders are associated with rhinosinusitis, both CRS and RARS, independently of other risk factors.

Pediatric chronic rhinosinusitis.

PURPOSE: An up-to-date overview of diagnosis, differential diagnosis, comorbidities, and current medical and surgical management of pediatric chronic rhinosinusitis (PCRS). METHODS: Review of current evidence-based literature on PCRS. RESULTS: Diagnosis of PCRS seems to be improving based on recent evidence using nasal endoscopy as well as computed tomography scanning. Recent literature supports the fact that chronic adenoiditis can be an independent etiology of symptoms of chronic sinusitis, that are very similar to chronic adenoiditis. Allergic rhinitis and immune deficiency play important roles in the management of PCRS. Surgery for PCRS has evolved significantly in the last 15-20 years to include adenoidectomy as well as endoscopic sinus surgery. CONCLUSIONS: PCRS is very common in children causing poor QOL for these children. Medical management remains the main stay of treatment with attention to management of co-morbidities that may contribute to the disease severity. Making the correct diagnosis will help with the choice of surgical intervention if medical management fails.

Recycling air conditioner-generated condensate water for microalgal biomass production and carbon dioxide sequestration.

Air conditioners alleviate the discomfort of human beings from heat waves that are consequences of climate change caused by anthropogenic activities. With each passing year, the effects of global warming worsen, increasing the growth of air conditioning industry. Air conditioning units produce substantial amounts of non-nutritive and (generally) neglected condensate water and greenhouse gases. Considering this, the study explored the potential of using air conditioner condensate water (ACW) to cultivate Chlorella sorokiniana, producing biomass, and sequestering carbon dioxide (CO2). The maximum biomass production was obtained in the BG11 medium (1.45 g L-1), followed by ACW-50 (1.3 g L-1). Similarly, the highest chlorophyll-a content was observed in the BG11 medium (11 µg mL-1), followed by ACW-50 (9.11 µg mL-1). The ACW-50 cultures proved to be better adapted to physiological stress (Fv/Fm > 0.5) and can be suitable for achieving maximum biomass with adequate lipid, protein, and carbohydrate production. Moreover, C. sorokiniana demonstrated higher lipid and carbohydrate yields in the ACW-50 medium, while biomass production and protein yields were comparable to the BG11 medium. The lipid, protein, and carbohydrate productivity were 23.43, 32.9, and 23.19 mg L-1 d-1, respectively for ACW-50. Estimation of carbon capture potential through this approach equals to 9.5% of the total emissions which is an added advantage The results indicated that ACW could be effectively utilized for microalgae cultivation, reducing the reliance on freshwater for large-scale microalgal biomass production and reduce the carbon footprints of the air conditioning industry.

Stabilization of Functional DNA Structures with Mild Photochemical Methods.

A significant barrier to biological applications of DNA structures is their instability to nucleases. UV-mediated thymine dimerization can crosslink and stabilize DNA nanostructures, but its effect on DNA strand hybridization fidelity and function is unclear. In this work, we first compare a number of methods for DNA irradiation with different wavelengths of light and different photosensitizers. We demonstrate that all approaches can achieve nuclease protection; however, the levels of DNA off-target crosslinking and damage vary. We then describe mild irradiation conditions intended to safeguard DNA against nuclease degradation. We demonstrate up to 25× increase in serum stability while minimizing off-target damage and maintaining functions such as hybridization efficiency, gene silencing, aptamer binding, and DNA nanostructure formation. Our methodology requires no complex instruments beyond a UV light source and no synthetic modification of the DNA itself, allowing for applications in numerous areas of nucleic acid therapy and nanotechnology.

The Vitamin D Binding Protein Gene Polymorphism Association with Covid-19-Infected Iraqi Patients.

Vitamin D deficiency, in general, is usually correlated with increased risks of chronic pulmonary disease such as COVID-19 infection. However, the mechanisms are still unknown. Herein, this study aimed to investigate the correlation between vitamin D binding protein gene polymorphism and COVID-19-infected Iraqi patients. The study has been conducted on patients with Covid-19 during the period extended from June, 2021 to April, 2022. 300 samples were collected from healthy and infected people. The demographic characteristics of patients (age, gender and residency) are shown non-significant in all. However, the distribution of DBP (rs12785878-T/G) Polymorphism was detected by Allele Specific PCR technique. The association between DBP (rs12785878) gene polymorphism and risk of Covid-19 is also shown, the heterozygous genotype TG was more frequent in the patients' group in comparison with the control group, 66 versus 58, respectively. Therefore, genotype TG was a genetic risk factor for Covid-19 with an odds ratio of 2.4074 (95% confidence interval of 1.2462-4.6505) and an etiologic fraction of 0.2963. In the addition, the homozygous genotype GG was more frequent in the patients' group in comparison with the control group, 65 versus 54, respectively, Therefore, genotype GG was a risk factor for Covid-19 with an odds ratio of 1.0578 (95% confidence interval of 0.6386-1.7522) and an etiologic fraction of 0.0299. thus, it can be seen that Covid-19 disease has a direct effect on the level of vitamin D in patients infected with the virus compared to healthy people.

Chiral Recognition of Amino Acids Using CC2 Porous Organic Cages.

Enantiomers have the same physical properties but different chemical properties due to the difference in the orientation of groups in space and thus Chiral discrimination is quite necessary, as an enantiomer of drug can have lethal effects. In this study, we used the CC2 cage for chiral discrimination of amino acids using density functional theory. The results indicated the physisorption of amino acids in the central cavity of the cage. Among the four selected amino acids, proline showed maximum interactions with the cage and maximum chiral discrimination energy is also observed in the case of proline that is 2.78 kcal/mol. Quantum theory of atoms in molecules and noncovalent interaction index analyses showed that the S enantiomer in each case has maximum interactions. The charge transfer between the analyte and surface is further studied through natural bond orbital analysis. It showed sensitivity of cage for both enantiomers, but a more pronounced effect is seen for S enantiomers. In frontier molecular orbital analysis, the least EH-L gap is observed in the case of R proline with a maximum charge transfer of -0.24 e-. Electron density difference analysis is carried out to analyze the pattern of the charge distribution. The partial density of state analysis is computed to understand the contribution of each enantiomer in overall density of the complexes. Our results show that S-CC2 porous organic cages have a good ability to differentiate between two enantiomers. S-CC2 porous organic cages efficiently differentiated the S enantiomer from the R enantiomers of selected amino acids.

Effect of magnetized water on blood indices and histomorphometric parameters of intestinal sections of Japanese quail.

A two-way experimental design was used to demonstrate the physiological effects of magnetized water and sex on blood indices and histomorphometric parameters of Japanese quail intestine sections. Red blood cell count (RBCs), packed cell volume (PCV), hemoglobin concentration (Hb), thrombocytes, white blood cell count (WBCs), and WBC differentiation were investigated. A total of 450 unsexed Japanese quail were randomized into three groups (45/replicate; 3 replicates; 135/group). As a monitoring group, the first group was given untreated tap water to drink. The two others were consumed magnetized water that were subjected to an electrical magnetic field with a power of 1 Tesla (10,000 Gauss) and 2 Tesla (20,000 Gauss), respectively. The treatments had a significant (p ≤ 0.05) effect on thrombocytes and Hb. Sex showed significant (p ≤ 0.05) differences for RBCs and PCV at 42 days of age. At different ages, significant effects were observed on histomorphometric parameters of the Japanese quail intestinal tract. It may be inferred that the influence of magnetized water, up to 1 Tesla, was positive on the haematological and histomorphometric parameters of the Japanese quail intestinal tract by augmenting the haematological measurements, which were within a normal range and increasing the surface area of the villus.

Using the sino-nasal outcome test (SNOT-22) to study outcome of treatment of nasal obstruction.

OBJECTIVE: To validate the sino-nasal outcome test (SNOT-22) as an outcome measure for nasal obstruction, and to determine if it correlates with the nasal obstruction and septoplasty effectiveness (NOSE) scale. STUDY DESIGN: Prospective cohort study. METHODS: All patients presenting to our otolaryngology clinic for nasal obstruction secondary to nasal septal deviation and/or inferior turbinate hypertrophy between August 2020 and June 2022 were asked to fill both the SNOT-22 and the NOSE questionnaires. Demographics and comorbidities were reviewed. Patients with chronic rhinosinusitis (CRS) were excluded. SNOT-22 total and subdomain scores were then compared to NOSE scores. RESULTS: 126 patients completed both surveys. Average age was 42.6 years (range 13.8-78.3 years), and 40.5 % were female. 35 patients had septoplasty and inferior turbinoplasty (IT), 34 had functional septorhinoplasty and IT, 6 patients had IT, 7 had nasal septal perforation repair and 44 patients had medical treatment. Overall, SNOT-22 and NOSE scores correlated well preoperatively and postoperatively (r = 0.54, p < 0.0001; r = 0.68, p < 0.0001 respectively). The rhinologic and sleep SNOT-22 subdomains scores had the strongest correlation to NOSE score (r = 0.56, p < 0.0001; r = 0.64, p < 0.0001 respectively). Both NOSE and SNOT-22 scores showed improvement postoperatively [NOSE: 67.4 vs 25.1 (p < 0.0001) at 3 months, 69.5 vs 34 (p < 0.0001) at 6 months; SNOT-22: 37.1 vs 25.2 (p = 0.002) at 3 months, 38.1 vs 22.6 (p = 0.002) at 6 months]. No significant improvement in NOSE or SNOT scores was seen in the medical treatment group. CONCLUSION: SNOT-22 instrument can be used to study the outcome of treatment for nasal obstruction secondary to nasal septal deviation and/or inferior turbinate hypertrophy.

Genomic signatures for drylands adaptation at gene-rich regions in African zebu cattle.

BACKGROUND: Indigenous Sudanese cattle are mainly indicine/zebu (humped) type. They thrive in the harshest dryland environments characterised by high temperatures, long seasonal dry periods, nutritional shortages, and vector disease challenges. Here, we sequenced 60 indigenous Sudanese cattle from six indigenous breeds and analysed the data using three genomic scan approaches to unravel cattle adaptation to the African dryland region. RESULTS: We identified a set of gene-rich selective sweep regions, detected mostly on chromosomes 5, 7 and 19, shared across African and Gir zebu. These include genes involved in immune response, body size and conformation, and heat stress response. We also identified selective sweep regions unique to Sudanese zebu. Of these, a 250 kb selective sweep on chromosome 16 spans seven genes, including PLCH2, PEX10, PRKCZ, and SKI, which are involved in alternative adaptive metabolic strategies of insulin signalling, glucose homeostasis, and fat metabolism. CONCLUSIONS: Our results suggest that environmental adaptation may involve recent and ancient selection at gene-rich regions, which might be under a common regulatory genetic control, in zebu cattle.

Natural adaptation and human selection of northeast African sheep genomes.

African sheep manifest diverse but distinct physio-anatomical traits, which are the outcomes of natural- and human-driven selection. Here, we generated 34.8 million variants from 150 indigenous northeast African sheep genomes sequenced at an average depth of ∼54× for 130 samples (Ethiopia, Libya) and ∼20× for 20 samples (Sudan). These represented sheep from diverse environments, tail morphology and post-Neolithic introductions to Africa. Phylogenetic and model-based admixture analysis provided evidence of four genetic groups corresponding to altitudinal geographic origins, tail morphotypes and possible historical introduction and dispersal of the species into and across the continent. Running admixture at higher levels of K (6 ≤ K ≤ 25), revealed cryptic levels of genome intermixing as well as distinct genetic backgrounds in some populations. Comparative genomic analysis identified targets of selection that spanned conserved haplotype structures overlapping clusters of genes and gene families. These were related to hypoxia responses, ear morphology, caudal vertebrae and tail skeleton length, and tail fat-depot structures. Our findings provide novel insights underpinning morphological variation and response to human-driven selection and environmental adaptation in African indigenous sheep.

Actinidia deliciosa Extract as a Promising Supplemental Agent for Hepatic and Renal Complication-Associated Type 2 Diabetes (In Vivo and In Silico-Based Studies).

Type 2 diabetes (T2D) is a chronic metabolic condition associated with obesity, oxidative stress-mediated inflammation, apoptosis, and impaired insulin signaling. The utilization of phytochemical therapy generated from plants has emerged as a promising approach for the treatment of diabetes and its complications. Kiwifruit is recognized for its substantial content of antioxidative phenolics. Therefore, this work aimed to examine the effect of Actinidia deliciosa (kiwi fruit) on hepatorenal damage in a high-fat diet (HFD) and streptozotocin (STZ)-induced T2D in rats using in vivo and in silico analyses. An increase in hepatic and renal lipid peroxidation was observed in diabetic rats accompanied by a decrease in antioxidant status. Furthermore, it is important to highlight that there were observable inflammatory and apoptotic responses in the hepatic and renal organs of rats with diabetes, along with a dysregulation of the phosphorylation levels of mammalian target of rapamycin (mTOR), protein kinase B (Akt), and phosphoinositide 3-kinase (PI3K) signaling proteins. However, the administration of kiwi extract to diabetic rats alleviated hepatorenal dysfunction, inflammatory processes, oxidative injury, and apoptotic events with activation of the insulin signaling pathway. Furthermore, molecular docking and dynamic simulation studies revealed quercetin, chlorogenic acid, and melezitose as components of kiwi extract that docked well with potential as effective natural products for activating the silent information regulator 1(SIRT-1) pathway. Furthermore, phenolic acids in kiwi extract, especially syringic acid, P-coumaric acid, caffeic acid, and ferulic acid, have the ability to inhibit the phosphatase and tensin homolog (PTEN) active site. In conclusion, it can be argued that kiwi extract may present a potentially beneficial adjunctive therapy approach for the treatment of diabetic hepatorenal complications.

Diagnostic usefulness of serum procalcitonin in patients with bacterial sepsis.

Background: The Sequential Organ Failure Assessment (SOFA) score is used for the diagnosis of sepsis and involves clinical and laboratory parameters that may not be readily and/or timely available in most resource-poor settings. Procalcitonin (PCT) has its level changed in response to bacterial sepsis and its measurement costs only a fraction of the total cost of investigations required to calculate SOFA score. This study aims to determine the diagnostic usefulness of PCT in bacterial sepsis. Materials and Methods: Ninety-nine participants were studied, divided into three groups: apparently healthy volunteers, those with bacterial infection without sepsis (SOFA score <2), and patients with bacterial sepsis (positive culture and SOFA ≥2). PCT level of each participant was measured and median group levels compared. Pearson's correlation was used to determine the correlation between serum PCT levels and SOFA scores in the sepsis group using a significance level of 5 percent (P < 0.05). Diagnostic usefulness of PCT was assessed using receiver operating characteristic (ROC). Result: Positive correlation was found between serum PCT levels and SOFA scores among patients with sepsis r = 0.42, P = 0.016. At a concentration of ≥4.25 ng/ml, serum PCT as a surrogate for SOFA score had a sensitivity and specificity of 57.60% and 84.80%, respectively, for indicating sepsis. The area under the ROC curve (AUC) was 0.74 (95% CI {0.62 to 0.86}, P = 0.001). Conclusion: Serum PCT concentration was significantly higher in bacterial sepsis compared to bacterial infection without sepsis and healthy state. PCT concentration demonstrated positive correlation with SOFA score in bacterial sepsis and can be used as surrogate for sepsis screening/monitoring in resource-poor settings.

Reprint of: Intracellular Production of Superoxide Radical and of Hydrogen Peroxide by Redox Active Compounds.

Several compounds have been found capable of diverting the electron flow in Escherichia coli and thus causing increased intracellular production of O2- and H2O2. One indication of this electron-shunting action was increased cyanide-resistant respiration and one cellular response was increased biosynthesis of the manganese-containing superoxide dismutase and of catalase. Blocking cytochrome oxidase with cyanide or azide increased the electron flow available for reduction of paraquat and presumably of the other exogenous compounds tested and thus increased their biological effects. Paraquat, pyocyanine, phenazine methosulfate, streptonigrin, juglone, menadione, plumbagin, methylene blue, and azure C were all effective in elevating intracellular production of O2- and H2O2. The effect of alloxan appeared paradoxical in that it increased cyanide-resistant respiration without significantly increasing the cell content of the manganese-superoxide dismutase and with only a small effect on the level of catalase. The alloxan effect on cyanide-resistant respiration was artifactual and was due to an oxygen-consuming reaction between alloxan and cyanide, rather than to a diversion of the intracellular electron flow. With paraquat as a representative electron-shunting compound, the increase in biosynthesis of the manganese-superoxide dismutase was prevented by inhibitors of transcription or of translation, but not by an inhibitor of replication. The increase in this enzyme activity, caused by paraquat and presumably by the other compounds, was thus due to de novo enzyme synthesis activated or derepressed at the level of transcription.

Artificial Intelligence and Machine Learning in Cancer Research: A Systematic and Thematic Analysis of the Top 100 Cited Articles Indexed in Scopus Database.

INTRODUCTION: Cancer is a major public health problem and a global leading cause of death where the screening, diagnosis, prediction, survival estimation, and treatment of cancer and control measures are still a major challenge. The rise of Artificial Intelligence (AI) and Machine Learning (ML) techniques and their applications in various fields have brought immense value in providing insights into advancement in support of cancer control. METHODS: A systematic and thematic analysis was performed on the Scopus database to identify the top 100 cited articles in cancer research. Data were analyzed using RStudio and VOSviewer.Var1.6.6. RESULTS: The top 100 articles in AI and ML in cancer received a 33 920 citation score with a range of 108 to 5758 times. Doi Kunio from the USA was the most cited author with total number of citations (TNC = 663). Out of 43 contributed countries, 30% of the top 100 cited articles originated from the USA, and 10% originated from China. Among the 57 peer-reviewed journals, the "Expert Systems with Application" published 8% of the total articles. The results were presented in highlight technological advancement through AI and ML via the widespread use of Artificial Neural Network (ANNs), Deep Learning or machine learning techniques, Mammography-based Model, Convolutional Neural Networks (SC-CNN), and text mining techniques in the prediction, diagnosis, and prevention of various types of cancers towards cancer control. CONCLUSIONS: This bibliometric study provides detailed overview of the most cited empirical evidence in AI and ML adoption in cancer research that could efficiently help in designing future research. The innovations guarantee greater speed by using AI and ML in the detection and control of cancer to improve patient experience.

Effect of 2'-5'/3'-5' phosphodiester linkage heterogeneity on RNA interference.

We report on the synthesis of siRNAs containing both 2'-5'- and 3'-5'-internucleotide linkages and their effects on siRNA structure, function, and interaction with RNAi proteins. Screening of these siRNAs against their corresponding mRNA targets showed that 2'-5' linkages were well tolerated in the sense strand, but only at a few positions in the antisense strand. Extensive modification of the antisense strand minimally affected 5'-phosphorylation of the siRNA by kinases, however, it negatively affected siRNA loading into human AGO2. Modelling and molecular dynamics simulations were fully consistent with these findings. Furthermore, our studies indicated that the presence of a single 5'p-rN1-(2'-5')-N2 unit in the antisense strand does not alter the 'clover leaf' bend and sugar puckers that are critical for anchoring the 5'-phosphate to Ago 2 MID domain. Importantly, 2'-5'-linkages had the added benefit of abrogating immune-stimulatory activity of siRNAs. Together, these results demonstrate that 2'-5'/3'-5'-modified siRNAs, when properly designed, can offer an efficient new class of siRNAs with diminished immune-stimulatory responses.

Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy.

Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.