Acquired resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer.

The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient's tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.

Host-microbiota interaction in intestinal stem cell homeostasis.

Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

Efficacy of bougie first approach for endotracheal intubation with video laryngoscopy during continuous chest compression: a randomized crossover manikin trial.

BACKGROUND: Endotracheal intubation is challenging during cardiopulmonary resuscitation, and video laryngoscopy has showed benefits for this procedure. The aim of this study was to compare the effectiveness of various intubation approaches, including the bougie first, preloaded bougie, endotracheal tube (ETT) with stylet, and ETT without stylet, on first-attempt success using video laryngoscopy during chest compression. METHODS: This was a randomized crossover trial conducted in a general tertiary teaching hospital. We included anesthesia residents in postgraduate year one to three who passed the screening test. Each resident performed intubation with video laryngoscopy using the four approaches in a randomized sequence on an adult manikin during continuous chest compression. The primary outcome was the first-attempt success defined as starting ventilation within a one minute. RESULTS: A total of 260 endotracheal intubations conducted by 65 residents were randomized and analyzed with 65 procedures in each group. First-attempt success occurred in 64 (98.5%), 57 (87.7%), 56 (86.2%), and 46 (70.8%) intubations in the bougie-first, preloaded bougie, ETT with stylet, and ETT without stylet approaches, respectively. The bougie-first approach had a significantly higher possibility of first-attempt success than the preloaded bougie approach [risk ratio (RR) 8.00, 95% confidence interval (CI) 1.03 to 62.16, P = 0.047], the ETT with stylet approach (RR 9.00, 95% CI 1.17 to 69.02, P = 0.035), and the ETT without stylet approach (RR 19.00, 95% CI 2.62 to 137.79, P = 0.004) in the generalized estimating equation logistic model accounting for clustering of intubations operated by the same resident. In addition, the bougie first approach did not result in prolonged intubation or increased self-reported difficulty among the study participants. CONCLUSIONS: The bougie first approach with video laryngoscopy had the highest possibility of first-attempt success during chest compression. These results helped inform the intubation approach during CPR. However, further studies in an actual clinical environment are warranted to validate these findings. TRIAL REGISTRATION: Clinicaltrials.gov; identifier: NCT05689125; date: January 18, 2023.

Deep Learning Detection and Segmentation of Facet Joints in Ultrasound Images Based on Convolutional Neural Networks and Enhanced Data Annotation.

The facet joint injection is the most common procedure used to release lower back pain. In this paper, we proposed a deep learning method for detecting and segmenting facet joints in ultrasound images based on convolutional neural networks (CNNs) and enhanced data annotation. In the enhanced data annotation, a facet joint was considered as the first target and the ventral complex as the second target to improve the capability of CNNs in recognizing the facet joint. A total of 300 cases of patients undergoing pain treatment were included. The ultrasound images were captured and labeled by two professional anesthesiologists, and then augmented to train a deep learning model based on the Mask Region-based CNN (Mask R-CNN). The performance of the deep learning model was evaluated using the average precision (AP) on the testing sets. The data augmentation and data annotation methods were found to improve the AP. The AP50 for facet joint detection and segmentation was 90.4% and 85.0%, respectively, demonstrating the satisfying performance of the deep learning model. We presented a deep learning method for facet joint detection and segmentation in ultrasound images based on enhanced data annotation and the Mask R-CNN. The feasibility and potential of deep learning techniques in facet joint ultrasound image analysis have been demonstrated.

Vaccination Shortens the Negative Nucleic Acid Conversion Time of the Older Population: A Retrospective Cohort Study of 73,456 Asymptomatic and Mild Patients with COVID-19 in Shanghai.

Purpose: To explore the influencing factors to predict the negative nucleic acid conversion time and ORF1ab gene CT value changes in patients with asymptomatic and mild COVID-19. Patients and Methods: A total of 73,456 patients with asymptomatic and mild COVID-19 admitted to the Mobile Cabin Hospital in Shanghai from April 3 to April 23, 2022 were selected as the research objects. Epidemiological, clinical, and laboratory data were collected. Correlation analysis was performed. Results: In patients <18 years old and ≥65 years old, COVID-19 vaccine can shorten the negative nucleic acid conversion time, which is reflected in the lower median or 75% quantile (P<0.001, P<0.05). In patients with underlying diseases, the negative nucleic acid conversion time of booster vaccination and complete vaccination was lower than that of non-vaccinated group (P<0.001, P<0.05). In patients ≤18 years of age or >65 years of age, patients with comorbidity and patients with symptoms, compared with patients 18-65 years of age, patients without comorbidity and patients without symptoms, there was a greater difference in the rate of rise of CT values between vaccinated and unvaccinated patients (P<0.05). Conclusion: The time of nucleic acid conversion to negative in patients with asymptomatic and mild COVID-19 is affected by age, comorbidity, and first nucleic acid CT value. Vaccination could shorten the negative nucleic acid conversion time of the older population, those with complications or symptoms. The vaccination of older patients does not increase the risk of symptoms.

Effects of selenium-cadmium co-enriched Cardamine hupingshanensis on bone damage in mice.

Selenium (Se) and cadmium (Cd) usually co-existed in soils, especially in areas with Se-rich soils in China. The potential health consequences for the local populations consuming foods rich in Se and Cd are unknown. Cardamine hupingshanensis (HUP) is Se and Cd hyperaccumulator plant that could be an ideal natural product to assess the protective effects of endogenous Se against endogenous Cd-caused bone damage. Male C57BL/6 mice were fed 5.22 mg/kg cadmium chloride (CdCl2) (Cd 3.2 mg/kg body weight (BW)), or HUP solutions containing Cd 3.2 mg/kg BW and Se 0.15, 0.29 or 0.50 mg/kg BW (corresponding to the HUP0, HUP1 and HUP2 groups) interventions. Se-enriched HUP1 and HUP2 significantly decreased Cd-induced femur microstructure damage and regulated serum bone osteoclastic marker levels and osteogenesis-related genes. In addition, endogenous Se significantly decreased kidney fibroblast growth factor 23 (FGF23) protein expression and serum parathyroid hormone (PTH) levels, and raised serum calcitriol (1,25(OH)2D3). Furthermore, Se also regulated gut microbiota involved in skeletal metabolism disorder. In conclusion, endogenous Se, especially with higher doses (the HUP2 group), positively affects bone formation and resorption by mitigating the damaging effects of endogenous Cd via the modulation of renal FGF23 expression, circulating 1,25(OH)2D3 and PTH and gut microbiota composition.

Baroreflex activation therapy for heart failure with reduced ejection fraction: A comprehensive systematic review and meta-analysis.

Background: In recent years, baroreflex activation therapy (BAT) has been utilized to treat heart failure with reduced ejection fraction (HFrEF). However, the supporting literature on its efficacy and safety is still limited. This investigation elucidates the effects of BAT in HFrEF patients to provide a reference for future clinical applications. Methods: This investigation follows Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. Relevant investigations on the use of BAT in HFrEF patients were searched and selected from 5 databases, including Web of Science, MEDLINE, PubMed, Embase, and Cochrane Library, from inception to December 2022. The methodological quality of eligible articles was assessed via the Cochrane risk of bias tool, and for meta-analysis, RevMan (5.3) was used. Results: Randomized controlled trials comprising 343 participants were selected for the meta-analysis, which revealed that in HFrEF patients, BAT enhanced the levels of LVEF (MD: 2.97, 95 % CI: 0.53 to 5.41), MLHFQ (MD: -14.81, 95 % CI: -19.57 to -10.06) and 6MWT (MD: 68.18, 95 % CI: 51.62 to 84.74), whereas reduced the levels of LVEDV (MD: -15.79, 95 % CI: -32.96 to 1.37) and DBP (MD: -2.43, 95 % CI: -4.18 to -0.68). Conclusion: It was concluded that BAT is an efficient treatment option for HFrEF patients. However, to validate this investigation, further randomized clinical trials with multiple centers and large sample sizes are needed.

Effect of modified endotracheal intubation protocol combined with early oral intake on postoperative recovery quality in thyroid and parathyroid surgery at a tertiary hospital in China: a 2x2 factorial randomised controlled trial protocol.

INTRODUCTION: Early oral intake (EOI) is supposed to be safe and beneficial to patients' recovery. However, the optimal timing of resuming oral intake has not been validated in thyroid and parathyroid surgery. On the other hand, a modified electromyography (EMG) endotracheal intubation protocol with real-time EMG monitoring during video laryngoscope/fibrescope-guided intubation was presented in 2022, which was regarded as an effective way to shorten the intubation time. We aimed to use Quality of Recovery-15 (QoR-15) questionnaire to compare the efficacy and safety of different EMG endotracheal intubation protocols combined with different postoperative oral intake strategy in thyroid and parathyroid surgery. METHODS AND ANALYSIS: This prospective, single-centre, 2×2 factorial, randomised controlled trial will be conducted in the Peking Union Medical College Hospital (PUMCH), China. We plan to recruit 200 adult patients who will receive thyroid or parathyroid surgery under intraoperative nerve monitoring. Eligible patients will be randomly divided into two groups, which will receive either the modified intubation protocol (M group) or conventional intubation process (C group). After patients enter postanaesthesia care unit and Steward scores ≥4, they will be randomly divided into two groups again, which will receive early resumption of oral intake (E group) or delayed resumption of oral intake (D group). Patients will be followed up during hospitalisation and the QoR-15 questionnaire will be administered to compare the quality of recovery on the day before surgery (T0), the first day after surgery (T1) and the day of discharge (T2). The primary outcome is the QoR-15 scores at T1. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of Peking Union Medical College Hospital (IRB K-2501). All participants will give written informed consent before participation. The results from this study will be shared at conferences and disseminated in international journals. TRIAL REGISTRATION NUMBER: NCT05624463.

Preoperative 6-minute walk distance is associated with postoperative complications in patients undergoing laparoscopic gastrointestinal cancer surgery.

OBJECTIVE: The 6-min walk test (6MWT) is a simple and valid method to evaluate cardiopulmonary function. We performed this prospective study in patients undergoing laparoscopic gastrointestinal cancer surgery to explore the association between preoperative 6MWT performance and overall postoperative complications. METHODS: This study was registered at clinicaltrials.gov (NCT03711526). The study consecutively enrolled patients receiving laparoscopic gastrointestinal cancer surgery in our institution. All patients performed the 6MWT upon recruitment and received 30 days of postoperative follow-up. The primary outcome was overall complications, defined by ≥ grade I Clavien-Dindo (CD) classification (2004) complications. Multivariable logistic regression was used to test the association of 6-min walk distance (6MWD) with the outcome. RESULTS: A total of 184 patients were included in the final analyses. In the 37 (20.1 %) patients with overall complications, the mean (standard deviation) preoperative 6MWD was 469.1 (86.8) m. In patients with no complications, the 6MWD was 502.6 (90.2) m. The mean difference was 33.5 m (95 % confidence interval, 1.3, 65.7; P = 0.042). A longer preoperative 6MWD was associated with a lower odds of developing postoperative complications (odds ratio, 0.994 per meter increase; 95 % confidence interval, 0.989, 0.999; p = 0.023). CONCLUSION: This study indicated an association between the preoperative 6MWD and postoperative complications in patients undergoing laparoscopic gastrointestinal cancer surgery.

Integrated bioinformatics and experiment revealed that cuproptosis is the potential common pathogenesis of three kinds of primary cardiomyopathy.

Cuproptosis is a recently reported new mode of programmed cell death which might be a potential co-pathogenesis of three kinds of primary cardiomyopathy. However, no investigation has reported a clear relevance between primary cardiomyopathy and cuproptosis. In this study, the differential cuproptosis-related genes (CRGs) shared by three kinds of primary cardiomyopathy were identified in training sets. As a result, four CRGs shared by three kinds of primary cardiomyopathy were acquired and they were mainly related to biological processes such as cell death and immuno-inflammatory response through differential analysis, correlation analysis, GSEA, GSVA and immune cell infiltration analysis. Then, three key CRGs (K-CRGs) with high diagnostic value were identified by LASSO regression. The results of nomogram, machine learning, ROC analysis, calibration curve and decision curve indicated that the K-CRGs exhibited outstanding performance in the diagnosis of three kinds of primary cardiomyopathy. After that, in each disease, two molecular subtypes clusters were distinguished. There were many differences between different clusters in the biological processes associated with cell death and immunoinflammation and K-CRGs had excellent molecular subtype identification efficacy. Eventually, results from validation datasets and in vitro experiments verified the role of K-CRGs in diagnosis of primary cardiomyopathy, identification of primary cardiomyopathic molecular subtypes and pathogenesis of cuproptosis. In conclusion, this study found that cuproptosis might be the potential common pathogenesis of three kinds of primary cardiomyopathy and K-CRGs might be promising biomarkers for the diagnosis and molecular subtypes identification of primary cardiomyopathy.

ATAT: Automated Tissue Alignment and Traversal in Spatial Transcriptomics with Self-Supervised Learning.

Spatial transcriptomics (ST) has enhanced RNA analysis in tissue biopsies, but interpreting these data is challenging without expert input. We present Automated Tissue Alignment and Traversal (ATAT), a novel computational framework designed to enhance ST analysis in the context of multiple and complex tissue architectures and morphologies, such as those found in biopsies of the gastrointestinal tract. ATAT utilizes self-supervised contrastive learning on hematoxylin and eosin (H&E) stained images to automate the alignment and traversal of ST data. This approach addresses a critical gap in current ST analysis methodologies, which rely heavily on manual annotation and pathologist expertise to delineate regions of interest for accurate gene expression modeling. Our framework not only streamlines the alignment of multiple ST samples, but also demonstrates robustness in modeling gene expression transitions across specific regions. Additionally, we highlight the ability of ATAT to traverse complex tissue topologies in real-world cases from various individuals and conditions. Our method successfully elucidates differences in immune infiltration patterns across the intestinal wall, enabling the modeling of transcriptional changes across histological layers. We show that ATAT achieves comparable performance to the state-of-the-art method, while alleviating the burden of manual annotation and enabling alignment of tissue samples with complex morphologies.

Evaluation the role of cuproptosis-related genes in the pathogenesis, diagnosis and molecular subtypes identification of atherosclerosis.

Background: At present, the pathogenesis of atherosclerosis has not been fully elucidated, and the diagnosis and treatment face great challenges. Cuproptosis is a novel cell death pattern that might be involved in the development of atherosclerosis. However, no research has reported the correlation between cuproptosis and atherosclerosis. Methods: The differential cuproptosis-related genes (CRGs) between atherosclerosis group and control group (A-CRGs) were discovered via differential expression analysis. The correlation analysis, PPI network analysis, GO, KEGG and GSEA analysis were performed to investigate the function of A-CRGs. The differences of biological function between atherosclerosis group and control group were investigated via immune infiltration analysis and GSVA. The LASSO regression, nomogram and machine learning models were constructed to predict atherosclerosis risk. The atherosclerosis molecular subtypes clusters were discovered via unsupervised cluster analysis. Subsequently, we used the above research methods to analyze the differential CRGs between clusters (M-CRGs) and evaluate the molecular subtypes identification performance of M-CRGs. Finally, we verified the diagnostic value for atherosclerosis and role in cuproptosis of these CRGs through the validation set and in vitro experiments. Results: Five A-CRGs were identified and they were mainly related to the biological function of copper ion metabolism and immune inflammatory response. The diagnostic models and nomogram of atherosclerosis based on 5 A-CRGs indicated that these genes had well diagnostic value. A total of two molecular subtypes clusters were obtained in the atherosclerosis group. There were many differences in biological functions between these two molecular subtypes clusters, such as mitochondrial outer membrane permeabilization and primary immunodeficiency. In addition, 3 M-CRGs were identified in the 2 clusters. Machine learning models and nomogram constructed based on M-CRGs showed that these genes had well molecular subtypes identification efficacy. In the end, the results of in vitro experiment and validation set confirmed the diagnostic value for atherosclerosis and role in cuproptosis of these genes. Conclusion: The cuproptosis may be a potential pathogenesis of atherosclerosis and CRGs may be promising markers for the diagnosis and molecular subtypes identification of atherosclerosis.

Isoquercitrin from Apocynum venetum L. Exerts Antiaging Effects on Yeasts via Stress Resistance Improvement and Mitophagy Induction through the Sch9/Rim15/Msn Signaling Pathway.

BACKGROUND: With the development of an aging sociality, aging-related diseases, such as Alzheimer's disease, cardiovascular disease, and diabetes, are dramatically increasing. To find small molecules from natural products that can prevent the aging of human beings and the occurrence of these diseases, we used the lifespan assay of yeast as a bioassay system to screen an antiaging substance. Isoquercitrin (IQ), an antiaging substance, was isolated from Apocynum venetum L., an herbal tea commonly consumed in Xinjiang, China. AIM OF THE STUDY: In the present study, we utilized molecular-biology technology to clarify the mechanism of action of IQ. METHODS: The replicative lifespans of K6001 yeasts and the chronological lifespans of YOM36 yeasts were used to screen and confirm the antiaging effect of IQ. Furthermore, the reactive oxygen species (ROS) and malondialdehyde (MDA) assay, the survival assay of yeast under stresses, real-time polymerase chain reaction (RT-PCR) and Western blotting analyses, the replicative-lifespan assay of mutants, such as Δsod1, Δsod2, Δgpx, Δcat, Δskn7, Δuth1, Δatg32, Δatg2, and Δrim15 of K6001, autophagy flux analysis, and a lifespan assay of K6001 yeast after giving a mitophagy inhibitor and activator were performed. RESULTS: IQ extended the replicative lifespans of the K6001 yeasts and the chronological lifespans of the YOM36 yeasts. Furthermore, the reactive nitrogen species (RNS) showed no change during the growth phase but significantly decreased in the stationary phase after treatment with IQ. The survival rates of the yeasts under oxidative- and thermal-stress conditions improved upon IQ treatment, and thermal stress was alleviated by the increasing superoxide dismutase (Sod) activity. Additionally, IQ decreased the ROS and MDA of the yeast while increasing the activity of antioxidant enzymes. However, it could not prolong the replicative lifespans of Δsod1, Δsod2, Δgpx, Δcat, Δskn7, and Δuth1 of K6001. IQ significantly increased autophagy and mitophagy induction, the presence of free green fluorescent protein (GFP) in the cytoplasm, and ubiquitination in the mitochondria of the YOM38 yeasts at the protein level. IQ did not prolong the replicative lifespans of Δatg2 and Δatg32 of K6001. Moreover, IQ treatment led to a decrease in Sch9 at the protein level and an increase in the nuclear translocation of Rim15 and Msn2. CONCLUSIONS: These results indicated that the Sch9/Rim15/Msn signaling pathway, as well as antioxidative stress, anti-thermal stress, and autophagy, were involved in the antiaging effects of IQ in the yeasts.

Patient Preferences for Anesthesiologist Attire During Preoperative Visits in China: A Cross-Sectional Survey.

Background: It is important for anesthesiologists to leave good impressions and build rapport with patients during preoperative visits. However, patient preferences for anesthesiologist attire have not been well studied in China. Purpose: To characterize patient perceptions of anesthesiologist attire during preoperative visits. Patients and Methods: In this cross-sectional survey, we included adult patients who underwent elective operations in various surgical departments. We presented photographs of both male and female models wearing six combinations of attire (formal in a white coat buttoned, formal in a white coat unbuttoned, casual in a white coat buttoned, casual in a white coat unbuttoned, scrubs in a white coat buttoned, and scrubs in a coat of the same green color buttoned) in a randomized sequence. Participants were asked to rate each attire combination in five domains, including professionalism, experience, attitude, approachability, and caring. Results: Of the 541 surveys distributed, 516 (95.4%) were completed and included in the analysis. The majority of respondents were female [389 (75.4%)] and aged 31-45 years [234 (45.3%)]. The combination of scrubs in a buttoned coat of the same color had the highest composite rating score [median (interquartile range): 50 (45, 50), adjusted P<0.001 compared with the other five combinations]. There was no significant difference in preference for standardized disposable or personalized cloth operating caps. Respondents' age was independently associated with the perceived importance of anesthesiologist attire (46-60 years vs 18-35 years: odds ratio 2.17, 95% confidence interval 1.12-4.18, P=0.021). Conclusion: Patients prefer anesthesiologists wearing scrubs in coats of the same color. Standardizing anesthesiologist attire based on these findings may improve patient satisfaction.

Association between post-COVID-19 status and perioperative morbidity and mortality: protocol for an ambispective cohort study.

INTRODUCTION: With COVID-19 bringing persistent impact on the worldwide population, perioperative management after SARS-CoV-2 infection needs to be revisited in the new period of different circulating coronavirus variants, vaccination status, increased reinfection rate and new disease control policies. This study aims to explore the association between time to surgery after COVID-19 diagnosis and the risk of postoperative morbidity and mortality. METHODS AND ANALYSIS: This is a single-centre ambispective cohort study. Patients with preoperative SARS-CoV-2 infection who require inpatient surgical intervention from 1 December 2022 to 28 February 2023 will be included. Baseline assessment will include the time interval between preoperative SARS-CoV-2 infection and surgery, COVID-19 diagnosis and symptoms, vaccination status and routine preoperative evaluations. The primary outcome will be postoperative composite complications within 30 days after surgery. Association between post-COVID-19 interval and the outcomes will be explored using logistic regression after adjusting for confounding variables. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of Peking Union Medical College Hospital (IRB K3570). We aim to publish and disseminate the findings in peer-reviewed journals, scientific conferences and on social media. TRIAL REGISTRATION NUMBER: NCT05689840.

The effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy: a randomized, double-blinded, controlled study.

BACKGROUND: We aimed to investigate the effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy. METHODS: Eighty 18-70 years old, American Society of Anesthesiologists level I-III patients scheduled for hepatectomy with a J-shaped subcostal incision were enrolled and randomized to receive either intermittent bolus paravertebral ropivacaine (0.5% loading, 0.2% infusion) or 0.9% saline infusion at 1:1 ratio (25 ml loading before surgery, 0.125 ml/kg/h bolus for postoperative 48 h). The primary outcome was set as postoperative 48 h cumulative intravenous morphine consumption recorded by a patient-controlled analgesic pump. RESULTS: Thirty-eight patients in each group completed the study. The cumulative morphine consumptions were lower in the paravertebral block than control group at postoperative 24 (difference -10.5 mg, 95%CI -16 mg to -6 mg, P < 0.001) and 48 (difference -12 mg, 95%CI -19.5 mg to -5 mg, P = 0.001) hours. The pain numerical rating scales at rest were lower in the paravertebral block than control group at postoperative 4 h (difference -2, 95%CI -3 to -1, P < 0.001). The active pain numerical rating scales were lower in the paravertebral block than control group at postoperative 12 h (difference -1, 95%CI -2 to 0, P = 0.005). Three months postoperatively, the paravertebral block group had lower rates of hypoesthesia (OR 0.28, 95%CI 0.11 to 0.75, P = 0.009) and numbness (OR 0.26, 95%CI 0.07 to 0.88, P = 0.024) than the control group. CONCLUSIONS: Intermittent bolus paravertebral block provided an opioid-sparing effect and enhanced recovery both in hospital and after discharge in patients undergoing hepatectomy. TRIAL REGISTRATION: clinicaltrials.gov (NCT04304274), date: 11/03/2020.

Molecular dynamics analyses of CLDN15 pore size and charge selectivity.

The Claudin-15 (CLDN15) channel is important for nutrient, electrolyte, and water transport in the gastrointestinal tract. We used cell culture studies and molecular dynamics simulations to elucidate its structure and permeability mechanisms. We provide a model that underscores the crucial role of the D55 residue in the CLDN15 selectivity filter, which interacts with permeating cations. Our studies demonstrated the mechanisms whereby the size and charge of the D55 residue influence paracellular permeability. By altering D55 to larger, negatively charged glutamic acid (E) or similarly sized neutral asparagine (N), we observed changes in pore size and selectivity, respectively. D55E mutation decreased pore size, favoring small ion permeability without affecting charge selectivity, while D55N mutation led to reduced charge selectivity without markedly altering size selectivity. These findings shed light on the complex interplay of size and charge selectivity of CLDN15 channels. This knowledge can inform the development of strategies to modulate the function of CLDN15 and similar channels, which has implications for tight junction modulation in health and disease.

Niclosamide (NA) overcomes cisplatin resistance in human ovarian cancer.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.