Additional Hepatic Arterial Infusion Chemotherapy to Sorafenib Was Cost-Effective for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis.

Purpose: The combination of sorafenib and hepatic arterial infusion chemotherapy (SoHAIC) has shown to enhance overall survival rates in patients with advanced hepatocellular carcinoma and major portal vein tumor thrombosis (HCC-Vp3-4) compared to sorafenib alone. Our objective was to evaluate the cost-effectiveness of SoHAIC versus sorafenib for the treatment of HCC-Vp3-4, taking into account the viewpoint of Chinese healthcare payers. Methods: This pharmacoeconomic study employed a Markov model to assess the cost-effectiveness of treating HCC-Vp3-4 with SoHAIC in comparison to sorafenib. The patient characteristics were drawn from individuals from the trial conducted between June 2017 and November 2019, with cost and health value data sourced from published literature. The primary outcome measure in this research was the incremental cost-effectiveness ratio (ICER), which indicates the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold per QALY was set at $30,492.00. Furthermore, 1-way sensitivity and probabilistic sensitivity analyses were carried out to validate the consistency of the results. Results: In the baseline scenario, sorafenib resulted in 0.42 QALY at a cost of $10,507.89, while SoHAIC generated 1.66 QALY at a cost of $32,971.56. When comparing SoHAIC to sorafenib, the ICER was $18,237.20 per QALY, which was below the WTP threshold per QALY. Furthermore, the 1-way sensitivity analysis demonstrated that the ICER remained within the WTP threshold despite fluctuations in variables. In the probabilistic sensitivity analysis, SoHAIC had a 98.8% probability of being cost-effective at the WTP threshold, considering a wide range of parameters. Conclusion: In this cost-effectiveness evaluation, SoHAIC demonstrated cost-effectiveness over sorafenib for HCC with major portal vein tumor thrombosis, as observed from the perspective of a Chinese payer.

TACE plus lenvatinib and tislelizumab for intermediate-stage hepatocellular carcinoma beyond up-to-11 criteria: a multicenter cohort study.

Background: Intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) beyond the up-to-11 criteria represent a significant therapeutic challenge due to high and heterogeneous tumor burden. This study evaluated the effectiveness and safety of transarterial chemoembolization (TACE) in combination with lenvatinib and tislelizumab for these patients. Methods: In this retrospective cohort study, patients with unresectable intermediate-stage HCC beyond the up-to-11 criteria were enrolled and divided into TACE monotherapy (T), TACE combined with lenvatinib (TL), or TACE plus lenvatinib and tislelizumab (TLT) group based on the first-line treatment, respectively. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to RESIST1.1 and modified RECIST, and adverse events (AEs). Results: There were 38, 45, and 66 patients in the T, TL, and TLT groups, respectively. The TLT group exhibited significantly higher ORR and DCR than the other two groups, as assessed by either mRECIST or RECIST 1.1 (all P<0.05). Median PFS and OS were significantly longer in the TLT group compared with the T group (PFS: 8.5 vs. 4.4 months; OS: 31.5 vs. 18.5 months; all P<0.001) and TL group (PFS: 8.5 vs. 5.5 months; OS: 31.5 vs. 20.5 months; all P<0.05). The incidence of TRAEs was slightly higher in the TLT and TL groups than in the T group, while all the toxicities were tolerable. No treatment-related death occurred in all groups. Conclusions: TACE combined with lenvatinib and tislelizumab significantly improved the survival benefit compared with TACE monotherapy and TACE plus lenvatinib in patients with intermediate-stage HCC beyond the up-to-11 criteria, with an acceptable safety profile.

A lysosome-targeted fluorescent probe for thiol detection in drug analysis and multiple biological systems.

Biothiols, characterized by their unique sulfhydryl (-SH) groups, possess excellent antioxidant properties, effectively neutralizing the damage to cellular structures caused by reactive oxygen species (ROS) in living organisms. Additionally, lysosomes play a crucial role in decomposing damaged biomolecules through the action of their internal enzymes, regulating the cellular redox state, and mitigating oxidative stress. To facilitate rapid monitoring of intracellular biothiols, particularly within lysosomes, we constructed a lysosome-targeted biothiol fluorescent probe, PHL-DNP, in this study. PHL-DNP exhibited excellent photophysical properties in an aqueous test system, including strong fluorescence enhancement response, excellent selectivity, and low detection limits (Cys 16.5 nM, Hcy 16.8 nM, GSH 21.3 nM, Cap 26.6 nM). These attributes enabled easy and efficient qualification of Cys on test strips and accurate determination of the effective content of captopril tablets. Notably, PHL-DNP demonstrated low cytotoxicity and precise lysosomal targeting. Through bioimaging, PHL-DNP not only monitored changes in biothiol levels under oxidative stress but also assessed biothiols in complex biological systems such as live HeLa cells, zebrafish, tumor tissue sections, and radish roots. This provides a promising tool for quantitative analysis of biothiols, disease marker detection, and drug testing.

Visualizing ClO- fluctuations in drug-induced liver injury and bacterium via a robust ratiometric fluorescent probe.

As a type of reactive oxygen species, hypochlorous acid (ClO-) plays an important role in sterilization, disinfection and protection in organisms. However, excessive production of ClO- is closely related to various diseases. In this work, we have designed a robust ratiometric fluorescent probe, RDB-ClO, using the excited-state intramolecular proton transfer (ESIPT) strategy. RDB-ClO was achieved by modifying 2-(2-(benzo[d]thiazol-2-yl)-6-(diethylamino)-3-oxo-3H-xanthen-9-yl) benzoic acid (RDB-OH) with a 1-naphthoyl chloride group, specifically for the sensitive detection of ClO-. In the presence of ClO-, RDB-ClO demonstrated relatively good performance, showing swift response time (35 s), low detection limit of 5.1 nM and high selectivity towards ClO-. Notably, the convenience and accessibility detection of ClO- has been implemented using test strip and agarose probe. RDB-ClO effectively tracked both endogenous and exogenous ClO- in HeLa cells, HepG2 cells and zebrafish. Additionally, it is successfully applied to detect changes of exogenous ClO- content in E. coli. and acetaminophen (APAP)-induced liver injury in mice. The development of RDB-ClO represents a promising molecular tool for studying the pathogenesis of DILI and biotransformation of ClO- in bacteria.

Coordination engineering for iron-based hexacyanoferrate as a high-stability cathode for sodium-ion batteries.

Iron-based hexacyanoferrate (Fe-HCF) are promising cathode materials for sodium-ion batteries (SIBs) due to their unique open-channel structure that facilitates fast ion transport and framework stability. However, practical implementation of SIBs has been hindered by low initial Coulombic efficiency (ICE), poor rate performance, and short lifespan. Herein, we report a coordination engineering to synthesize sodium-rich Fe-HCF as cathodes for SIBs through a uniquely designed 10-kg-scale chemical reactor. Our study systematically investigated the relationship between coordination surroundings and the electrochemical behavior. Building on this understanding, the cathode delivered a reversible capacity of 99.3 mAh g-1 at 5 C (1 C = 100 mA g-1), exceptional rate capability (51 mAh g-1 even at 100 C), long lifespan (over 15,000 times at 50 C), and a high ICE of 92.7%. A full cell comprising the Fe-HCF cathode and hard carbon (HC) anode exhibited an impressive cyclic stability with a high-capacity retention rate of 98.3% over 1,000 cycles. Meanwhile, this material can be readily scaled to the practical levels of yield. The findings underscore the potential of Fe-HCF as cathodes for SIBs and highlight the significance of controlling nucleation and morphology through coordination engineering for a sustainable energy storage system.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

Construction of V2O5@MXene Cathodes toward a High Specific Capacity Aqueous Aluminum-Ion Battery.

Aqueous aluminum-ion batteries (AAIBs) are considered a strong candidate for the new generation of energy storage devices. The lack of suitable cathode materials has been a bottleneck factor hindering the future development of AAIBs. In this work, we design and construct a highly effective cathode with dual morphologies. Two-dimensional (2D) layered MXene materials possessed good conductivity and hydrophilicity, which are used as the substrates to deposit rod-shaped vanadium oxides (V2O5) to form a three-dimensional (3D) cathode. The cathode design provides a strong boost for the rapid electrochemical activities of rod-shaped V2O5 by embedding/extracting both protons (H+) and aluminum-ion (Al3+). As a result, the V2O5@MXene cathode based AAIB delivers an ultrahigh initial specific capacity of 626 mAh/g at 0.1 A/g with a stable cycle performance up to 100 cycles. This work is a breakthrough for the development of cathode materials for AAIBs.

Microbial diversity and oil biodegradation potential of northern Barents Sea sediments.

The Arctic, an essential ecosystem on Earth, is subject to pronounced anthropogenic pressures, most notable being the climate change and risks of crude oil pollution. As crucial elements of Arctic environments, benthic microbiomes are involved in climate-relevant biogeochemical cycles and hold the potential to remediate upcoming contamination. Yet, the Arctic benthic microbiomes are among the least explored biomes on the planet. Here we combined geochemical analyses, incubation experiments, and microbial community profiling to detail the biogeography and biodegradation potential of Arctic sedimentary microbiomes in the northern Barents Sea. The results revealed a predominance of bacterial and archaea phyla typically found in the deep marine biosphere, such as Chloroflexi, Atribacteria, and Bathyarcheaota. The topmost benthic communities were spatially structured by sedimentary organic carbon, lacking a clear distinction among geographic regions. With increasing sediment depth, the community structure exhibited stratigraphic variability that could be correlated to redox geochemistry of sediments. The benthic microbiomes harbored multiple taxa capable of oxidizing hydrocarbons using aerobic and anaerobic pathways. Incubation of surface sediments with crude oil led to proliferation of several genera from the so-called rare biosphere. These include Alkalimarinus and Halioglobus, previously unrecognized as hydrocarbon-degrading genera, both harboring the full genetic potential for aerobic alkane oxidation. These findings increase our understanding of the taxonomic inventory and functional potential of unstudied benthic microbiomes in the Arctic.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Identification and transcriptome analysis of a photosynthesis deficient mutant of Populus davidiana Dode.

Photosynthesis is the main source of energy for plants to sustain growth and development. Abnormalities in photosynthesis may cause defects in plant development. The elaborate regulatory mechanism underlying photosynthesis remains unclear. In this study, we identified a natural mutant from the Greater Khingan Mountains and named it as "1-T". This mutant had variegated leaf with irregular distribution of yellow and green. Chlorophyll contents and photosynthetic capacity of 1-T were significantly reduced compared to other poplar genotypes. Furthermore, a transcriptome analysis revealed 3269 differentially expressed genes (DEGs) in 1-T. The products of the DEGs were enriched in photosystem I and photosystem II. Three motifs were significantly enriched in the promoters of these DEGs. Yeast one-hybrid, Electrophoretic mobility shift assays and tobacco transient transformation experiments indicated that PdGLKs may bind to the three motifs. Further analysis indicated that these photosystem related genes were also significantly down-regulated in PdGLK-RNAi poplars. Therefore, we preliminarily concluded that the down-regulation of PdGLKs in 1-T may affect the expression of photosystem-related genes, resulting in abnormal photosystem development and thus affecting the growth and development. Our results provide new insights into the molecular mechanism of photosynthesis regulating plant growth.

Blockage of TMEM189 induces G2/M arrest and inhibits the growth of breast tumors.

Cancer is the major cause of premature death in humans worldwide, demanding more efficient therapeutics. Aberrant cell proliferation resulting from the loss of cell cycle regulation is the major hallmark of cancer, so targeting cell cycle is a promising strategy to combat cancer. However, the molecular mechanism underlying the dysregulation of cell cycle of cancer cells remains poorly understood. TMEM189, a newly identified protein, plays roles in the biosynthesis of ethanolamine plasmalogen and the regulation of autophagy. Here, we demonstrated that the expression level of TMEM189 was negatively correlated with the survival rate of the cancer patients. TMEM189 deficiency significantly suppresses the cancer cell proliferation and migration, and causes cell cycle G2/M arrest both in vitro and in vivo. Furthermore, TMEM189 depletion suppressed the growth of breast tumors in vivo. Taken together, our work indicated that TMEM189 promotes cancer progression by regulating cell cycle G2/M transition, suggesting that it is a promising target in cancer therapy.

Factors associated with dysmenorrhoea and menorrhagia improvement in patients with adenomyosis after uterine artery embolisation.

BACKGROUND: This study examined the improvement of dysmenorrhoea and menorrhagia after uterine artery embolisation (UAE) in women with symptomatic adenomyosis and identified factors that could predict the improvement of dysmenorrhoea and menorrhagia. METHODS: This retrospective study included women with adenomyosis who underwent bilateral UAE between December 2014 and December 2016. The percentage of the volume of the absence of contrast enhancement on T1-weighted images was evaluated 5-7 days after UAE. A receiver operating characteristic (ROC) analysis was used to determine a cut-off point and predict the improvement of dysmenorrhoea and menorrhagia. RESULTS: Forty-eight patients were included. At 24 and 36 months after UAE, the improvement rates for dysmenorrhoea and menorrhagia were 60.4% (29/48) and 85.7% (30/35), and the recurrence rates were 19.4% (7/36) and 9.1% (3/33), respectively. Only the percentage of the volume of the absence of contrast enhancement on T1-weighted images was associated with the improvement of dysmenorrhoea (p = 0.001, OR = 1.051; 95% CI: 1.02-1.08) and menorrhagia (p = 0.006, OR = 1.077; 95% CI: 1.021-1.136). When the cut-off value of the ROC analysis was 73.1%, sensitivity, specificity, positive predictive value, and negative predictive value for the improvement of dysmenorrhoea were 58.6%, 94.7%, 94.4%, and 60%, while they were 58.9%, 80%, 100%, 100%, and 45.5% for the improvement of dysmenorrhoea. CONCLUSION: Bilateral UAE for symptomatic adenomyosis led to good improvement of dysmenorrhoea and menorrhagia. The percentage of the volume of the absence of contrast enhancement on T1-weighted images of the uterus in postoperative magnetic resonance imaging might be associated with the improvement of dysmenorrhoea and menorrhagia.

This study examined the improvement of dysmenorrhoea and menorrhagia after uterine artery embolisation in women with symptomatic adenomyosis and identified factors that could predict the improvement of dysmenorrhoea and menorrhagia. This retrospective study included women with adenomyosis who underwent uterine artery embolisation. A total of 48 patients were included. Only the percentage of the volume of the absence of contrast enhancement on T1-weighted images was associated with improvement of dysmenorrhoea and menorrhagia. Bilateral uterine artery embolisation for symptomatic adenomyosis led to good improvement. The percentage of the volume of the absence of contrast enhancement on images in postoperative T1-weighted magnetic resonance imaging of the uterus might be associated with the improvement of dysmenorrhoea and menorrhagia.

Mechanism of PTPN18 for regulating the migration and invasion of endometrial cancer cells via the MYC/PI3K/AKT pathway.

OBJECTIVE: Endometrial cancer (EC) is a prevalent gynecologic malignancy. The critical role of PTPN18 in EC has been reported, while its role in the aerobic glycolysis of EC cells remains unclear. Our current study focused on the mechanism of PTPN18 in the regulation of aerobic glycolysis in EC. METHODS: PTPN18 expression levels in endometrial stromal cells (KC02-44D) and EC cells (KLE, HEC-1-A, HEC-1B, and HEC-50) were determined. Following transfection of sh-PTPN18 in HEC-1-A cells, the changes in cell migratory and invasive abilities were assessed by the Transwell assay, and the changes in glucose consumption, lactic acid secretion, and ATP levels were detected using kits. The expression levels of glycolysis-related proteins HIF-1α, PKM2, and LDHA and the activation of the MYC/PI3K/AKT pathway were detected by Western blot. Additionally, sh-PTPN18 and pcDNA3.1-MYC were transfected into HEC-1-A cells to further explore their roles in the changes in aerobic glycolysis, migration, and invasion ability of EC cells. RESULTS: Expression of PTPN18 in EC cells was up-regulated (HEC-1-A>HEC-1B>HEC-50>KLE). PTPN18 knockdown suppressed EC cell migration and invasion. Additionally, PTPN18 knockdown reduced glucose consumption, lactate production, ATP levels, and glycolysis-related protein levels (HIF-1α, PKM2, LDHA). PTPN18 knockdown inhibited the activation of the MYC/PI3K/AKT pathway in EC cells. MYC overexpression partially annulled the inhibitory effects of PTPN18 knockdown on aerobic glycolysis, migration, and invasion of EC cells. CONCLUSION: Our present study provided evidence that the knockdown of PTPN18 inhibited the aerobic glycolysis, migration, and invasion of EC cells by suppressing the MYC/PI3K/AKT pathway.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104).

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.

Serum proteomics study on cognitive impairment after cardiac valve replacement surgery: a prospective observational study.

Objective: The incidence of perioperative neurocognitive disorders (PND) is high, especially after cardiac surgeries, and the underlying mechanisms remain elusive. Here, we conducted a prospective observational study to observe serum proteomics differences in PND patients after cardiac valve replacement surgery. Methods: Two hundred and twenty-six patients who underwent cardiac valve surgery were included. They were categorized based on scoring into non-PND group (group non-P) and PND group (group P'). The risk factors associated with PND were analyzed. These patients were further divided into group C and group P by propensity score matching (PSM) to investigate the serum proteome related to the PND by serum proteomics. Results: The postoperative 6-week incidence of PND was 16.8%. Risk factors for PND include age, chronic illness, sufentanil dosage, and time of cardiopulmonary bypass (CPB). Proteomics identified 31 down-regulated proteins and six up-regulated proteins. Finally, GSTO1, IDH1, CAT, and PFN1 were found to be associated with PND. Conclusion: The occurrence of PND can impact some oxidative stress proteins. This study provided data for future studies about PND to general anaesthesia and surgeries.

The tumour suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets that is sustained following transformation, predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout (cKO) mice where Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multi-panel flow cytometry revealed no ostensible differences between Fat1 cKO mice and normal littermates. Further functional comparisons involving colony forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.

Plasma profiles of inflammatory cytokines in children with moderate to severe traumatic brain injury: a prospective cohort study.

The role of inflammatory cytokines in children with moderate to severe TBI (m-sTBI) is still incompletely understood. We aimed to investigate the associations between early plasma expression profiles of inflammatory cytokines and clinical outcomes in children with m-sTBI. We prospectively recruited children admitted to the intensive care unit (ICU) of a tertiary pediatric hospital due to m-sTBI from November 2022 to May 2023. Plasma interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-α concentrations were detected by flow cytometry on admission and on days 5 to 7. The primary outcome was in-hospital mortality. The secondary outcome was the 6-month functional outcome assessed by the Glasgow Outcome Scale Extended-Pediatrics (GOS-E Peds) score, dichotomized as favorable (1-4) or unfavorable (5-8). Fifty patients and 20 healthy controls were enrolled. Baseline IL-6, IL-8 and IL-10 levels were significantly higher in TBI patients than in healthy controls. Twelve patients died in the hospital. Compared with survivors, nonsurvivors had significantly increased baseline IL-6 and IL-8 levels. Baseline IL-5, IL-6 and IL-8 levels were also significantly greater in children with unfavorable versus favorable outcomes. The area under the receiver operating characteristic curve (AUC) of the IL-6 and IL-8 levels and motor Glasgow Coma Scale (GCS) score for predicting in-hospital mortality was 0.706, 0.754, and 0.776, respectively. Baseline IL-1ß, IL-2, IL-4, IL-10, IL-12p70, IL-17A, IFN-γ, IFN-α and TNF-α levels were not associated with in-hospital mortality or an unfavorable 6-month outcome. On days 5 to 7, the IL-6 and IL-8 levels were significantly decreased in survivors but increased in nonsurvivors compared to their respective baselines. CONCLUSION: After m-sTBI, the plasma profiles of inflammatory cytokines are markedly altered in children. The trends of IL-6 and IL-8 expression vary among m-sTBI children with different outcomes. Elevated plasma IL-6 and IL-8 levels are related to in-hospital mortality and unfavorable 6-month outcomes. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2200065505). Registered November 7, 2022. WHAT IS KNOWN: • Inflammation is an important secondary physiological response to TBI. WHAT IS NEW: • The plasma profiles of inflammatory cytokines are markedly altered in children with m-sTBI. Elevated IL-6 and IL-8 levels are related to mortality and unfavorable outcomes.

Intestinal microflora promotes Th2-mediated immunity through NLRP3 in damp and heat environments.

Background: With the worsening of the greenhouse effect, the correlation between the damp-heat environment (DH) and the incidence of various diseases has gained increasing attention. Previous studies have demonstrated that DH can lead to intestinal disorders, enteritis, and an up-regulation of NOD-like receptor protein 3 (NLRP3). However, the mechanism of NLRP3 in this process remains unclear. Methods: We established a DH animal model to observe the impact of a high temperature and humidity environment on the mice. We sequenced the 16S rRNA of mouse feces, and the RNA transcriptome of intestinal tissue, as well as the levels of cytokines including interferon (IFN)-γ and interleukin (IL)-4 in serum. Results: Our results indicate that the intestinal macrophage infiltration and the expression of inflammatory genes were increased in mice challenged with DH for 14 days, while the M2 macrophages were decreased in Nlrp3 -/- mice. The alpha diversity of intestinal bacteria in Nlrp3 -/- mice was significantly higher than that in control mice, including an up-regulation of the Firmicutes/Bacteroidetes ratio. Transcriptomic analysis revealed 307 differentially expressed genes were decreased in Nlrp3 -/- mice compared with control mice, which was related to humoral immune response, complement activation, phagocytic recognition, malaria and inflammatory bowel disease. The ratio of IFN-γ/IL-4 was decreased in control mice but increased in Nlrp3 -/- mice. Conclusions: Our study found that the inflammation induced by DH promotes Th2-mediated immunity via NLRP3, which is closely related to the disruption of intestinal flora.

Immunosenescence-related T cell phenotypes and white matter in schizophrenia patients with tardive dyskinesia.

Schizophrenia patients with tardive dyskinesia (TD) are associated with accelerated biological aging, immunological dysfunction, and premature morbidity and mortality. Older individuals are particularly vulnerable to TD development. As a characteristic of immunosenescence, alterations in the relative proportions of naïve or memory T cell subpopulations may be negatively or positively associated with brain structure abnormalities; however, whether these changes are correlated with TD remains unclear. In this study, we investigated correlations between distributions of T cell phenotypes and brain structure abnormalities (especially white matter) in schizophrenia patients with (TD) and without (NTD) TD (n = 50 and 58, respectively) relative to healthy controls (HC, n = 41). Immune markers, including naïve (CD45RA+), memory (CD45RO+), and apoptotic (CD95+) CD4+ and CD8+ T cells, were examined by flow cytometry, as were the intracellular levels of cytokines (interferon (IFN)-γ, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α) in CD8 + CD45RA + CD95+ and CD8 + CD45RO + CD95+ T cells. MRI was employed to evaluate the fractional anisotropy (FA) of white matter tracts and subcortical volumes, following published routines. The percentage of CD8 + CD45RO + CD95+ T cells was higher in TD compared with NTD and HC groups and correlated with the choroid plexus volume in TD group. The intracellular level of IFN-γ in CD8 + CD45RO + CD95+ T cells, the FA of the fornix/stria terminalis, and the pallidum volume were correlated with orofacial TD, whereas the FAs of the inferior fronto-occipital fasciculus, cingulum, and superior longitudinal fasciculus were correlated with limb-truncal TD. These findings provide preliminary evidence that the association between immunosenescence-related T cell subpopulations and brain structure may underline the pathological process of TD.