Ocean internal tides suppress tropical cyclones in the South China Sea.

Tropical Cyclones (TCs) are devastating natural disasters. Analyzing four decades of global TC data, here we find that among all global TC-active basins, the South China Sea (SCS) stands out as particularly difficult ocean for TCs to intensify, despite favorable atmosphere and ocean conditions. Over the SCS, TC intensification rate and its probability for a rapid intensification (intensification by ≥ 15.4 m s-1 day-1) are only 1/2 and 1/3, respectively, of those for the rest of the world ocean. Originating from complex interplays between astronomic tides and the SCS topography, gigantic ocean internal tides interact with TC-generated oceanic near-inertial waves and induce a strong ocean cooling effect, suppressing the TC intensification. Inclusion of this interaction between internal tides and TC in operational weather prediction systems is expected to improve forecast of TC intensity in the SCS and in other regions where strong internal tides are present.

Tea Consumption, Milk or Sweeteners Addition, Genetic Variation in Caffeine Metabolism, and Incident Venous Thromboembolism.

OBJECTIVE: The association between tea consumption and venous thromboembolism (VTE) remains unknown. We aimed to evaluate the association between tea consumption with different additives (milk and/or sweeteners) and incident VTE, and the modifying effects of genetic variation in caffeine metabolism on the association. METHODS: A total of 190,189 participants with complete dietary information and free of VTE at baseline in the UK Biobank were included. The primary outcome was incident VTE, including incident deep vein thrombosis and pulmonary embolism. RESULTS: During a median follow-up of 12.1 years, 4,485 (2.4%) participants developed incident VTE. Compared with non-tea drinkers, tea drinkers who added neither milk nor sweeteners (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.76-0.94), only milk (HR: 0.86; 95% CI: 0.80-0.93), and both milk and sweeteners to their tea (HR: 0.90; 95% CI: 0.81-0.99) had a lower risk of VTE, while those who added only sweeteners to their tea did not (HR: 0.94; 95% CI: 0.75-1.17). Moreover, there was an L-shaped relationship between tea consumption and incident VTE among tea drinkers who added neither milk nor sweeteners, only milk, and both milk and sweeteners to their tea, respectively. However, a nonsignificant association was found among tea drinkers who added only sweeteners to their tea. Genetic variation in caffeine metabolism did not significantly modify the association (p-interaction = 0.659). CONCLUSION: Drinking unsweetened tea, with or without added milk, was associated with a lower risk of VTE. However, there was no significant association between drinking tea with sweeteners and incident VTE.

Mitochondria-localizing triphenylphosphine-8-hydroxyquinoline Ru complexes induce ferroptosis and their antitumor evaluation.

Ruthenium complexes are one of the most promising anticancer drugs and ferroptosis is a novel form of regulated cell death, the study on the effect of Ru complexes on ferroptosis is helpful to find more effective antitumor drugs. Here, the synthesis and characterization of two Ru complexes containing 8-hydroxylquinoline and triphenylphosphine as ligands, [Ru(L1) (PPh3)2Cl2] (Ru-1), [Ru(L2) (PPh3)2Cl2] (Ru-2), were reported. Complexes Ru-1 âˆ¼ Ru-2 showed good anticancer activity in Hep-G2 cells. Researches indicated that complexes Ru-1 âˆ¼ Ru-2 could be enriched and appear as red fluorescence in the mitochondria, arouse dysfunction of mitochondria, induce the accumulation of reactive oxygen species (ROS) and lipid peroxidation (LPO), while the morphology of nuclei and cell apoptosis had no significant change. Further experiments proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in Hep-G2 cells. Remarkably, Ru-1 showed high inhibitory activity against xenograft tumor growth in vivo (TGIR = 49%). This study shows that the complex Ru-1 could act as a novel drug candidate by triggering cell ferroptosis.

Perioperative Hypothermia in Elderly Patients During Pelvic Floor Reconstruction Surgery: An Observational Study.

INTRODUCTION AND HYPOTHESIS: The potential predictors of pelvic floor reconstruction surgery hypothermia remain unclear. This prospective cohort study was aimed at identifying these predictors and evaluating the outcomes associated with perioperative hypothermia. METHODS: Elderly patients undergoing pelvic floor reconstruction surgery were consecutively enrolled from April 2023 to September 2023. Perioperative temperature was measured at preoperative (T1), every 15 min after the start of anesthesia (T2), and 15 min postoperative (T3) using a temperature probe. Perioperative hypothermia was defined as a core temperature below 36°C at any point during the procedure. Multivariate logistic regression analysis was conducted to determine factors associated with perioperative hypothermia. RESULTS: A total of 229 patients were included in the study, with 50.7% experiencing hypothermia. Multivariate analysis revealed that the surgical method involving pelvic floor combined with laparoscopy, preoperative temperature < 36.5°C, anesthesia duration ≥ 120 min, and the high levels of anxiety were significantly associated with perioperative hypothermia. The predictive value of the multivariate model was 0.767 (95% CI, 0.706 to 0.828). CONCLUSIONS: This observational prospective study identified several predictive factors for perioperative hypothermia in elderly patients during pelvic floor reconstruction surgery. Strategies aimed at preventing perioperative hypothermia should target these factors. Further studies are required to assess the effectiveness of these strategies, specifically in elderly patients undergoing pelvic floor reconstruction surgery.

Automated insulin delivery in children with type 1 diabetes during physical activity: a meta-analysis.

OBJECTIVES: The aim of this study was to evaluating the performance of the automated insulin delivery (AID) in adolescents, and children with type 1 diabetes (T1D) during physical activity. METHODS: Relevant studies were searched electronically in the Cochrane Library, PubMed, and Embase utilizing the key words "Child", "Insulin Infusion Systems", and "Diabetes Mellitus" from inception to 17th March 2024 to evaluate the performance of the AID in adolescents, and children with T1D during physical activity. RESULTS: Twelve studies involving 514 patients were identified. AID did not show a beneficial effect on duration of hypoglycemia<70 mg/dL during study period (p>0.05; I 2=96 %) and during the physical activity (p>0.99). Percentage of sensor glucose values in TIR was higher in AID than the non-AID pumps during study period (p<0.001; I 2=94 %). The duration of hyperglycemic time was significantly decreased in AID group compared to the non-AID pumps group during study period (p<0.05; I 2>50 %). CONCLUSIONS: AID improved TIR and decreased the duration of hyperglycemic time, but did not appear to have a significant beneficial effect on the already low post-exercise duration of hypoglycemia achievable by open loop or sensor-augmented pumps in adolescents and children with T1D during physical activity; further research is needed to confirm the beneficial effect of AID on duration of hypoglycemia.

Performance of large language models on benign prostatic hyperplasia frequently asked questions.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition, yet it is challenging for the average BPH patient to find credible and accurate information about BPH. Our goal is to evaluate and compare the accuracy and reproducibility of large language models (LLMs), including ChatGPT-3.5, ChatGPT-4, and the New Bing Chat in responding to a BPH frequently asked questions (FAQs) questionnaire. METHODS: A total of 45 questions related to BPH were categorized into basic and professional knowledge. Three LLM-ChatGPT-3.5, ChatGPT-4, and New Bing Chat-were utilized to generate responses to these questions. Responses were graded as comprehensive, correct but inadequate, mixed with incorrect/outdated data, or completely incorrect. Reproducibility was assessed by generating two responses for each question. All responses were reviewed and judged by experienced urologists. RESULTS: All three LLMs exhibited high accuracy in generating responses to questions, with accuracy rates ranging from 86.7% to 100%. However, there was no statistically significant difference in response accuracy among the three (p > 0.017 for all comparisons). Additionally, the accuracy of the LLMs' responses to the basic knowledge questions was roughly equivalent to that of the specialized knowledge questions, showing a difference of less than 3.5% (GPT-3.5: 90% vs. 86.7%; GPT-4: 96.7% vs. 95.6%; New Bing: 96.7% vs. 93.3%). Furthermore, all three LLMs demonstrated high reproducibility, with rates ranging from 93.3% to 97.8%. CONCLUSIONS: ChatGPT-3.5, ChatGPT-4, and New Bing Chat offer accurate and reproducible responses to BPH-related questions, establishing them as valuable resources for enhancing health literacy and supporting BPH patients in conjunction with healthcare professionals.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors Versus Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma with First- or Lower-Order Portal Vein Tumor Thrombosis.

PURPOSE: To compare the efficacy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICI) versus TKIs plus ICIs (TKI-ICI) for unresectable hepatocellular carcinoma (HCC) with first- or lower-order portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: A retrospective study was performed in HCC patients with first- or lower-order PVTT receiving TKIs (Lenvatinib or sorafenib) plus ICIs (camrelizumab, sintilimab, or atezolizumab) with or without TACE from four institutions between January 2019 and January 2022. Propensity score-based method was performed to minimize bias by confounding factors. Tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. RESULTS: After inverse probability of treatment weighting, two balanced pseudopopulations were created: 106 patients in the TACE-TKI-ICI group and 109 patients in the TKI-ICI group. The objective response rate was higher in the TACE-TKI-ICI group (50.9% vs. 28.4%, P < 0.001). The median PFS and OS were significantly longer in the TACE-TKI-ICI group than in the TKI-ICI group (PFS: 9.1 vs. 5.0 months, P = 0.005; OS: 19.1 vs. 12.7 months, P = 0.002). In Cox regression, TACE-TKI-ICI treatment was an independent predictor of favorable OS. Treatment-related grade 3/4 AEs were comparable between the two groups (22.6% vs. 17.9%, P = 0.437). CONCLUSION: TACE-TKI-ICI therapy contributed to better tumor control, PFS and OS than TKI-ICI therapy in unresectable HCC patients with first- or lower-order PVTT.

Effect of RARC-ERAS nursing program on clinical outcomes in patients undergoing RARC surgery: a retrospective, propensity matching study.

Currently, there is no specific perioperative nursing standard for RARC based on the ERAS concept. This retrospective study investigates to analyze the effect of RARC-ERAS nursing program on VTE and other clinical outcomes in patients undergoing RARC surgery. This retrospective study included 216 patients undergoing RARC surgery From January 1, 2022 to December 30, 2023, and propensity score adjustment analysis was applied. The study compares a control group receiving traditional nursing and an observation group receiving RARC-ERAS nursing program. Perioperative variables and other postoperative complications were retrieved from the hospital medical records. After propensity score matching, there were no significant differences in the demographic and clinical characteristics between the two groups (p > 0.05). The ERAS group exhibited aa significantly higher rate of postoperative unobstructed venous blood flow in the lower extremities by color Doppler ultrasound as compared to the control group (94.6% VS 80.4%, p = 0.042). Before anesthesia induction, lower preoperative anxiety and surgical information needs scores were observed in the ERAS group than in the control group (p < 0.05). Compared to the control group, the ERAS group demonstrated a shorter surgical duration, a lower incidence of perioperative hypothermia, less time needed for getting out of bed, anal exhaust, and for defecation after returning to the ward (p < 0.05). RARC-ERAS nursing program significantly increased the rate of postoperative unobstructed venous blood flow in the lower extremities by color doppler ultrasound, lower preoperative anxiety and intraoperative hypothermia in patients undergoing RARC. This nursing approach presents a valuable strategy for enhancing patient outcomes and merits further exploration in clinical practice.Trial registration:ChiCTR2400081118; http://www.chictr.org.cn , Principal investigator: Mang-mang He, Date of registration: Feb 22, 2024.

Evaluation of models to predict prognosis in patients with advanced hepatocellular carcinoma treated with TACE combined with apatinib.

BACKGROUND: The HAP, Six-and-Twelve, Up to Seven, and ALBI scores have been substantiated as reliable prognostic markers in patients presenting with intermediate and advanced hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) treatment. Given this premise, our research aims to assess the predictive efficacy of these models in patients with intermediate and advanced HCC receiving a combination of TACE and Apatinib. Additionally, we have conducted a meticulous comparative analysis of these four scoring systems to discern their respective predictive capacities and efficacies in combined therapy. METHODS: Performing a retrospective analysis on the clinical data from 200 patients with intermediate and advanced HCC, we studied those who received TACE combined with Apatinib at the First Affiliated Hospital of the University of Science and Technology of China between June 2018 and December 2022. To identify the factors affecting survival, the study performed univariate and multivariate Cox regression analyses, with calculations of four different scores: HAP, Six-and-Twelve, Up to Seven, and ALBI. Lastly, Harrell's C-index was employed to compare the prognostic abilities of these scores. RESULTS: Cox proportional hazards model results revealed that the ALBI score, presence of portal vein tumor thrombus (PVTT, )and tumor size are independent determinants of prognostic survival. The Kaplan-Meier analyses showed significant differences in survival rates among patients classified by the HAP, Six-and-Twelve, Up to Seven, and ALBI scoring methods. Of the evaluated systems, the HAP scoring demonstrated greater prognostic precision, with a Harrell's C-index of 0.742, surpassing the alternative models (P < 0.05). In addition, an analysis of the area under the AU-ROC curve confirms the remarkable superiority of the HAP score in predicting short-term survival outcomes. CONCLUSION: Our study confirms the predictive value of HAP, Six-and-Twelve, Up to Seven, and ALBI scores in intermediate to advanced Hepatocellular Carcinoma (HCC) patients receiving combined Transarterial Chemoembolization (TACE) and Apatinib therapy. Notably, the HAP model excels in predicting outcomes for this specific HCC subgroup.

Efficacy and safety of precision-guided transjugular extrahepatic portosystemic shunt (TEPS) in the management of cavernous transformation of the portal vein with portal hypertension: a case series.

BACKGROUND AND AIMS: Performing a Transjugular intrahepatic portal system shunt (TIPS) in patients with portal vein cavernous transformation (CTPV) poses significant challenges. As an alternative, transjugular extrahepatic portal vein shunt (TEPS) may offer a potential solution for these patients. Nonetheless, the effectiveness and safety of TEPS remain uncertain. This case series study aimed to evaluate the efficacy and safety of TEPS in treating patients with CTPV portal hypertension complications. METHODS: The study encompassed a cohort of 22 patients diagnosed with CTPV who underwent TEPS procedures. Of these, 13 patients manifested recurrent hemorrhagic episodes subsequent to conventional therapies, 8 patients grappled with recurrent or refractory ascites, and 1 patient experienced acute bleeding but refused endoscopic treatment. Comprehensive postoperative monitoring was conducted for all patients to rigorously evaluate both the technical and clinical efficacy of the intervention, as well as long-term outcomes. RESULTS: The overall procedural success rate among the 22 patients was 95.5% (21/22).During the TEPS procedure, nine patients were guided by percutaneous splenic access, three patients were guided by percutaneous hepatic access, five patients were guided by transmesenteric vein access from the abdomen, and two patients were guided by catheter marking from the hepatic artery. Additionally, guidance for three patients was facilitated by pre-existing TIPS stents. The postoperative portal pressure gradient following TEPS demonstrated a statistically significant decrease compared to preoperative values (24.95 ± 3.19 mmHg vs. 11.48 ± 1.74 mmHg, p < 0.01).Although three patients encountered perioperative complications, their conditions ameliorated following symptomatic treatment, and no procedure-related fatalities occurred. During a median follow-up period of 14 months, spanning a range of 5 to 39 months, we observed four fatalities. Specifically, one death was attributed to hepatocellular carcinoma, while the remaining three were ascribed to chronic liver failure. During the follow-up period, no instances of shunt dysfunction were observed. CONCLUSIONS: Precision-guided TEPS appears to be a safe and efficacious intervention for the management of CTPV.

[Mechanism of traditional Chinese medicine in treating ulcerative colitis-related colorectal cancer by regulating NF-κB-related signaling pathways: a review].

Ulcerative colitis is a chronic, recurrent, and nonspecific intestinal inflammatory disease, which is difficult to cure and has the risk of deterioration into related tumors. Long-term chronic inflammatory stimulation can increase the risk of cancerization. With the signaling pathway as a key link in the regulation of tumor microenvironments, nuclear factor-kappa B(NF-κB) is an important regulator of intestinal inflammation. It can also be co-regulated as downstream factors of other signaling pathways, such as TLR4, MAPK, STAT, PI3K, and so on. At present, a large number of animal experiments have proved that traditional Chinese medicine(TCM) can reduce inflammation by interfering with NF-κB-related signaling pathways, improve intestinal inflammation, and inhibit the progression of inflammation to tumors. This article reviewed the relationship between NF-κB-related signaling pathways and the intervention mechanism of TCM, so as to provide a reference for the clinical treatment of ulcerative colitis and the optimization of related cancer prevention strategies.

Prognostic Value of an Immune Long Non-Coding RNA Signature in Liver Hepatocellular Carcinoma.

In recent years, there has been a growing recognition of the important role that long non-coding RNAs (lncRNAs) play in the immunological process of hepatocellular carcinoma (LIHC). An increasing number of studies have shown that certain lncRNAs hold great potential as viable options for diagnosis and treatment in clinical practice. The primary objective of our investigation was to devise an immune lncRNA profile to explore the significance of immune-associated lncRNAs in the accurate diagnosis and prognosis of LIHC. Gene expression profiles of LIHC samples obtained from TCGA database were screened for immune-related genes. The optimal immune-related lncRNA signature was built via correlational analysis, univariate and multivariate Cox analysis. Then, the Kaplan-Meier plot, ROC curve, clinical analysis, gene set enrichment analysis, and principal component analysis were performed to evaluate the capability of the immune lncRNA signature as a prognostic indicator. Six long non-coding RNAs were identified via correlation analysis and Cox regression analysis considering their interactions with immune genes. Subsequently, tumor samples were categorized into two distinct risk groups based on different clinical outcomes. Stratification analysis indicated that the prognostic ability of this signature acted as an independent factor. The Kaplan-Meier method was employed to conduct survival analysis, results showed a significant difference between the two risk groups. The predictive performance of this signature was validated by principal component analysis (PCA). Additionally, data obtained from gene set enrichment analysis (GSEA) revealed several potential biological processes in which these biomarkers may be involved. To summarize, this study demonstrated that this six-lncRNA signature could be identified as a potential factor that can independently predict the prognosis of LIHC patients.

Dehydrozaluzanin C- derivative protects septic mice by alleviating over-activated inflammatory response and promoting the phagocytosis of macrophages.

Host-directed therapy (HDT) is a new adjuvant strategy that interfere with host cell factors that are required by a pathogen for replication or persistence. In this study, we assessed the effect of dehydrozaluzanin C-derivative (DHZD), a modified compound from dehydrozaluzanin C (DHZC), as a potential HDT agent for severe infection. LPS-induced septic mouse model and Carbapenem resistant Klebsiella pneumoniae (CRKP) infection mouse model was used for testing in vivo. RAW264.7 cells, mouse primary macrophages, and DCs were used for in vitro experiments. Dexamethasone (DXM) was used as a positive control agent. DHZD ameliorated tissue damage (lung, kidney, and liver) and excessive inflammatory response induced by LPS or CRKP infection in mice. Also, DHZD improved the hypothermic symptoms of acute peritonitis induced by CRKP, inhibited heat-killed CRKP (HK-CRKP)-induced inflammatory response in macrophages, and upregulated the proportions of phagocytic cell types in lungs. In vitro data suggested that DHZD decreases LPS-stimulated expression of IL-6, TNF-α and MCP-1 via PI3K/Akt/p70S6K signaling pathway in macrophages. Interestingly, the combined treatment group of DXM and DHZD had a higher survival rate and lower level of IL-6 than those of the DXM-treated group; the combination of DHZD and DXM played a synergistic role in decreasing IL-6 secretion in sera. Moreover, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in a clathrin- and actin-dependent manner. This data suggests that DHZD may be a potential drug candidate for treating bacterial infections.

Diagnostic accuracy of magnetically guided capsule endoscopy with a detachable string for detecting oesophagogastric varices in adults with cirrhosis: prospective multicentre study.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of using magnetically guided capsule endoscopy with a detachable string (ds-MCE) for detecting and grading oesophagogastric varices in adults with cirrhosis. DESIGN: Prospective multicentre diagnostic accuracy study. SETTING: 14 medical centres in China. PARTICIPANTS: 607 adults (>18 years) with cirrhosis recruited between 7 January 2021 and 25 August 2022. Participants underwent ds-MCE (index test), followed by oesophagogastroduodenoscopy (OGD, reference test) within 48 hours. The participants were divided into development and validation cohorts in a ratio of 2:1. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity and specificity of ds-MCE in detecting oesophagogastric varices compared with OGD. Secondary outcomes included the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices and the diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices. RESULTS: ds-MCE and OGD examinations were completed in 582 (95.9%) of the 607 participants. Using OGD as the reference standard, ds-MCE had a sensitivity of 97.5% (95% confidence interval 95.5% to 98.7%) and specificity of 97.8% (94.4% to 99.1%) for detecting oesophagogastric varices (both P<0.001 compared with a prespecified 85% threshold). When using the optimal 18% threshold for luminal circumference of the oesophagus derived from the development cohort (n=393), the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices in the validation cohort (n=189) were 95.8% (89.7% to 98.4%) and 94.7% (88.2% to 97.7%), respectively. The diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices was 96.3% (92.6% to 98.2%), 96.9% (95.2% to 98.0%), and 96.7% (95.0% to 97.9%), respectively. Two serious adverse events occurred with OGD but none with ds-MCE. CONCLUSION: The findings of this study suggest that ds-MCE is a highly accurate and safe diagnostic tool for detecting and grading oesophagogastric varices and is a promising alternative to OGD for screening and surveillance of oesophagogastric varices in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03748563.

Inborn errors of immunity and its clinical significance in children with lymphoma in China: a single-center study.

OBJECTIVE: To investigate the incidence, clinical and genetic characteristics of pediatric lymphoma patients of China with inborn errors of immunity (IEI)-related gene mutations, which have not been fully studied. METHOD: From Jan. 2020 to Mar. 2023, IEI-related genetic mutations were retrospectively explored in 108 children with lymphomas admitted to Beijing Children's Hospital by NGS. Genetic rule and clinical characteristics as well as treatment outcomes were compared between patients with or without IEI-related gene mutations. RESULTS: A total of 17 patients (15.7 %) harbored IEI-associated mutations, including 4 cases with X-linked lymphoproliferative syndrome (XLP), 3 cases had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), 2 cases with Activated p110 syndrome (APDS). Patients with IEI all had alteration of immunocompetence with decreased levels of immunoglobulin and lymphocyte subsets. Recurrent infection existed in 41.2 % of patients. The 18-month event-free survival (EFS) and the overall response rate (ORR) of patients with IEI are significantly lower than those without IEI (33.86% vs. 73.26 %, p = 0.011; 52.94% vs. 87.91 %, p = 0.002, respectively). In addition, patients with IEI had a higher progression disease (PD) rate of 23.5 % than those without IEI of 4.4 % (p = 0.006). CONCLUSION: The present study demonstrated that IEI-associated lymphomas were much more common than originally appreciated in pediatric lymphomas, and those were insensitive to treatment and more likely to progress or relapse. The genomic analysis and a thorough review of the medical history of IEI can be used to distinguish them from pediatric lymphomas without IEI, which are beneficial for the early diagnosis and direct intervention.

Efficacy and Safety of TACE Combined with a Tyrosine Kinase Inhibitor for the Treatment of TACE-Refractory Hepatocellular Carcinoma: A Retrospective Comparative Study.

PURPOSE: Combining angiogenesis inhibitors may enhance therapeutic efficacy synergistically after TACE refractoriness. The purpose of this study was to compare the outcomes of transarterial chemoembolization (TACE) plus a tyrosine kinase inhibitor (TACE-TKI) with TKI only for patients with TACE-refractory hepatocellular carcinoma (HCC). METHODS: From January 2019 to March 2022, 101 HCC patients confirmed with TACE-refractory were retrospectively reviewed in the study. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were evaluated between groups. RESULTS: Fifty-two patients undergoing TACE-TKI, while 32 patients receiving TKI alone were included. The objective response rate (ORR) was higher in the TACE-TKI group compared with the TKI group (55.8% vs. 25.0%, P = 0.006). The median PFS in the TACE-TKI group was significantly longer than that in the TKI group (7.6 months vs. 4.9 months, P = 0.018). The median OS was non reach to statistical longer than that in the TKI alone group (19.5 months vs. 17.7 months, P = 0.055). Subgroup analysis showed that TACE-TKI treatment resulted in a significantly longer median PFS and OS for Barcelona Clinic Liver Cancer (BCLC) stage B patients (PFS 11.8 months vs. 5.1 months, P = 0.017; OS 30.3 months vs. 19.4 months, P = 0.022). CONCLUSION: For patients with TACE-refractory HCC, TACE-TKI appeared to be superior to TKI monotherapy with regard to tumor control and PFS. Furthermore, for the BCLC stage B subgroup, TACE-TKI therapy was superior to TKI monotherapy in both OS and PFS.

α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata.

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.

Expression profiles of host miRNAs and circRNAs and ceRNA network during Toxoplasma gondii lytic cycle.

Toxoplasma gondii is an opportunistic protozoan parasite that is highly prevalent in the human population and can lead to adverse health consequences in immunocompromised patients and pregnant women. Noncoding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), play important regulatory roles in the pathogenesis of many infections. However, the differentially expressed (DE) miRNAs and circRNAs implicated in the host cell response during the lytic cycle of T. gondii are unknown. In this study, we profiled the expression of miRNAs and circRNAs in human foreskin fibroblasts (HFFs) at different time points after T. gondii infection using RNA sequencing (RNA-seq). We identified a total of 7, 7, 27, 45, 70, 148, 203, and 217 DEmiRNAs and 276, 355, 782, 1863, 1738, 6336, 1229, and 1680 DEcircRNAs at 1.5, 3, 6, 9, 12, 24, 36, and 48 h post infection (hpi), respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that the DE transcripts were enriched in immune response, apoptosis, signal transduction, and metabolism-related pathways. These findings provide new insight into the involvement of miRNAs and circRNAs in the host response to T. gondii infection.

Structural analysis of PTPN21 reveals a dominant-negative effect of the FERM domain on its phosphatase activity.

PTPN21 belongs to the four-point-one, ezrin, radixin, moesin (FERM) domain-containing protein tyrosine phosphatases (PTP) and plays important roles in cytoskeleton-associated cellular processes like cell adhesion, motility, and cargo transport. Because of the presence of a WPE loop instead of a WPD loop in the phosphatase domain, it is often considered to lack phosphatase activity. However, many of PTPN21's biological functions require its catalytic activity. To reconcile these findings, we have determined the structures of individual PTPN21 FERM, PTP domains, and a complex between FERM-PTP. Combined with biochemical analysis, we have found that PTPN21 PTP is weakly active and is autoinhibited by association with its FERM domain. Disruption of FERM-PTP interaction results in enhanced ERK activation. The oncogenic HPV18 E7 protein binds to PTP at the same location as PTPN21 FERM, indicating that it may act by displacing the FERM domain from PTP. Our results provide mechanistic insight into PTPN21 and benefit functional studies of PTPN21-mediated processes.

J-shaped association between dietary thiamine intake and the risk of cognitive decline in cognitively healthy, older Chinese individuals.

Background: The prospective association of dietary thiamine intake with the risk of cognitive decline among the general older adults remains uncertain. Aims: To investigate the association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals. Methods: The study included a total of 3106 participants capable of completing repeated cognitive function tests. Dietary nutrient intake information was collected through 3-day dietary recalls and using a 3-day food-weighed method to assess cooking oil and condiment consumption. Cognitive decline was defined as the 5-year decline rate in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified. Results: The median follow-up duration was 5.9 years. There was a J-shaped relationship between dietary thiamine intake and the 5-year decline rate in global and composite cognitive scores, with an inflection point of 0.68 mg/day (95% confidence interval (CI): 0.56 to 0.80) and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake. Before the inflection point, thiamine intake was not significantly associated with cognitive decline. Beyond the inflection point, each unit increase in thiamine intake (mg/day) was associated with a significant decrease of 4.24 (95% CI: 2.22 to 6.27) points in the global score and 0.49 (95% CI: 0.23 to 0.76) standard units in the composite score within 5 years. A stronger positive association between thiamine intake and cognitive decline was observed in those with hypertension, obesity and those who were non-smokers (all p<0.05). Conclusions: This study revealed a J-shaped association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals, with an inflection point at 0.68 mg/day and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake.