Association between changes in high-density lipoprotein cholesterol and risk of cardiovascular disease.

BACKGROUND: The present study was performed to determine the association between changes in the HDL-C concentration and incident CVD. METHODS: Time-dependent Cox regression models were used to evaluate the association between changes in the HDL-C concentration and the risk of incident CVD. Participants were followed up from 2015 to 2021. RESULTS: In total, 24,123 participants with a median follow-up of 4.26 years were analyzed, and the mean age of the cohort was 56.24 years, 57.8 % were female, 24.3 % were current smokers, and 12.8 % had a history of alcohol use. Low, normal, and high HDL-C was defined as <40, 40-80, and >80 mg/dL, respectively. The average time for the two HDL-C measurements was 2.8 years,compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was higher in those whose HDL-C changed to a low level, remained unchanged at a low level(HR, 1.24; 95 % CI, 1.01-1.40,P < 0.001), similarly, the risk of CVD was higher in those whose HDL-C changed from very high level to normal level(HR, 0.81; 95 % CI, 0.67-0.99,P = 0.039). Also compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was lower in those whose HDL-C increased from low to normal and high(HR, 0.80; 95 % CI, 0.66-0.98,P = 0.029). CONCLUSIONS: Participants whose HDL-C changed to a low level and whose low HDL-C level was maintained had a higher risk of CVD, whereas participants whose HDL-C changed from low to high had a lower risk of CVD.

Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress.

BACKGROUND: Long-term accumulation of misfolded proteins leads to endoplasmic reticulum (ER) stress in colorectal cancer (CRC). However, the precise pathways controlling the decision between survival and apoptosis in CRC are unclear. Therefore, in this study, we investigated the function and molecular mechanism of glucosidase I (GCS1) in regulating ER stress in CRC. METHODS: A public database was used to confirm the expression level of GCS1 in CRC and normal tissues. Clinical samples from our center were used to confirm the mRNA and protein expression levels of GCS1. Cell proliferation, migration, invasion, and apoptosis assays revealed the biological role of GCS1. Immunohistochemical techniques were used to evaluate the expression of key proteins in subcutaneous implanted tumors in nude mice, which provided further evidence for the biological function of GCS1 in promoting cancer in vivo. The results of coimmunoprecipitation-mass spectrometry analysis and immunofluorescence colocalization analysis the interaction between GCS1 and GRP78. In addition, the mechanism of action of USP10, GRP78, and GCS1 at the post- translational level was investigated. Finally, a tissue microarray was used to examine the connection between GCS1 and GRP78 expression and intracellular localization of these proteins using immunohistochemistry and immunofluorescence. RESULTS: The experimental results revealed that GCS1 was substantially expressed in CRC, with higher expression indicating a worse prognosis. Thus, GCS1 can enhance the proliferation and metastasis while inhibiting the apoptosis of CRC cells both in vivo and in vitro. Mechanistically, GCS1 binds to GRP78, recruits USP10 for deubiquitination of GRP78 to promote its degradation, and decreases ER stress-mediated apoptosis, increasing CRC cell proliferation and metastasis. CONCLUSIONS: In summary, GCS1 stimulates CRC growth and migration and reduces ER stress-mediated apoptosis via USP10-mediated deubiquitination of GRP78. Our findings identify a possible therapeutic target for CRC.

Efficacy and safety of MR-guided adaptive simultaneous integrated boost radiotherapy to primary lesions and positive lymph nodes in the neoadjuvant treatment of locally advanced rectal cancer: a randomized controlled phase III trial.

BACKGROUND: In locally advanced rectal cancer (LARC), optimizing neoadjuvant strategies, including the addition of concurrent chemotherapy and dose escalation of radiotherapy, is essential to improve tumor regression and subsequent implementation of anal preservation strategies. Currently, dose escalation studies in rectal cancer have focused on the primary lesions. However, a common source of recurrence in LARC is the metastasis of cancer cells to the proximal lymph nodes. In our trial, we implement simultaneous integrated boost (SIB) to both primary lesions and positive lymph nodes in the experimental group based on magnetic resonance-guided adaptive radiotherapy (MRgART), which allows for more precise (and consequently intense) targeting while sparing neighboring healthy tissue. The objective of this study is to evaluate the efficacy and safety of MRgART dose escalation to both primary lesions and positive lymph nodes, in comparison with the conventional radiotherapy of long-course concurrent chemoradiotherapy (LCCRT) group, in the neoadjuvant treatment of LARC. METHODS: This is a multi-center, randomized, controlled phase III trial (NCT06246344). 128 patients with LARC (cT3-4/N+) will be enrolled. During LCCRT, patients will be randomized to receive either MRgART with SIB (60-65 Gy in 25-28 fractions to primary lesions and positive lymph nodes; 50-50.4 Gy in 25-28 fractions to the pelvis) or intensity-modulated radiotherapy (50-50.4 Gy in 25-28 fractions). Both groups will receive concurrent chemotherapy with capecitabine and consolidation chemotherapy of either two cycles of CAPEOX or three cycles of FOLFOX between radiotherapy and surgery. The primary endpoints are pathological complete response (pCR) rate and surgical difficulty, while the secondary endpoints are clinical complete response (cCR) rate, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates, acute and late toxicity and quality of life. DISCUSSION: Since dose escalation of both primary lesions and positive nodes in LARC is rare, we propose conducting a phase III trial to evaluate the efficacy and safety of SIB for both primary lesions and positive nodes in LARC based on MRgART. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov with the Identifier: NCT06246344 (Registered 7th Feb 2024).

Piezoelectric Properties of As-Spun Poly(vinylidene Fluoride)/Multi-Walled Carbon Nanotube/Zinc Oxide Nanoparticle (PVDF/MWCNT/ZnO) Nanofibrous Films.

Conductive multi-walled carbon nanotubes (MWCNTs) as well as piezoelectric zinc oxide (ZnO) nanoparticles are frequently used as a single additive and dispersed in polyvinylidene fluoride (PVDF) solutions for the fabrication of piezoelectric composite films. In this study, MWCNT/ZnO binary dispersions are used as spinning liquids to fabricate composite nanofibrous films by electrospinning. Binary additives are conducive to increasing the crystallinity, piezoelectric voltage coefficient, and consequent piezoelectricity of as-spun films owing to the stretch-enhanced polarization of the electrospinning process under an applied electric field. PCZ-1.5 film (10 wt. % PVDF/0.1 wt. % MWCNTs/1.5 wt. % ZnO nanoparticles) contains the maximum ß-phase content of 79.0% and the highest crystallinity of 87.9% in nanofibers. A sensor using a PCZ-1.5 film as a functional layer generates an open-circuit voltage of 10 V as it is subjected to impact loads with an amplitude of 6 mm at 10 Hz. The piezoelectric sensor reaches a power density of 0.33 µW/cm2 and a force sensitivity of 582 mV/N. In addition, the sensor is successfully applied to test irregular motions of a bending finger and stepping foot. The result indicates that electrospun PVDF/MWCNT/ZnO nanofibrous films are suitable for wearable devices.

A Review on Concrete Superplasticizers and Their Potential Applications for Enhancing the Performance of Thermally Activated Recycled Cement.

With the rapid development of the construction industry worldwide, a large amount of waste concrete is generated each year, which has caused serious environmental problems. As a green and sustainable building material, thermally activated recycled cement (RC) has received widespread attention. However, the unique properties of RC, such as the high water demand and short setting time, necessitate the use of specialized superplasticizers that are different from those used in ordinary Portland cement. As an important component for the application of RC, superplasticizer has an important impact on the performance modification of RC. This article summarizes the recent research progress of potential superplasticizers for RC, with a view to providing a reference for the research and application of superplasticizers for RC. Based on the differences between ordinary Portland cement and RC, the paper discusses potential superplasticizers that may be suitable for RC, and points out that future development of potential modified superplasticizers can include altering the molecular structure to improve adsorption onto the surfaces of RC or to enhance the durability of concrete with RC.

m6A-modified cenRNA stabilizes CENPA to ensure centromere integrity in cancer cells.

m6A modification is best known for its critical role in controlling multiple post-transcriptional processes of the mRNAs. Here, we discovered elevated levels of m6A modification on centromeric RNA (cenRNA) in cancerous cells compared with non-cancerous cells. We then identified CENPA, an H3 variant, as an m6A reader of cenRNA. CENPA is localized at centromeres and is essential in preserving centromere integrity and function during mitosis. The m6A-modified cenRNA stabilizes centromeric localization of CENPA in cancer cells during the S phase of the cell cycle. Mutations of CENPA at the Leu61 and the Arg63 or removal of cenRNA m6A modification lead to loss of centromere-bound CENPA during S phase. This in turn results in compromised centromere integrity and abnormal chromosome separation and hinders cancer cell proliferation and tumor growth. Our findings unveil an m6A reading mechanism by CENPA that epigenetically governs centromere integrity in cancer cells, providing potential targets for cancer therapy.

Development of a zoledronate-modified functional alginate hydrogel with effects of promoting osteogenesis for potential osteoporosis treatment.

Osteoporosis is one of the most prevalent age-related diseases worldwide. It is characterized by a systemic deterioration in bone strength (bone density and bone mass), leading to an increase in fragility fractures. The complex pathological environment of osteoporosis presents a significant challenge to the induction of bone regeneration under osteoporotic conditions. Therefore, the development of a system for local delivery of active substances with osteoinductive effects is of practical significance in the clinical treatment of osteoporosis. In this study, we successfully loaded the anti-osteoporotic small molecule drug zoledronate (ZOL) into calcium alginate to prepare a biologically functional hydrogel, designated as ALG-ZOL-Ca. The prepared ALG-ZOL-Ca hydrogel gels quickly, making the hydrogel easy to inject and adapt to irregularly shaped bone defects, and simultaneously exhibits good bioactivity and osteoconductivity. The RT-qPCR results suggested that this hydrogel effectively promoted the expression levels of ß-catenin and Axin2, which indicating a stimulative effect on the Wnt/ß-catenin pathway in vitro. Moreover, ALG-ZOL-Ca hydrogel effectively promoted the expression of the OCN and SP7 genes. Therefore, this study proposes a new functional composite hydrogel that provides a potential treatment strategy for osteoporosis.

Causal relationships between neuropsychiatric disorders and nonalcoholic fatty liver disease: A bidirectional Mendelian randomization study.

BACKGROUND: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. METHODS: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. RESULTS: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. CONCLUSIONS: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.

Environmental pollutant Di-(2-ethylhexyl) phthalate induces asthenozoospermia: new insights from network toxicology.

The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets.

Computational recognition of regulator genes and signature for ferroptosis with implications on immunological properties and clinical management of atopic dermatitis.

Background: Atopic dermatitis (AD) is a common chronic dermatitis of autoimmune origin that considerably affects the quality of life of patients. Ferroptosis, a newly regulated form of cell death, is essential for inflammation-related damage-associated molecular patterns (DAMPs). In this study, we aimed to identify ferroptosis regulators relevant to AD pathogenesis and reveal the mechanisms by which ferroptosis regulates the pathogenesis of AD. Methods: We analyzed the GEO AD cohorts (GSE16161, GSE32924, GSE107361, and GSE120721), identifying AD-related differentially expressed genes (DEGs) using edgeR. Co-expression and STRING database analyses were used to elucidate the interactions between DEGs and ferroptosis markers. Through functional enrichment analysis, we defined potential biological functions within the protein-protein interaction (PPI) network and developed FerrSig using LASSO regression. The utility of FerrSig in guiding the clinical management of AD was evaluated using the GSE32473 cohort. Subsequently, our in silico findings were confirmed, and mechanistic insights were expanded through both in vitro and in vivo studies, validating the relevance of FerrSig. Results: In the GEO AD cohort, 278 DEGs were identified, including seven ferroptosis signature genes. Co-expression analysis and STRING database review revealed a 63-node PPI network linked to cell cycle and pro-inflammatory pathways. Four ferroptosis genes (ALOXE3, FABP4, MAP3K14, and EGR1) were selected to create FerrSig, which was significantly downregulated in samples collected from patients with AD. In addition, immune-related signaling pathways were significantly differentially enriched between the stratifications of samples collected from patients with AD with high and low ferritin levels, whereas in the GSE32473 cohort, FerrSig was significantly increased in cohorts effectively treated with pimecrolimus or betamethasone. Finally, in vitro and in vivo models showed a notable FerrSig decrease in patients with AD versus healthy control. Treatment with betamethasone and tacrolimus restored FerrSig, and the magnitude of the increase in FerrSig was higher in samples collected from patients with AD with better efficacy assessments. In addition, FerrSig was significantly positively correlated with the ferroptosis inhibitors GPX4 and SLC7A11 and negatively correlated with reactive oxygen species (ROS) levels and p-STAT3/STAT3. This implies that the FerrSig signature genes may regulate ferroptosis through the JAK/STAT3 signaling pathway. Conclusion: Our study further explored the pathogenesis of AD, and FerrSig could serve as a potential biomarker for identifying AD morbidity risks and determining treatment efficacy.

Conditional survival and changing risk profile in patients with gliosarcoma.

Background: Conditional survival (CS) considers the duration since the initial diagnosis and can provide supplementary informative insights. Our objective was to evaluate CS among gliosarcoma (GSM) patients and develop a CS-incorporated nomogram to predict the conditional probability of survival. Methods: This retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database included patients with GSM between 2000 and 2017. The CS was defined as the probability of surviving additional y years after already surviving for x years. The formula utilized for CS was: CS(y|x) = S(y + x)/S(x), where S(x) denotes the overall survival at x years. Univariate Cox regression, best subset regression (BSR) and the least absolute shrinkage and selection operator (LASSO) were used for significant prognostic factors screening. Following this, backward stepwise multivariable Cox regression was utilized to refine predictor selection. Finally, a novel CS-integrated nomogram model was developed and we also employed diverse evaluation methods to assess its performance. Results: This study included a total of 1,015 GSM patients, comprising 710 patients in training cohort and 305 patients in validation cohort. CS analysis indicated a gradual increase in the probability of achieving a 5-year survival, ascending from 5% at diagnosis to 13, 31, 56, and 74% with each subsequent year survived after 1, 2, 3, and 4 years post-diagnosis, respectively. Following variable screening through univariate Cox regression, BSR, and LASSO analysis, five factors-age, tumor stage, tumor size, radiotherapy, and chemotherapy-were ultimately identified for constructing the CS-nomogram model. The performance of the nomogram model was validated through discrimination and calibration assessments in both the training and validation cohorts. Furthermore, we confirmed that the effectiveness of the CS-nomogram in stratifying GSM patient risk status. Conclusion: This nationwide study delineated the CS of patients diagnosed with GSM. Utilizing national data, a CS-nomogram could provide valuable guidance for patient counseling during follow-up and risk stratification.

Fatal graft-versus-host disease in recipient with pretransplant exposure to immune checkpoint inhibitors and donor-dominant one-way HLA matching after liver transplantation: A case report.

INTRODUCTION AND IMPORTANCE: Graft-versus-host disease (GvHD) is a rare but severe complication following liver transplantation (LT), occurring in 1-2 % of cases with a mortality rate exceeding 80 %. Immune checkpoint inhibitors (ICIs) used pretransplant are associated with increased allograft rejection risk, but their impact on GvHD in LT remains unclear. Dominant one-way donor-recipient human leukocyte antigen (HLA) matching is a known risk factor for GvHD. This report presents a rare case of fatal GvHD in a hepatocellular carcinoma (HCC) patient treated with PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching. CASE PRESENTATION: A 59-year-old male with a 30-year history of hepatitis B and unresectable HCC underwent LT after receiving the last dose of PD-1 inhibitors 7 days prior to the transplant. On post-operative day (POD) 12, the patient developed a skin rash, fever, and vomiting, and was diagnosed with GvHD. Despite aggressive treatment, including high-dose corticosteroids and extracorporeal membrane oxygenation (ECMO), the patient succumbed to gastrointestinal bleeding and multi-organ failure on POD 30. HLA genotyping revealed typical donor-dominant one-way HLA matching. CLINICAL DISCUSSION: This case highlights a potential link between pretransplant exposure to ICIs and GvHD, particularly with donor-dominant one-way HLA matching. Residual anti-PD-1 antibodies may activate graft-resident immune cells, precipitating GvHD. Further research with larger cohorts and animal models is required to clarify this relationship and understand the underlying mechanisms. CONCLUSION: Besides allograft rejection, caution should also be exercised regarding GvHD in patients with prior exposure to ICIs before LT.

Electronic excitations and spin interactions in chromium trihalides from embedded many-body wavefunctions.

Although chromium trihalides are widely regarded as a promising class of two-dimensional magnets for next-generation devices, an accurate description of their electronic structure and magnetic interactions has proven challenging to achieve. Here, we quantify electronic excitations and spin interactions in CrX 3 (X = Cl, Br, I) using embedded many-body wavefunction calculations and fully generalized spin Hamiltonians. We find that the three trihalides feature comparable d-shell excitations, consisting of a high-spin 4 A 2 ( t 2 g 3 e g 0 ) ground state lying 1.5-1.7 eV below the first excited state 4 T 2 ( t 2 g 2 e g 1 ). CrCl3 exhibits a single-ion anisotropy A sia = - 0.02 meV, while the Cr spin-3/2 moments are ferromagnetically coupled through bilinear and biquadratic exchange interactions of J 1 = - 0.97 meV and J 2 = - 0.05 meV, respectively. The corresponding values for CrBr3 and CrI3 increase to A sia = -0.08 meV and A sia= - 0.12 meV for the single-ion anisotropy, J 1 = -1.21 meV, J 2 = -0.05 meV and J 1 = -1.38 meV, J 2 = -0.06 meV for the exchange couplings, respectively. We find that the overall magnetic anisotropy is defined by the interplay between A sia and A dip due to magnetic dipole-dipole interaction that favors in-plane orientation of magnetic moments in ferromagnetic monolayers and bulk layered magnets. The competition between the two contributions sets CrCl3 and CrI3 as the easy-plane (A sia + A dip >0) and easy-axis (A sia + A dip <0) ferromagnets, respectively. The differences between the magnets trace back to the atomic radii of the halogen ligands and the magnitude of spin-orbit coupling. Our findings are in excellent agreement with recent experiments, thus providing reference values for the fundamental interactions in chromium trihalides.

Efficiency and safety of laparoscopic left hemihepatectomy: A study of intrathecal vs extrathecal Glissonean pedicle techniques.

BACKGROUND: Selective hemihepatic vascular occlusion is utilized in both right and left hemihepatectomies to preserve blood supply to the intact lobe, maintain hemodynamic stability, and mitigate surgical risks. While this technique encompasses both intrathecal and extrathecal Glissonean pedicle transection methods, there is a lack of systematic comparative reports on these two approaches. AIM: To retrospectively analyze the clinical data of patients with hepatocellular carcinoma (HCC) undergoing laparoscopic anatomical hepatectomy in our hospital to explore the feasibility, safety, and short- and long-term efficacy of extrathecal and intrathecal Glissonean pedicle transection methods in laparoscopic left hemihepatectomy. METHODS: A retrospective study was performed to analyze the clinical data of 49 HCC patients who underwent laparoscopic left hemihepatectomy from January 2019 to December 2022 in our hospital. These patients were divided into extrathecal Glissonean pedicle transection (EGP) group (n = 24) and intrathecal Glissonean pedicle transection (IGP) group (n = 25) according to the different approaches used for selective hemihepatic vascular occlusion. The perioperative indicators, liver function indexes, complications, and follow-up findings were compared between these two groups. RESULTS: The surgeries were smooth in both groups, and no perioperative death was noted. The hepatic pedicle transection time and the operation time were (16.1 ± 2.3) minutes and (129.6 ± 19.0) minutes, respectively, in the EGP group, which were significantly shorter than those in the IGP group [(25.5 ± 2.4) minutes and (184.8 ± 26.0) minutes, respectively], both P < 0.01. There were no significant differences in intraoperative blood loss, time to anal exhaust, hospital stay, drain indwelling time, and postoperative liver function between the two groups (all P > 0.05). The incidence of postoperative complications showed no significant difference [16.67% (4/24) vs 16.0% (4/25), P > 0.05). All the 49 HCC patients were followed up after surgery (range: 11.2-53.3 months; median: 36.4 months). The overall survival rate and disease-free survival rate were not significantly different (both P > 0.05). CONCLUSION: Both extrathecal and intrathecal Glissonean pedicle approaches are effective and safe hepatic inflow occlusion techniques in laparoscopic left hemihepatectomy for HCC. However, the extrathecal approach simplifies the hepatic pedicle transection, shortens the operation time, and increases the surgical efficiency, making it a more feasible technique.

Construction of 3D Fibonacci Cauliflower-Like NiCo2S4/Expanded Graphite Heterogeneous Structures for Enhanced Electromagnetic Wave Absorption.

Highly efficient electromagnetic wave (EMW)-absorbing multicomposites can be fabricated by constructing particular structures using suitable components. Expanded graphite (EG) has a 3D, low-density porous structure; however, it suffers from poor impedance matching and EMW absorption properties. Based on this information, in the present study, NiCo2S4 components with different morphologies are successfully loaded onto a 3D EG surface using a facile microwave solvothermal method to achieve a synergistic effect between the different components. The NiCo2S4 content is adjusted to alter the compositional morphology and electromagnetic parameters of the composites to achieve impedance-matching and obtain excellent EMW absorption properties. The heterogeneous interface between EG and NiCo2S4 induces an inhomogeneous spatial charge distribution and enhances interfacial polarization. The defects in the material and oxygen-containing groups induce dipole polarization, which enhances the polarization-relaxation process of the composites. The 3D porous heterostructure of the "Fibonacci cauliflower"-shaped NiCo2S4/EG composites results in an optimal reflection loss of -64.93 dB at a filler rate of only 14 wt.%. Analysis of the synergistic conduction loss and polarization loss mechanisms in carbon-based materials with heterogeneous interfaces has led to the development of excellent EMW absorption materials.

Survival analysis and prognostic nomogram for patients with cholangiocarcinoma after radical resection in Asia.

BACKGROUND: CCA has a poor prognosis. Different anatomical subtypes are characterized by distinct clinical features, surgical options, and prognoses, which can potentially impact survival outcomes following radical resection. In addition to the malignancy of CCA itself, clinical staging and treatment methods are the main factors that can affect survival. This study aims to update a more reliable prediction model for the prognosis of CCA based on different anatomical locations. METHODS: A total of 1172 CCA patients (305 iCCA, 467 pCCA, and 400 dCCA) who underwent surgical resection between 2015 and 2022 were included in the analysis. The covariates included in the analysis were age, sex, tumor diameter, differentiation grade, T stage, N stage, M stage, neural invasion, cancer thrombus, history of hepatitis B or biliary calculi, and receipt of adjuvant chemotherapy. The data were randomly divided into training (80 %) and validation cohort (20 %). RESULTS: We developed a nomogram of the sensitive model and calculated concordance indices of different constructed prognostic survival models. Meanwhile, we validated the effectiveness of the nomogram model and compared it with the TNM system through decision curve analysis (DCA) and internal cohort validation. The nomogram model had a better net benefit than the TNM system at any given threshold for iCCA, pCCA, and dCCA, regardless of their location. CONCLUSIONS: We have updated the prognostic model for OS in CCA patients who underwent radical resection according to the different tumor locations. This model can effectively predict OS and has the potential to facilitate individual clinical decision-making.

Ginkgolic Acid as a carbapenem synergist against KPC-2 positive Klebsiella pneumoniae.

The successful evolution of KPC-2 in bacteria has limited the clinical practice of carbapenems. This dilemma deteriorated the prognosis of associated infections and hence attracted increasing attention from researchers to explore alternative therapeutic options. Here, the enzyme inhibition assay was first performed to screen for a potent KPC-2 inhibitor. The synergistic effect of the candidate with carbapenems was further confirmed by checkboard minimum inhibitory concentration (MIC) assay, time-killing assay, disk diffusion method, and live/dead bacteria staining analysis. The mechanisms by which the candidate acts were subsequently explored through molecular dynamics (MD) simulations, etc. Our study found that Ginkgolic Acid (C13:0) (GA) exhibited effective KPC-2 inhibitory activity in both laboratory strain and clinical strain containing KPC-2. It could potentiate the killing effect of carbapenems on KPC-2-positive Klebsiella pnenmoniae (K. pnenmoniae). Further explorations revealed that GA could competitively bind to the active pocket of KPC-2 with meropenem (MEM) via residues Trp104, Gly235, and Leu166. The secondary structure and functional groups of KPC-2 were subsequently altered, which may be the main mechanism by which GA exerted its KPC-2 inhibitory effect. In addition, GA was also found to synergize with MEM to disrupt membrane integrity and increase membrane permeability, which may be another mechanism by which GA reinforced the bactericidal ability of carbapenems. Our study indicated that GA was a significant KPC-2 inhibitor that could prolong the lifespan of carbapenems and improve the prognosis of patients.

Photodynamic Therapy Using RGD-Functionalized Quantum Dots Elicit a Potent Immune Response in a Syngeneic Mouse Model of Pancreatic Cancer.

Purpose: Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy. Methods: The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody. Results: QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors. Conclusion: QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses.

Multisensory working memory capture of attention.

During visual search, representations in working memory (WM) can guide the deployment of attention toward memory-matching visual input. Although previous studies have demonstrated that multisensory interactions facilitate WM and visual search, it remains unclear whether multisensory interaction influences attentional capture by WM. To address this issue, the present study adopted a dual-task paradigm, pairing a visual search task with a WM task, in which the memory modality was manipulated to be either visual or audiovisual. The results revealed that memory-driven attentional capture was observed under the visual and the audiovisual condition. Additionally, the capture effects and response time (RT) costs under the audiovisual condition were weaker than those under the visual condition, even on the trials with the earliest RTs. Furthermore, RT benefits under the audiovisual condition were comparable with those under the visual condition. These findings suggest that multisensory interactions can enhance cognitive control, leading to robust strategic effects and improved search performance. In this process, cognitive control tends to suppress the attentional capture by WM-matching distractors rather than enhance the attentional capture by WM-matching targets. The present study offers new insights into the influence of multisensory interactions on attentional capture by WM.

VSV infection and LPS treatment alter serum bile acid profiles, bile acid biosynthesis, and bile acid receptors in mice.

Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes (Cyp7a1, Cyp27a1, Cyp8b1, and Hsd3b7) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection. IMPORTANCE: This study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.