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 and expression profiling of ATP binding cassette (ABC) transporters gene family in lentil (Lens culinaris Medikus) under aluminium stress condition.

Adenosine triphosphate-binding cassette transporters (ABC transporters) are involved in regulating plant growth, development and tolerance to environmental stresses. In this study, a total of 138 ABC transporter genes were identified in the lentil genome that were classified into eight subfamilies. Four lentil ABC transporters from subfamily B and I were clustered together with the previously characterized ABC transporter proteins related to aluminium (Al) detoxification. Lentil ABC transporter genes were distributed across the chromosomes. Tandem duplication was the main driving force for expansion of the ABC gene family. Collinearity of lentil with soybean indicated that ABC gene family is closely linked to Glycine max. ABC genes in the same subfamily showed similar gene structure and conserved motifs. The ABC promoter regions harboured a large number of plant hormones and multiple stress responsive cis-regulatory elements. The qRT-PCR showed that ABC genes had varied expression in roots of lentil at different time points under Al stress. This is the first report on genome wide identification and expression analyses of genes encoding ABC transporter genes in lentil which has provided in-depth insight for future research on evolution and elucidation of molecular mechanisms for aluminium tolerance.

Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma.

BACKGROUND: The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. METHODS: We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 µM) and Sorafenib (1-10 µM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. RESULTS: The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. CONCLUSIONS: In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.

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.

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.

Role of epigenetic drugs in sensitizing cancers to anticancer therapies: emerging trends and clinical advancements.

Epigenetic changes play a significant role in cancer progression, maintenance and therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.

Epigenetic changes play a significant role in cancer development and progression. Epigenetic drugs (epi-drugs) target enzymes involved in regulating epigenetic changes to maintain normal cell functioning. Epi-drugs include histone deacetylase inhibitors and DNA methyltransferase inhibitors, among others. These drugs have shown potential as standalone treatments for cancer and have also been found to work well in combination with other therapies (chemotherapy, radiotherapy and immunotherapy), helping to overcome treatment resistance. By targeting the epigenetic alterations that contribute to treatment resistance, epi-drugs have the potential to enhance the effectiveness of these therapies. This review article focuses on how epi-drugs overcome resistance to different cancer treatments. Combining epi-drugs with conventional anticancer therapies could provide better management of cancer. However, more preclinical and clinical research is needed to understand the potential benefits and optimize the use of these combinations fully. Overall, epi-drugs offer a promising avenue for improving cancer treatment outcomes and warrant further investigation.

Anti-cancer activity of guggulsterone by modulating apoptotic markers: a systematic review and meta-analysis.

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C21H28O2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized. Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta-analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool. Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/ß-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty three studies were selected for meta-analysis following the PRISMA statements. Fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment. Conclusion: This study suggested that Guggulsterone has apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.

Exogenous hydrogen sulfide alleviates chromium toxicity by modulating chromium, nutrients and reactive oxygen species accumulation, and antioxidant defence system in mungbean (Vigna radiata L.) seedlings.

Chromium (Cr), a highly toxic redox-active metal cation in soil, seriously threatens global agriculture by affecting nutrient uptake and disturbing various physio-biochemical processes in plants, thereby reducing yields. Here, we examined the effects of different concentrations of Cr alone and in combination with hydrogen sulfide (H2S) application on the growth and physio-biochemical performance of two mungbeans (Vigna radiata L.) varieties, viz. Pusa Vishal (PV; Cr tolerant) and Pusa Ratna (PR; Cr sensitive), growing in a pot in hydroponics. Plants were grown in the pot experiment to examine their growth, enzymatic and non-enzymatic antioxidant levels, electrolyte balance, and plasma membrane (PM) H+-ATPase activity. Furthermore, root anatomy and cell death were analysed 15 days after sowing both varieties in hydroponic systems. The Cr-induced accumulation of reactive oxygen species caused cell death and affected the root anatomy and growth of both varieties. However, the extent of alteration in anatomical features was less in PV than in PR. Exogenous application of H2S promoted plant growth, thereby improving plant antioxidant activities and reducing cell death by suppressing Cr accumulation and translocation. Seedlings of both cultivars treated with H2S exhibited enhanced photosynthesis, ion uptake, glutathione, and proline levels and reduced oxidative stress. Interestingly, H2S restricted the translocation of Cr to aerial parts of plants by improving the nutrient profile and viability of root cells, thereby relieving plants from oxidative bursts by activating the antioxidant machinery through triggering the ascorbate-glutathione cycle. Overall, H2S application improved the nutrient profile and ionic homeostasis of Cr-stressed mungbean plants. These results highlight the importance of H2S application in protecting crops against Cr toxicity. Our findings can be utilised to develop management strategies to improve heavy metal tolerance among crops.

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.

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.

Protective effect of green synthesized Selenium Nanoparticles against Doxorubicin induced multiple adverse effects in Swiss albino mice.

AIMS: Doxorubicin (DOX) is a widely used drug against multiple cancers. However, its clinical Use is often restricted due to multiple adverse effects. Recently, Selenium Nanoparticles (SeNPs) are gaining attention due to their low toxicity and higher biocompatibility, making them attractive nanoparticles (NPs) in medical and pharmaceutical sciences. Therefore, the current study aimed to assess if our biosynthesized SeNP from the endophytic fungus Fusarium oxysporum conjugated with DOX could alleviate the DOX-induced adverse effects. MAIN METHODS: For this purpose, we investigated various genotoxic, biochemical, histopathological, and immunohistochemical parameters and finally analyzed the metabolite profile by LC-MS/MS. KEY FINDINGS: We observed that DOX causes an increase in reactive oxygen and nitrogen species (ROS, RNS), 8-OHdG, and malondialdehyde (MDA), decreases antioxidant defense systems and reduces BCL-2 expression in cardiac tissue. In addition, a significant increase in DNA damage and alteration in the cytoarchitecture of the liver, kidney, and heart tissues was observed by Comet Tail Length and histopathological studies, respectively. Interestingly, the DOX-SeNP conjugate reduced ROS/RNS, 8-OHdG, and MDA levels in the liver, kidney, and heart tissues. It also restored the antioxidant enzymes and cytoarchitectures of the examined tissues, reduced genotoxicity, and increased the BCL-2 levels. Finally, metabolic profiling showed that DOX reduced the number of cardioprotective metabolites, which DOX-SeNP restored. SIGNIFICANCE: Collectively, the present results describe the protective effect of DOX-conjugated SeNP against DOX-induced toxicities. In conclusion, DOX-SeNP conjugate might be better for treating patients receiving DOX alone. However, it warrants further thorough investigation.

Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models.

BACKGROUND: Apigenin is being increasingly recognized as a cancer chemopreventive agent. We aimed to investigate the anticancer effects of Apigenin in in-vivo studies to know its present research status and how close or how far it is from the clinics. METHODS: Several electronic databases such as PubMed, Springer, Cochrane, and ctri.gov.in were searched to fetch the relevant articles. We focused only on published animal studies that reported the anticancer effects of Apigenin against various cancers. Two reviewers independently assessed the risk of bias for each analysis, and the conflicting views were resolved later by consensus. RESULTS: A total of 25 studies focused on the anticancer effects of Apigenin on various cancer types, including liver, prostate, pancreatic, lung, nasopharyngeal, skin, colon, colorectal, colitis-associated carcinoma, head and neck squamous cell carcinoma, leukemia, renal cell carcinoma, Ehrlich ascites carcinoma, and breast cancer were included. Overall, Apigenin reduces tumor volume (SMD=-3.597, 95% CI: -4.502 to -2.691, p < 0.001), tumor-weight (SMD=-2.213, 95% CI: -2.897 to -1.529, p < 0.001), tumor number (SMD=-1.081, 95% CI: -1.599 to -0.563, p < 0.001) and tumor load (SMD=-1.556, 95% CI: -2.336 to -0.776, p < 0.001). Further, it has no significant effect on the animal's body-weight (SMD=-0.345, 95% CI: -0.832 to 0.143, p = 0.165). Apigenin exerts anti-tumor effects mainly by inducing apoptosis/cell-cycle arrest. CONCLUSIONS: Our analysis suggests that Apigenin has potential anticancer effects against various cancers. However, the poor symmetry of the funnel plot suggested publication bias. Thus, it warrants further research to evaluate the potential of Apigenin alone or as an adjuvant for cancer treatment.

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.

Glycine betaine modulates chromium (VI)-induced morpho-physiological and biochemical responses to mitigate chromium toxicity in chickpea (Cicer arietinum L.) cultivars.

Chromium (Cr) accumulation in crops reduces yield. Here, we grew two chickpea cultivars, Pusa 2085 (Cr-tolerant) and Pusa Green 112 (Cr-sensitive), in hydroponic and pot conditions under different Cr treatments: 0 and 120 µM Cr and 120 µM Cr + 100 mM glycine betaine (GB). For plants grown in the hydroponic media, we evaluated root morphological attributes and plasma membrane integrity via Evans blue uptake. We also estimated H+-ATPase activity in the roots and leaves of both cultivars. Plants in pots under conditions similar to those of the hydroponic setup were used to measure growth traits, oxidative stress, chlorophyll contents, enzymatic activities, proline levels, and nutrient elements at the seedling stage. Traits such as Cr uptake in different plant parts after 42 days and grain yield after 140 days of growth were also evaluated. In both cultivars, plant growth traits, chlorophyll contents, enzymatic activities, nutrient contents, and grain yield were significantly reduced under Cr stress, whereas oxidative stress and proline levels were increased compared to the control levels. Further, Cr uptake was remarkably decreased in the roots and leaves of Cr-tolerant than in Cr-sensitive cultivars. Application of GB led to improved root growth and morpho-physiological attributes and reduced oxidative stress along with reduced loss in plasma membrane integrity and subsequently increase in H+-ATPase activity. An increment in these parameters shows that the exogenous application of GB improves the Cr stress tolerance in chickpea plants.

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.

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.

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.

Specific targeting of cancer stem cells by immunotherapy: A possible stratagem to restrain cancer recurrence and metastasis.

Cancer stem cells (CSCs), the tumor-initiating cells playing a crucial role in cancer progression, recurrence, and metastasis, have the intrinsic property of self-renewal and therapy resistance. The tumorigenic properties of these cells include generation of cellular heterogeneity and immuno-suppressive tumor microenvironment (TME), conferring them the capability to resist a variety of anti-cancer therapeutics. Further, CSCs possess several unique immunological properties that help them escape recognition by the innate and adaptive immune system and shape a TME into a pro-tumorigenic and immunosuppressive landscape. In this context, immunotherapy is considered one of the best therapeutic options for eliminating CSCs to halt cancer recurrence and metastasis. In this review, we discuss the various immunomodulatory properties of CSCs and the interaction of CSCs with the immune system enabling immune evasion. In addition, we also highlight the present research update on immunotherapeutic targeting of CSCs and the possible further scope of research on this topic. We believe that a deeper understanding of CSCs' immunological properties and the crosstalk between CSCs and the immune system can develop better innovative immune-therapeutics and enhance the efficacy of current therapy-resistant cancer treatments.

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.