Hydrogeochemical controls on contrasting co-occurrence of geogenic Arsenic (As) and Fluoride (F-) in complex aquifer system of Upper Indus Basin, (UIB) western Himalaya.

Arsenicosis and fluorosis have become severe health hazards associated with the drinking of Arsenic (As) and Fluoride (F-) contaminated groundwater across south-east Asia. Although, significant As and F- concentration is reported from major Himalayan river basins but, the hydrogeochemical processes and mechanisms controlling their contrasting co-occurrence in groundwater is still poorly explored and understood. In the present study, groundwater samples were collected from phreatic and confined aquifers of Upper Indus Basin (UIB), India to understand the hydrogeochemical processes controlling the distribution and co-occurrence of geogenic As and F- in this complex aquifer system. Generally, the groundwater is circum-neutral to alkaline with Na+-HCO3-, Ca2+-Na+-HCO3- and Ca2+-Mg2+-HCO3- water facies signifying the dominance of silicate and carbonate dissolution. The poor correlation of As and F- in groundwater depicted that these geogenic elements have discrete sources of origin with distinct mechanisms controlling their distribution. As enrichment in groundwater is associated with high pH, Fe, Mn and NH4-N suggesting dominance of metal oxide/hydroxide reduction with organic matter degradation. However, F- enrichment in groundwater is associated with high pH, HCO3- and Na+, which is assisted by the incessant dissolution of fluorinated minerals. The study also revealed that high HCO3- facilitates the exchange of hydroxides (OH-) with As and F- on sediment surfaces that contribute to As and F- enrichment in groundwater through desorption. 70% groundwater samples have As and F- concentration above the permissible limit given by WHO. Therefore, continuous exposure to these contaminants may pose severe health hazard of arsenicosis and fluorosis to people living in the region and downstream. The study provides insights into geological sources, hydrogeochemical processes and mechanisms controlling distribution of As and F- in groundwater that will help in developing the appropriate measures to mitigate the impact these contaminants on human health.

Region-specific gene expression profile in the epididymis of high- and low-fertile dromedary camels.

The scenario of the fertile spermatozoa with high fertilizing capability is basically dependent on gene expression-based epididymal function. The current investigation aimed to declare the varied expression of different candidate genes (PLA2G4D, LCN15, CLUAP1, SPP1, AQP12B, DEFB110 and ESR1) relevant to spermatozoa features between the different epididymal segments in the mature dromedary camels (n = 30). Scrotal contents were collected post-slaughtering, during the breeding season and the epididymis was separated from the testicles and divided into three segments (caput, corpus and cauda) based on its morphology and anatomical characteristics. Epididymal spermatozoa were harvested from each epididymal portion and evaluated for motility, count, viability and morphology. Samples were grouped depending on their epididymal sperm cells features into high-fertile (n = 15) and low-fertile (n = 15) groups. The gene expression of the candidate genes was defined in the isolated RNA from each epididymal portion tissue. The segmental sperm motion and count were significantly (p < .05 and p < .01) higher in the three epididymal parts of high-fertile camels than the lower ones. There were some candidate genes markedly up-regulated in its expression in epididymal head of high-fertile camels (PLA2G4D and LCN15) and low fertile (CLUAP1), while others in the body region of the high-fertile group (SPP1, AQP12B and DEFB110). Nevertheless, ER1 did not differ in the expression among the epididymal segments. In conclusion, the variant expression patterns of these epididymal genes in relation to the regional spermatozoa features might suggest important roles of these genes in sperm maturation process in the epididymis and focusing more interest on their potential utility as markers for male camel fertility prediction.

Association of first-line thrombectomy technique and outcome in late-window large vessel occlusion strokes: A post hoc analysis of the MR CLEAN-LATE trial.

BACKGROUND: This study aimed to compare direct aspiration, stent retriever, and the combined thrombectomy technique on clinical, safety, and technical outcomes in late-window stroke patients included in the MR CLEAN-LATE trial. METHODS: This post hoc analysis of the MR CLEAN-LATE trial included patients treated with direct aspiration, stent retriever, or combined thrombectomy technique as first-line approach. Primary outcome was the modified Rankin Scale (mRS) score at 90 days follow-up, and compared between the three groups with ordinal logistic regression analysis. Secondary outcomes included mortality at 90 days, total technique switches, procedure time, recanalization rate measured with the expanded thrombolysis in cerebral infarction (eTICI) score, and symptomatic intracranial hemorrhage (sICH). Predefined variables were used for adjustments. RESULTS: In the MR CLEAN-LATE trial, 258 patients underwent endovascular treatment and 232 were included in our analyses. The mRS at 90 days did not differ (stent retriever vs. direct aspiration: adjusted common odds ratio (acOR) = 1.35, 95% confidence interval (CI) = 0.73 to 2.50; stent retriever vs. combined: acOR = 1.13, 95% CI = 0.64 to 2.00; direct aspiration vs. combined: acOR = 1.19, 95% CI = 0.64 to 2.21). Direct aspiration thrombectomy was accompanied with more switches to another technique compared to the stent retriever (adjusted odds ratio (aOR) = 6.50, 95% CI = 2.52 to 16.8) or combined group (aOR = 4.67, 95% CI = 1.80 to 12.1) and with higher sICH rates compared to the combined technique (13% vs. 2.5%; aOR = 8.19, 95% CI = 1.49 to 45.1). Mortality, procedure time, and eTICI did not differ. CONCLUSION: Stent retriever, direct aspiration, or the combined thrombectomy technique as first-line approach showed no differences in clinical outcome in late-window stroke patients. Direct aspiration was accompanied with higher sICH rates and more switcher to another technique compared to the combined group.

Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Predicting Tumor Dynamics Post-Staged GKRS: Machine Learning Models in Brain Metastases Prognosis.

This study assesses the predictive performance of six machine learning models and a 1D Convolutional Neural Network (CNN) in forecasting tumor dynamics within three months following Gamma Knife radiosurgery (GKRS) in 77 brain metastasis (BM) patients. The analysis meticulously evaluates each model before and after hyperparameter tuning, utilizing accuracy, AUC, and other metrics derived from confusion matrices. The CNN model showcased notable performance with an accuracy of 98% and an AUC of 0.97, effectively complementing the broader model analysis. Initial findings highlighted that XGBoost significantly outperformed other models with an accuracy of 0.95 and an AUC of 0.95 before tuning. Post-tuning, the Support Vector Machine (SVM) demonstrated the most substantial improvement, achieving an accuracy of 0.98 and an AUC of 0.98. Conversely, XGBoost showed a decline in performance after tuning, indicating potential overfitting. The study also explores feature importance across models, noting that features like "control at one year", "age of the patient", and "beam-on time for volume V1 treated" were consistently influential across various models, albeit their impacts were interpreted differently depending on the model's underlying mechanics. This comprehensive evaluation not only underscores the importance of model selection and hyperparameter tuning but also highlights the practical implications in medical diagnostic scenarios, where the accuracy of positive predictions can be crucial. Our research explores the effects of staged Gamma Knife radiosurgery (GKRS) on larger tumors, revealing no significant outcome differences across protocols. It uniquely considers the impact of beam-on time and fraction intervals on treatment efficacy. However, the investigation is limited by a small patient cohort and data from a single institution, suggesting the need for future multicenter research.

Plasticised chitosan: Dextran polymer blend electrolyte for energy harvesting application: Tuning the ion transport and EDLC charge storage capacity through TiO2 dispersion.

This study investigates the performance of biopolymer electrolytes based on chitosan and dextran for energy storage applications. The optimization of ion transport and performance of electric double-layer capacitors EDCL using these electrolytes, incorporating different concentrations of glycerol as a plasticizer and TiO2 as nanoparticles, is explored. Impedance measurements indicate a notable reduction in charge transfer resistance with the addition of TiO2. DC conductivity estimates from AC spectra plateau regions reach up to 5.6 × 10-4 S/cm. The electric bulk resistance Rb obtained from the Nyquist plots exhibits a substantial decrease with increasing plasticizer concentration, further enhanced by the addition of the nanoparticles. Specifically, Rb decreases from ∼20 kΩ to 287 Ω when glycerol concentration increases from 10 % to 40 % and further drops to 30 Ω with the introduction of TiO2. Specific capacitance obtained from cyclic voltammetry shows a notable increase as the scan rate decreases, indicating improved efficiency and stability of ion transport. The TiO2-enriched EDCL achieves 12.3 F/g specific capacitance at 20 mV/s scan rate, with high ion conductivity and extended electrochemical stability. These results suggest the great potential of plasticizer and TiO2 with biopolymers in improving the performance of energy storage systems.

Yoga, a mindfulness therapy to prevent PTSD as to encompass athletes' performance.

Introduction: Yoga is one of the physical and mental activities used in elite sports training for risk prevention and medical rehabilitation in case of injuries caused by overtraining or accidents. This study examined the opinions of Romanian elite athletes and coaches on the feasibility of incorporating yoga practice into training regimens for purposes of injury prevention and medical recovery. Methods: This study surveyed a group of 500 athletes, coaches, and medical personnel from three universities in Romania, all of which are part of the Faculty of Physical Education and Sport (PES). An online survey was administered which evaluates athletes' experience of yoga integration in pre/post training and its positive effects on reducing posttraumatic stress disorder (PTSD). The data were then analyzed with a structural equation model utilizing SmartPLS software. Results: According to the survey, Romanian athletes use yoga both before and after competitions to improve their focus, balance, muscle, and joint elasticity, foster a winning mindset, control their emotions and PTSD, visualize their competition performance, and see themselves as winners. The survey also found that yoga is seen as useful for cardiac rehabilitation, neuropathic pain, pulmonary disease, orthopedic illness, muscle strain, and managing symptoms of Posttraumatic Stress Disorder (PTSD). Conclusion: This study contributes to enhancing athletes' mindfulness and health, offering valuable insights to trainers and athletes interested in incorporating yoga into professional sports activity. The results support the notion that yoga integration in training activity promises to positively influence athletes' performance and reduce collateral side effects of competitions. The results are also in line with the objectives of the Global Action Plan on Physical Activity 2018-2030 (GAPPPA) - with the theme of "being more efficient to prevent than to treat" - which places special emphasis on the demands for certain programs and services, sports coverage, and healthy workplace initiatives. The study further indicates that Romanian elite athletes and coaches support the use of yoga is an effective method for enhancing athletic training and medical therapy for post-traumatic illnesses and stress disorders.

Expression profile of viability and stress response genes as a result of resveratrol supplementation in vitrified and in vitro produced cattle embryos.

BACKGROUND: Resveratrol, a potent antioxidant, is known to induce the up-regulation of the internal antioxidant system. Therefore, it holds promise as a method to mitigate cryopreservation-induced injuries in bovine oocytes and embryos. This study aimed to (i) assess the enhancement in the quality of in vitro produced bovine embryos following resveratrol supplementation and (ii) monitor changes in the expression of genes associated with oxidative stress (GPX4, SOD, CPT2, NFE2L2), mitochondrial function (ATP5ME), endoplasmic reticulum function (ATF6), and embryo quality (OCT4, DNMT1, CASP3, ELOVL5). METHODS AND RESULTS: Three groups of in vitro bovine embryos were cultured with varying concentrations of resveratrol (0.01, 0.001, and 0.0001 µM), with a fourth group serving as a control. Following the vitrification process, embryos were categorized as either good or poor quality. Blastocysts were then preserved at - 80 °C for RNA isolation, followed by qRT-PCR analysis of selected genes. The low concentrations of resveratrol (0.001 µM, P < 0.05 and 0.0001 µM, P < 0.01) significantly improved the blastocyst rate compared to the control group. Moreover, the proportion of good quality vitrified embryos increased significantly (P < 0.05) in the groups treated with 0.001 and 0.0001 µM resveratrol compared to the control group. Analysis of gene expression showed a significant increase in OCT4 and DNMT1 transcripts in both good and poor-quality embryos treated with resveratrol compared to untreated embryos. Additionally, CASP3 expression was decreased in treated good embryos compared to control embryos. Furthermore, ELOVL5 and ATF6 transcripts were down-regulated in treated good embryos compared to the control group. Regarding antioxidant-related genes, GPX4, SOD, and CPT2 transcripts increased in the treated embryos, while NFE2L2 mRNA decreased in treated good embryos compared to the control group. CONCLUSIONS: Resveratrol supplementation at low concentrations effectively mitigated oxidative stress and enhanced the cryotolerance of embryos by modulating the expression of genes involved in oxidative stress response.

Bioluminescence-Based Determination of Cytosolic Accumulation of Antibiotics in Escherichia coli.

Antibiotic resistance is an alarming public health concern that affects millions of individuals across the globe each year. A major challenge in the development of effective antibiotics lies in their limited ability to permeate cells, noting that numerous susceptible antibiotic targets reside within the bacterial cytosol. Consequently, improving the cellular permeability is often a key consideration during antibiotic development, underscoring the need for reliable methods to assess the permeability of molecules across cellular membranes. Currently, methods used to measure permeability often fail to discriminate between the arrival within the cytoplasm and the overall association of molecules with the cell. Additionally, these techniques typically possess throughput limitations. In this work, we describe a luciferase-based assay designed for assessing the permeability of molecules in the cytosolic compartment of Gram-negative bacteria. Our findings demonstrate a robust system that can elucidate the kinetics of intracellular antibiotic accumulation in live bacterial cells in real time.

Impact of Aphis pomi-tending Formica rufa (Hymenoptera: Formicidae) on biological parameters of Hippodamia variegata (Coleoptera: Coccinellidae).

One of the key reasons for the poor performance of natural enemies of honeydew-producing insect pests is mutualism between ants and some aphid species. The findings demonstrated that red wood ant, Formica rufa Linnaeus (Hymenoptera: Formicidae) had a deleterious impact on different biological parameters of the lady beetle, Hippodamia variegata Goeze (Coleoptera: Coccinellidae). H. variegata laid far fewer eggs in ant-tended aphid colonies, laying nearly 2.5 times more eggs in ant absence. Ants antennated and bit the lady beetle eggs, resulting in significantly low egg hatching of 66 per cent over 85 per cent in ant absent treatments. The presence of ants significantly reduced the development of all larval instars. The highest reduction was found in the fourth larval instar (31.33% reduction), and the lowest in the first larval instar (20% reduction). Later larval instars were more aggressively attacked by ants than earlier instars. The first and second larval instars stopped their feeding and movement in response to ant aggression. The third and fourth larval instars modified their mobility, resulting in increased ant aggression towards them. Adult lady beetles were shown to be more vulnerable to ant attacks than larvae. However, H. variegata adults demonstrated counterattacks in the form of diverse defensive reaction behaviours in response to F. rufa aggression.

Comportamento evolutivo de extrassístoles ventriculares por provável hiper automatismo em adolescente. Quando o seguimento clínico é melhor que a intervenção. / Evolutionary behavior of ventricular extrasystoles due to probable hyperautomatism in adolescents. When clinical follow-up is better than intervention

INTRODUÇÃO: As extrassístoles ventriculares (EVs) em adolescentes são fenômenos relativamente frequentes e podem apresentar densidade menor do que em fases de infância e pré- -puberdade. Dados de literatura sugerem que durante a puberdade há redução da densidade de ectopias ventriculares, principalmente quando o mecanismo arrítmico é atividade deflagrada ou hiper automatismo. A atividade deflagrada apresenta como característica o período de acoplamento fixo e habitualmente remissão no pico do esforço com exacerbação da arritmia na fase de recuperação do teste ergométrico. O hiper automatismo apresenta o mesmo comportamento na maioria dos casos, podendo ser diferenciado pelo acoplamento variável durante a monitorização de Holter, caracterizando um foco Parassistólico que não depende do batimento anterior para ocorrer. OBJETIVO: Descrever o quadro clínico de uma adolescente com EVs frequentes com comportamento parassistólico, que apresenta uma densidade arrítmica em redução após o término da puberdade. DESCRIÇÃO DO CASO: Adolescente, feminina, 19 anos, com histórico de palpitações frequentes na infância. Iniciou acompanhamento por quadro de EVs com morfologia de origem na via de saída do ventrículo direito em provável posição póstero lateral na via de saída. Análise ecocardiográfica e de ressonância magnética não evidenciava alterações estruturais no coração. O Holter de 24 horas demonstrava EVs frequentes em processo de redução na evolução (figuras 1 e 2). O teste ergométrico evidenciava EVs com melhora da densidade arrítmica no pico do esforço. Análise detalhada da eletrocardiografia dinâmica demonstrava período de acoplamento variável, denotando a possibilidade de hiper automatismo com EVs de acoplamento variável. Durante a evolução clínica houve melhora das queixas de palpitação e redução da densidade de ectopias em relação a admissão em nosso serviço aos 12 anos de idade (ainda pré menarca). CONCLUSÃO: Arritmias ventriculares, em pacientes jovens e sem cardiopatia estrutural, podem apresentar redução ou remissão espontânea; a avaliação do acoplamento entre o batimento antecessor e a extrassístole pode ajudar a descartar batimentos de maior risco (acoplamento curto) e indicar hiper automatismo como nos casos de acoplamento variável (figuras 1 e 2); a remissão das extrassístoles no pico do esforço indica um critério de benignidade para remissão ou redução da densidade arrítmica após o termino do desenvolvimento corpóreo.

Elevated venous lactate level as an early predictive marker of organ failure in acute pancreatitis: a retrospective study.

OBJECTIVE: The aim of this study was to elucidate the relationship between venous lactate levels and the severity of acute pancreatitis (AP). PATIENTS AND METHODS: Retrospective data analysis was conducted on patients diagnosed with acute pancreatitis. The comparative assessment encompassed baseline characteristics, laboratory data, illness severity, local consequences, and organ failure instances. This comparison was performed between patients exhibiting normal serum lactic acid levels (HL) and those displaying elevated HL levels. The association between serum HL levels and other pertinent clinical markers was investigated using linear regression. Logistic regression analysis was employed to evaluate the utility of elevated serum lactate levels in identifying high-risk groups. RESULTS: Significantly elevated serum HL levels were observed in patients with moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) in contrast to those with mild acute pancreatitis (MAP) (p<0.01). Multivariate logistic analysis demonstrated that higher lactate levels independently predicted organ failure (95% CI 0.738-0.902, p<0.05). Receiver operating characteristic (ROC) curve analysis indicated that the lactate (LAC) cut-off value of 2.45 mmol/L yielded sensitivity and specificity values of 76.5% and 79.1%, respectively, for predicting AP-associated organ failure. The corresponding area under the curve (AUC) was 0.820. CONCLUSIONS: In AP patients, elevated serum HL levels signify disease severity and hold predictive potential for assessing the risk of organ failure.

Functionalization of a cast NaAl/binary ZnO/SiO2 nanohybrid with amine and Schiff base ligands as an adsorbent of divalent cations in water system.

Casting method was used to synthesize a novel sodium alginate nanohybrid functionalized with aminated ZnO/SiO2 Schiff base for adsorption of nickel (Ni2+) and copper (Cu2+) divalent cations in single and binary water systems. The cast Schiff base nanohybrids were investigated using FESEM, XRD, BET, FTIR, TGA, and XPS analyses. The influence of unfunctionalized binary ZnO/SiO2 nano oxides and aminated Schiff base ligands formed by the reaction between salicylaldehyde and O-phenylenediamine on the adsorption of Ni2+ and Cu2+ cations was evaluated. The results confirmed that the aminated Schiff base ligands led to a higher adsorption ability of the cast nanohybrids containing interaction of divalent cations with nitrogen and oxygen atoms, as well as carboxyl and hydroxyl groups. The adsorption kinetics and isotherm for both cations followed a double-exponential model and the Redlich-Peterson model, respectively. The maximum monolayer capacity was found to be 249.8 mg/g for Cu2+ cation and 96.4 mg/g for Ni2+ cation. Thermodynamic analysis revealed an endothermic and spontaneous adsorption process with an increase in entropy. Furthermore, the synthesized Schiff base adsorbent could be easily reused over five times. The simultaneous adsorption in binary system exhibited a higher adsorption selectivity of the cast Schiff base nanohybrid for Cu2+ cation compared to Ni2+ cation. It was found that the removal percentages of Cu2+ and Ni2+ from industrial electroplating wastewater were 91.3 and 64.5%, respectively. Lastly, cost analysis of the synthesized nanohybrid was investigated.

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death.

Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway.

Objectives: The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study. Methods: We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions. Results: The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings. Conclusions: Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.

Silica/Annona muricata nano-hybrid: Synthesis and anticancer activity against breast cancer.

Biogenically derived silica nanoparticles may serve as a well-defined target vehicle for drug delivery and have a wide range of applications in biomedicine. Silica nanoparticles are an excellent candidate as drug carriers due to their mesoporous structure, high drug loading capacity, low toxicity, environmental friendliness and low economic synthesis procedures. In this study, nano structured silica was extracted from sugarcane bagasse through an alkali leaching extraction and conjugated with A. muricata extract overcoming its poor solubility and improving its bioavailability within the host system. The Silica Nanoparticles (SNP) and Annona muricata conjugated Silica Nanoparticles (AM/SNP) were characterized using SEM, FTIR, TGA, EDAX, XRD and zeta potential. The AM/SNP was subjected to kinetic release studies and exhibited a sustained release of 64 % over the course of 12 h in contrast to extract, indicating the slow release of the drug under synthetic conditions. A. muricata pose a high affinity against tumor cells as an anti-cancer agent, and the potential of binding was testified using in-silico virtual screening against breast cancer receptors with lead acetogenins with Annomuricin (-7.4 kcal/mol) and Gigantecin (-7.4 kcal/mol) exhibiting a high binding affinity against ER and HER2+ receptors respectively. The AM/SNP conjugate exhibited high cytotoxicity against the MCF-7 breast cancer cell line with an IC50 value of 33.43 µg, indicating high potency of the conjugate at low concentrations, facilitating low systemic toxicity on administration.

[Root resection: tooth preservation by targeting the root of the problem]. / Wortelresectie: tandbehoud door problemen bij de wortel aan te pakken.

When problems occur in multirooted teeth, such as persistent endodontic problems following endodontic treatment, problems involving fracture or furcation, extraction may be decided on. However, removal of the tooth will result in loss of occlusal units and the alveolar process. By removing the compromised root and preserving the healthy part, the tooth can remain functional, but only after restorative treatment. A correct indication or diagnosis, a properly performed endodontic, restorative and surgical treatment and proper follow-up are mandatory for a successful treatment outcome.

Efficacy and safety of camrelizumab combined with TACE for hepatocellular carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Hepatocellular carcinoma (HCC) represents a highly lethal and recurrent neoplasm, with limited effective treatment regimens available. Camrelizumab, as a novel PD1 inhibitor combined with transcatheter arterial chemoembolization (TACE), has been widely used in the treatment of HCC. However, there remains a contentious debate regarding the clinical value of the TACE and camrelizumab combination. This study seeks to investigate the efficacy and safety of this combination treatment regimen in patients with HCC. MATERIALS AND METHODS: The related studies were retrieved from four online databases, including Pubmed, Cochrane Library, EMBASE, and Web of Science, up to June 1, 2023. The selection of studies was based on screening of titles, abstracts, and full-texts. The primary efficacy outcomes included complete response (CR), objective response rate (ORR), and disease control rate (DCR), while safety outcomes evaluated all treatment-related adverse events (AEs). Additionally, secondary outcomes such as overall (OS) and progression-free survival (PFS) were extracted for further survival analysis. The quality of the included trials was assessed using the MINORS tool. Publication bias was evaluated through funnel plot and Egger's test. RESULTS: A total of 17 publications involving 1,377 cases were included. The pooled CR rate, ORR, and DCR of the patients treated with TACE plus camrelizumab had a pooled CR rate of 8% (95% CI: 0.01-0.15, p=0.03), ORR of 47% (95% CI: 0.42-0.52, p<0.00001) and DCR of 82% (95% CI: 0.77-0.88, p<0.00001), respectively. Compared with a control group that did not receive TACE or camrelizumab, the pooled RR of CR rate, ORR, and DCR were 1.61 (95% CI: 1.27-2.04, p<0.0001), 1.56 (95% CI: 1.19-2.05, p=0.001) and 1.55 (95% CI: 1.19-2.03, p=0.001), respectively. Besides, the combination regimen can prolong the OS (HR=2.60, 95% CI: 2.25-3.02, p<0.00001) and PFS (HR=4.90, 95% CI: 1.94-12.38, p=0.0008). However, the incidence of treatment-related AEs was relatively high (77%), with 29% for grade 3 AEs. The most common AEs observed were pain (47%), fever (46%), hepatic function abnormalities (44%), hypoalbuminemia (39%), and hypertension (37%). The combination treatment did not increase the incidence of AEs compared to the control group, except for the hand-foot skin reaction (RR=0.85, 0.74-0.97, p=0.01), hepatic encephalopathy (RR=4.29, 2.51-7.35, p<0.00001) and nausea (RR=1.35, 1.13-1.61, p=0.001). CONCLUSIONS: Combination therapy of TACE plus camrelizumab has shown notable clinical benefits, improved survival, and a manageable safety profile in patients with HCC, but it is essential to monitor and manage the specific toxicities, especially for the camrelizumab-related AEs.

Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.

Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.