Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance.

Cancer cells undergo phenotypic switching (cancer cell plasticity) in response to microenvironmental cues, including exposure to therapy/treatment. Phenotypic plasticity enables the cancer cells to acquire more mesenchymal traits promoting cancer cells' growth, survival, therapy resistance, and disease recurrence. A significant program in cancer cell plasticity is epithelial-to-mesenchymal transition (EMT), wherein a comprehensive reprogramming of gene expression occurs to facilitate the translational shift from epithelial-to-mesenchymal phenotypes resulting in increased invasiveness and metastasis. In addition, EMT plays a pivotal role in facilitating cancer cells' escape from the body's immune system using several mechanisms, such as the downregulation of major histocompatibility complex-mediated antigen presentation, upregulation of immune checkpoint molecules, and recruitment of immune-suppressive cells. Cancer cells' ability to undergo phenotypic switching and EMT-driven immune escape presents a formidable obstacle in cancer management, highlighting the need to unravel the intricate mechanisms underlying these processes and develop novel therapeutic strategies. This article discusses the role of EMT in promoting immune evasion and therapy resistance. We also discuss the ongoing research on developing therapeutic approaches targeting intrinsic and induced cell plasticity within the immune suppressive microenvironment. We believe this review article will update the current research status and equip researchers, clinicians, and other healthcare professionals with valuable insights enhancing their existing knowledge and shedding light on promising directions for future cancer research. This will facilitate the development of innovative strategies for managing therapy-resistant cancers and improving patient outcomes.

Role of p53-miRNAs circuitry in immune surveillance and cancer development: A potential avenue for therapeutic intervention.

The genome's guardian, p53, is a master regulatory transcription factor that occupies sequence-specific response elements in many genes and modulates their expression. The target genes transcribe both coding RNA and non-coding RNA involved in regulating several biological processes such as cell division, differentiation, and cell death. Besides, p53 also regulates tumor immunology via regulating the molecules related to the immune response either directly or via regulating other molecules, including microRNAs (miRNAs). At the post-transcriptional level, the regulations of genes by miRNAs have been an emerging mechanism. Interestingly, p53 and various miRNAs cross-talk at different regulation levels. The cross-talk between p53 and miRNAs creates loops, turns, and networks that can influence cell metabolism, cell fate, cellular homeostasis, and tumor formation. Further, p53-miRNAs circuit has also been insinuated in the regulation of immune surveillance machinery. There are several examples of p53-miRNAs circuitry where p53 regulates immunomodulatory miRNA expression, such as miR-34a and miR-17-92. Similarly, a reverse process occurs in which miRNAs such as miR-125b and miR-let-7 regulate the expression of p53. Thus, the p53-miRNAs circuitry connects the immunomodulatory pathways and may shift the pro-inflammatory balance towards the pro-tumorigenic condition. In this review, we discuss the influence of p53-miRNAs circuitry in modulating the immune response in cancer development. We assume that thorough studies on the p53-miRNAs circuitry in various cancers may prove useful in developing effective new cancer therapeutics for successfully combating this disease.

Surgical Cholecystectomy Score (SCS) for grading the difficulty of laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard of care for symptomatic gall stone disease. A good scoring system is necessary to standardize the reporting. Our aim was to develop and validate an objective scoring system, the Surgical Cholecystectomy Score (SCS) to grade the difficulty of LC. METHODS: The study was conducted in a single surgical unit at a tertiary care hospital in two phases from January 2017 to April 2021. Retrospective data was analysed and the difficulty of each procedure was graded according to the modified Nassar's scoring system. Significant preoperative and intraoperative data obtained was given a weightage score. In phase II, these scores were validated on a prospective cohort. Each procedure was classified either as easy, moderately difficult or difficult. STATISTICAL ANALYSIS: A univariate analysis was performed on the data followed by a multivariate regression analysis. Bidirectional stepwise selection was done to select the most significant variables. The Beta /Schneeweiss scoring system was used to generate a rounded risk score. RESULTS: Data of 800 patients was retrieved and graded. 10 intraoperative parameters were found to be significant. Each variable was assigned a rounded risk score. The final SCS range for intraoperative parameters was 0-15. The scoring system was validated on a cohort of 249 LC. In the final scoring, cut off SCS of > 8 was found to correlate with difficult procedures. Score of < 2 was equivalent to easy LC. A score between 2 and 8 indicated moderate difficulty. The area under ROC curve was 0.98 and 0.92 for the intraoperative score indicating that the score was an excellent measure of the difficulty level of LCs. CONCLUSION: The scoring system developed in this study has shown an excellent correlation with the difficulty of LC. It needs to be validated in different cohorts and across multiple centers further.

Genome-wide identification of MATE and ALMT genes and their expression profiling in mungbean (Vigna radiata L.) under aluminium stress.

The Multidrug and toxic compound extrusion (MATE) and aluminium activated malate transporter (ALMT) gene families are involved in response to aluminium (Al) stress. In this study, we identified 48 MATE and 14 ALMT gene families in Vigna radiata genome and classified into 5 (MATE) and 3 (ALMT) clades by phylogenetic analysis. All the VrMATE and VrALMT genes were distributed across mungbean chromosomes. Tandem duplication was the main driving force for evolution and expansion of MATE gene family. Collinearity of mungbean with soybean indicated that MATE gene family is closely linked to Glycine max. Eight MATE transporters in clade 2 were found to be associated with previously characterized Al tolerance related MATEs in various plant species. Citrate exuding motif (CEM) was present in seven VrMATEs of clade 2. Promoter analysis revealed abundant plant hormone and stress responsive cis-elements. Results from quantitative real time-polymerase chain reaction (qRT-PCR) revealed that VrMATE19, VrMATE30 and VrALMT13 genes were markedly up-regulated at different time points under Al stress. Overall, this study offers a new direction for further molecular characterization of the MATE and ALMT genes in mungbean for Al tolerance.

Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.

Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy.

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.

Canonical insulin signaling is not significantly impaired in early stages of depression.

Patients with major depression (MD) are at high-risk for insulin resistance (IR), type-2 diabetes, metabolic syndrome, cardiovascular morbidity and mortality. However, our recent study published in this journal [Eur Arch Psychiatry Clin Neurosci. 2019 Jun;269(4):373-377], found no evidence of IR in acutely-ill drug-naive first-episode MD (FEMD) using the homeostatic model assessment of insulin resistance (HOMA-IR). We concluded, that MD may be related to impaired glucose/insulin homeostasis in the long-term but not in early disease stages. Now, we performed a complementary analysis of the canonical insulin signalling pathway containing the set of control and FEMD samples from the study mentioned above. The first node (pS312-IRS-1, pY-IRS-1) and downstream pathway which affects glucose and lipid homeostasis (phosphorylated proteins: pS473-AKT, pS9-GSK3ß, pS2448-mTOR, pT389-p70S6K; total proteins AKT, GSK3ß, mTOR, p70S6K) were analyzed by electrochemiluminescence (ECL) in neuronal extracellular vesicles (nEVs) enriched for L1 neural cell adhesion molecule (L1CAM) expression. No significant diagnosis-related differences were observed for the pS312-IRS-1 / pYIRS-1 ratio (P = 0.093), but the mean ratio was reduced by ~ 70% in FEMD versus controls. Moreover, omnibus analysis of downstream phosphorylated / total signaling protein ratios and respective post-hoc analyses revealed no significant changes in FEMD patients versus controls (P = 0.734). HAMD-21 scores were not correlated with pS312-IRS-1 / pY-IRS-1 or downstream phosphorylated/total signaling protein ratios. In summary, we did not find evidence for altered neuronal insulin signaling in early disease stages of MD. This is in contrast to schizophrenia, where we and other researchers have seen evidence of IR in first-episode patients.

Cytokine alterations in CSF and serum samples of patients with a first episode of schizophrenia: results and methodological considerations.

We determined cytokine levels in paired serum/CSF samples from first-episode schizophrenia (FES) participants (n = 20) and controls (n = 21) using a 13-plex immunoassay. Applying strictly-determined detection limits, 12 cytokines were found in serum and two in CSF. Higher serum MCP-1 levels (p = 0.007) were present in FES versus controls, which correlated with serum IgG (R = - 0.750; p = 0.013). Finally, IL-18 levels correlated with body weight in FES (R = 0.691; p = 0.041). This study demonstrates potential limitations in the sensitivity of multiplex cytokine assays for CSF studies in mental disorders and suggests that some published studies in this area should be re-evaluated.

Implementing a quality improvement initiative for private healthcare facilities to achieve accreditation: experience from India.

BACKGROUND: The Manyata program is a quality improvement initiative for private healthcare facilities in India which provided maternity care services. Under this initiative, technical assistance was provided to selected facilities in the states of Uttar Pradesh, Jharkhand and Maharashtra which were interested in obtaining 'entry level certification' under the National Accreditation Board for Hospitals and Healthcare Providers (NABH) for provision of quality services. This paper describes the change in quality at those Manyata-supported facilities when assessed by the NABH standards of care. METHODS: Twenty-eight private-sector facilities underwent NABH assessments in the three states from August 2017 to February 2019. Baseline assessment (by program staff) and NABH assessment (by NABH assessors) findings were compared to assess the change in quality of care as per NABH standards of care. The reported performance gaps from NABH assessments were then also classified by thematic areas and suggested corrective actions based on program implementation experience. RESULTS: The overall adherence to NABH standards of care improved from 9% in the baseline assessment to 80% in the NABH assessment. A total of 831 performance gaps were identified by the NABH assessments, of which documentation issues accounted for a majority (70%), followed by training (19%). Most performance gaps could be corrected either by revising existing documentation or creating new documentation (62%), or by orienting facility staff on various protocols (35%). CONCLUSION: While the adherence of facilities to the NABH standards of care improved considerably, certain performance gaps remained, which were primarily related to documentation of facility policies and protocols and training of staff, and required corrective actions for the facilities to achieve NABH entry level certification.

Flubendiamide induced genetic and cellular damages directly influence the life cycle of the oriental leaf worm, Spodoptera litura.

Indiscriminate uses of insecticide greatly damage the environment as well as non-target organisms. Thus, multiple levels of bioassays can help better management of our environment. Flubendiamide is a phthalic acid diamide insecticide that ceases the function of insect muscle leading to paralysis and death. Here, we aimed to explore the effects of Flubendiamide on the life cycle of Spodoptera litura vis-a-vis the mode of action. Fourth instar larvae of the same age (120 ± 2 h) and size were fed with different concentrations (20-80 µg/mL) of Flubendiamide for 12-72 h. We performed a pharmacokinetics study, different biochemical assays, p450, Ecdysone receptor (EcR) and other genes expression analyses by Real-Time PCR and gross damages by Dye exclusion assay and histopathology. Our results demonstrate that the mean concentration of Flubendiamide after 48 h is 9.907 µg/mL and (i) altered the molting, metamorphosis, and reproduction at 80 µg/mL (24 h) (ii) increases all oxidative stress parameters (ROS/RNS, MDA, 8OHdG), decreases oxidative defense mechanisms (SOD, CAT, GST) at 80 µg/mL (48 h) and p450 in a time and concentration-dependent manner, (iii) activates CncC/Maf apoptotic pathways at 80 µg/mL concentration at 24 h while the expression declined from 48 h onwards, (iii) downregulates the EcR expression in a time and concentration-dependent manner, which might be responsible for disturbed molting, metamorphosis, and reproduction, and (iv) increase the expression of apoptotic genes (Caspase 1, -3, and - 5), in time and concentration-dependent manner causing gross morphological and histological damages. In conclusion, indiscriminate use of this insecticide can affect the ecosystem and have the capacity to cause multiple hazardous effects on experimental organisms. Thus, it warrants further investigations to improve and optimize the integrated pest management packages, including Flubendiamide for better management.

Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol.

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5-20 µM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10-50 µM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Protective effects of a polyherbal medicine, Majoon Suranjan against bisphenol-A induced genetic, oxidative and tissue damages.

Bisphenol-A (BPA) is a toxic chemical largely produced and used in polycarbonate plastics worldwide. Majoon Suranjan (MS), a polyherbal formulation, is used as an anti-inflammatory medicine against rheumatoid arthritis. The present study aimed to evaluate BPA-induced toxicity and its possible amelioration by MS. To test our hypothesis, we performed gas chromatography-mass spectrometry (GC-MS) analysis, DNA interaction studies, genotoxicity tests, oxidative stress parameters, and histopathological examinations. GC-MS profiling of MS revealed the presence of various anti-oxidant compounds. DNA interaction studies showed that both chemicals intercalate between DNA base pairs. Next, we observed BPA-induced genotoxicity and oxidative damage. The observed effects might be due to BPA-induced reactive oxygen species production. Further, BPA changed the anti-oxidant enzyme activities, increased the malondialdehyde, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and caused gross damage to the liver and kidney. Interestingly, these effects were significantly reversed by MS. In conclusion, MS shows protective effects against BPA-induced toxicity and could be a potential alternative medicine against BPA toxicity, especially in third-world countries where BPA uses are not strictly regulated.Highlights:Bisphenol-A (BPA) induces multiple toxic effects.BPA induces genotoxicity, oxidative and tissue damage.Majoon Suranjan (MS) ameliorates the BPA induced toxic effects.GC-MS profiling show various active anti-oxidant compounds in MS.MS is anti-genotoxic, anti-oxidant, and hepato-renal protective.

Biosurfactants: Forthcomings and Regulatory Affairs in Food-Based Industries.

The terms discussed in this review-biosurfactants (BSs) and bioemulsifiers (BEs)-describe surface-active molecules of microbial origin which are popular chemical entities for many industries, including food. BSs are generally low-molecular-weight compounds with the ability to reduce surface tension noticeably, whereas BEs are high-molecular-weight molecules with efficient emulsifying abilities. Some other biomolecules, such as lecithin and egg yolk, are useful as natural BEs in food products. The high toxicity and severe ecological impact of many chemical-based surfactants have directed interest towards BSs/BEs. Interest in food surfactant formulations and consumer anticipation of "green label" additives over synthetic or chemical-based surfactants have been steadily increasing. BSs have an undeniable prospective for replacing chemical surfactants with vast significance to food formulations. However, the commercialization of BSs/BEs production has often been limited by several challenges, such as the optimization of fermentation parameters, high downstream costs, and low yields, which had an immense impact on their broader adoptions in different industries, including food. The foremost restriction regarding the access of BSs/BEs is not their lack of cost-effective industrial production methods, but a reluctance regarding their potential safety, as well as the probable microbial hazards that may be associated with them. Most research on BSs/BEs in food production has been restricted to demonstrations and lacks a comprehensive assessment of safety and risk analysis, which has limited their adoption for varied food-related applications. Furthermore, regulatory agencies require extensive exploration and analysis to secure endorsements for the inclusion of BSs/BEs as potential food additives. This review emphasizes the promising properties of BSs/BEs, trailed by an overview of their current use in food formulations, as well as risk and toxicity assessment. Finally, we assess their potential challenges and upcoming future in substituting chemical-based surfactants.

In vivo study to assess dosage of allogeneic pig retinal progenitor cells: Long-term survival, engraftment, differentiation and safety.

Despite notable efforts and significant therapeutical advances, age-related macular degeneration remains the single most common reason for vision loss. Retinal progenitor cells (RPCs) are considered promising candidates for cellular treatments that repair and restore vision. In this allogenic study, the phenotypic profile of pig and human RPCs derived using similar manufacturing processes is compared. The long-term (12-week) survival of green fluorescent protein-pig retinal progenitor cells GFP-pRPC after subretinal transplantation into normal miniature pig (mini-pig) retina is investigated. Human eyes are both anatomically and physiologically mimicked by pig eyes, so the pig is an ideal model to show an equivalent way of delivering cells, immunological response and dosage. The phenotypic equivalency of porcine and clinically intended human RPCs was established. Thirty-nine mini-pigs are used in this study, and vehicle-injected eyes and non-injected eyes serve as controls. Six groups are given different dosages of pRPCs, and the cells are found to survive well in all groups. At 12 weeks, strong evidence of integration is indicated by the location of the grafted cells within the neuro-retina, extension of processes to the plexiform layers and expression of key retinal markers such as recoverin, rhodopsin and synaptophysin. No immunosuppression is used, and no immune response is found in any of the groups. No pRPC-related histopathology findings are reported in the major organs investigated. An initial dose of 250 k cells in 100 µl of buffer is established as an appropriate initial dose for future human clinical trials.

Linking genome wide RNA sequencing with physio-biochemical and cytological responses to catalogue key genes and metabolic pathways for alkalinity stress tolerance in lentil (Lens culinaris Medikus).

BACKGROUND: Alkaline soils cause low productivity in crop plants including lentil. Alkalinity adaptation strategies in lentil were revealed when morpho-anatomical and physio-biochemical observations were correlated with transcriptomics analysis in tolerant (PDL-1) and sensitive (L-4076) cultivars at seedling stage. RESULTS: PDL-1 had lesser salt injury and performed better as compared to L-4076. Latter showed severe wilting symptoms and higher accumulation of Na+ and lower K+ in roots and shoots. PDL-1 performed better under high alkalinity stress which can be attributed to its higher mitotic index, more accumulation of K+ in roots and shoots and less aberrantly dividing cells. Also, antioxidant enzyme activities, osmolytes' accumulation, relative water content, membrane stability index and abscisic acid were higher in this cultivar. Differentially expressed genes (DEGs) related to these parameters were upregulated in tolerant genotypes compared to the sensitive one. Significantly up-regulated DEGs were found to be involved in abscisic acid (ABA) signalling and secondary metabolites synthesis. ABA responsive genes viz. dehydrin 1, 9-cis-epoxycarotenoid dioxygenase, ABA-responsive protein 18 and BEL1-like homeodomain protein 1 had log2fold change above 4.0. A total of 12,836 simple sequence repeats and 4,438 single nucleotide polymorphisms were identified which can be utilized in molecular studies. CONCLUSIONS: Phyto-hormones biosynthesis-predominantly through ABA signalling, and secondary metabolism are the most potent pathways for alkalinity stress tolerance in lentil. Cultivar PDL-1 exhibited high tolerance towards alkalinity stress and can be used in breeding programmes for improving lentil production under alkalinity stress conditions.

Changes in leukocytes and CRP in different stages of major depression.

BACKGROUND: We recently reported increased levels of neutrophils, monocytes and C-reactive protein (CRP) correlated with symptom severity in acute schizophrenia. Here, we investigated if a similar pattern of innate immune system activation occurs in major depression (MD). METHODS: We assessed differential blood counts, CRP, depression symptoms (HAMD-21) and psychosocial functioning (GAF) in controls (n = 129) and patients with first (FEMD: n = 82) or recurrent (RMD: n = 47) disease episodes of MD at baseline (T0; hospital admission) and after 6-weeks treatment (T6). RESULTS: Considering smoking, BMI and gender as covariates, neutrophils (FEMD: p = 0.034, RMD: p = 0.034) and CRP (FEMD: p < 0.001, RMD: p = 0.021) were higher, and eosinophils (FEMD: p = 0.005, RMD: p = 0.004) lower in patients versus controls at T0. Baseline lymphocyte counts were elevated in RMD (p = 0.003) but not FEMD. Results were confirmed by analyses of nonsmokers. At follow-up, eosinophils rose significantly in FEMD (p = 0.011) but no significant changes were observed in RMD. Improvement in HAMD-21 correlated with T0-T6 changes of neutrophil counts in FEMD (r = 0.364, p = 0.024). Compared with our previous schizophrenia study, raised baseline neutrophil and reduced eosinophil counts in MD had smaller effect sizes and treatment had a weaker association with T0-T6 changes in neutrophils. In addition, lymphocytes were elevated at T0 in recurrent MD but not in schizophrenia patients. CONCLUSIONS: These findings suggest that innate immunity may be involved in early stages of MD, and adaptive immunity may be involved in chronic disease. Thus, further studies may lead to new disease stage-dependent MD treatment strategies targeting different aspects of immune system activation.

Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress.

Sorafenib is an FDA-approved chemotherapeutic drug used as standard therapy for advanced-stage cancers. However, Sorafenib-induced multiple adverse effects are a major limitation that directly impacts patients' physical and physiological well-being. Therefore, it is vital to identify agents that can lessen the associated adverse effects and enhance efficacy. Apigenin, a dietary plant flavone, is a bioactive-compound present in fruits and vegetables having anti-oxidant, anti-inflammatory, and anti-cancer properties. Our study aimed to investigate Sorafenib-induced toxic effects at genomic, cellular, and tissue level and the potential protective effects of Apigenin. To achieve our goal, we treated Swiss albino mice with Apigenin (50 mg/kg bw) alone or in combination with Sorafenib (40 mg/kg bw). Next, we performed DNA interaction, genotoxicity, oxidative damages, anti-oxidant activities, liver enzyme levels, and histopathological studies. We demonstrated that Apigenin and Sorafenib bind DNA via electrostatic interaction. Further, Sorafenib induces genetic, oxidative, and tissue damages characterized by an increase in chromosomal aberrations and micronucleus, reactive oxygen species (ROS) and reactive nitrogen species (RNS), oxidative and DNA damage, lipid peroxidation, and hepato-renal damages, and a decrease in antioxidant-enzymes. Interestingly, the Sorafenib-induced adverse effects were ameliorated by Apigenin. Our findings indicate that Apigenin has protective effects against Sorafenib-induced toxicity and could be combined with Sorafenib to lessen its adverse effects and enhance its efficacy. However, further pre-clinical and clinical studies are required to evaluate Apigenin's effectiveness with Sorafenib.

Assessing the sustainability of post-Green Revolution cereals in India.

Sustainable food systems aim to provide sufficient and nutritious food, while maximizing climate resilience and minimizing resource demands as well as negative environmental impacts. Historical practices, notably the Green Revolution, prioritized the single objective to maximize production over other nutritional and environmental dimensions. We quantitatively assess outcomes of alternative production decisions across multiple objectives using India's rice-dominated monsoon cereal production as an example. We perform a series of optimizations to maximize nutrient production (i.e., protein and iron), minimize greenhouse gas (GHG) emissions and resource use (i.e., water and energy), or maximize resilience to climate extremes. We find that increasing the area under coarse cereals (i.e., millets, sorghum) improves nutritional supply (on average, +1% to +5% protein and +5% to +49% iron), increases climate resilience (1% to 13% fewer calories lost during an extreme dry year), and reduces GHGs (-2% to -13%) and demand for irrigation water (-3% to -21%) and energy (-2% to -12%) while maintaining calorie production and cropped area. The extent of these benefits partly depends on the feasibility of switching cropped area from rice to coarse cereals. Based on current production practices in 2 states, supporting these cobenefits could require greater manure and draft power but similar or less labor, fertilizer, and machinery. National- and state-level strategies considering multiple objectives in decisions about cereal production can move beyond many shortcomings of the Green Revolution while reinforcing the benefits. This ability to realistically incorporate multiple dimensions into intervention planning and implementation is the crux of sustainable food production systems worldwide.

Examining the behavioural intention of inpatients in Indian government hospitals.

PURPOSE: The purpose of this research is to examine the impact of perceived service quality (PSQ) on the behavioural intention (BI) of patients in Indian government hospitals. The underlying mechanism of trust and patient satisfaction (SAT) is examined as multiple mediating effect. DESIGN/METHODOLOGY/APPROACH: Data from 510 respondents were collected using structured questionnaires. Six government hospitals, namely, S.M.S. Hospital, J.L.N. Hospital, New Medical College Hospital, Maharana Bhupal Medical Hospital, Mathuradas Hospital and P.B.N. Hospital, were selected from the cities of Jaipur, Ajmer, Kota, Udaipur, Jodhpur and Bikaner, respectively. The data were collected from adult patients (>18 years old) who spent at least two nights in a government hospital between 1 October, 2020 and 30 December, 2020. PSQ formed as a reflective-formative model was analysed using the repeated indicator approach. Structural equation modelling (SEM) using SMART-PLS software was used to test the hypothesised model(s) derived deductively from literature. FINDINGS: The findings support the following conclusions: (1) the positive relationship between PSQ and BI is significant; (2) SAT mediates the PSQ and BI relationship; (3) trust mediates the PSQ and BI relationship; (4) the mediation effect of SAT is stronger than that of trust. PRACTICAL IMPLICATIONS: The results indicate that, in order to enhance the positive BI of patients towards government hospitals, it is necessary for the hospitals to work on strategies to enhance the service quality provided to patients. The outcome of this study will enable state government hospitals to get a better understanding of the different dimensions of service quality and will help in observing the factors that contribute to patients' satisfaction and trust in building long-term relationships by encouraging a positive BI. ORIGINALITY/VALUE: There is a dearth of research in India that evaluates the relationships between the constructs PSQ, trust, BI and SAT in the context of healthcare service. This empirical study is an attempt to fill this gap by focussing on the government hospitals in India.

Performance of three-dimensional and ultra-high-definition (4K) technology in laparoscopic surgery: A systematic review and meta-analysis.

Background: The technology in the field of laparoscopy is rapidly evolving and is primarily focussed on increasing the quality of image and depth perception in the form of 4K and three-dimensional (3D) technology. There has been no conclusion yet regarding the better technology. Methods: A systematic search was performed independently by two authors across MEDLINE, Google Scholar and Embase using the PRISMA guidelines. All randomised control trials comparing 3D and 4K technologies were included. Meta-analysis was conducted using random-effects statistics for time taken for different tasks across the studies. Results: The search strategy revealed a total of 1835 articles, out of which nine studies were included. Three studies showed no superiority of 3D over 4K, while the remaining six did. Meta-analysis for the time taken for peg transfer favoured 3D over 4K (overall effect: Z = 2.12; P = 0.03). Forest plots for time taken for suturing (Z = 1.3; P = 0.19) and knot tying (Z = 1.7; P = 0.09) also favoured 3D over 4K; the results however were statistically insignificant. Path length was reported by two studies and was found to be lesser in the 3D group. Two studies measured the workload by NASA/Surg-TLX score, which was lower in the 3D group. Visual side effects were found to be higher in the 3D group. Conclusion: 3D technology is likely to result in a shorter operative time and better efficiency of movement as compared to the 4K technology by the virtue of its better depth perception.