Rhodium(III) Complex Noncanonically Potentiates Antitumor Immune Responses by Inhibiting Wnt/ß-Catenin Signaling.

Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.

Early postnatal whisker deprivation cross-modally modulates prefrontal cortex myelination and leads to social novelty deficit.

Sensory experience affects not only the corresponding primary sensory cortex, but also synaptic and neural circuit functions in other brain regions in a cross-modal manner. However, it remains unclear whether oligodendrocyte (OL) generation and myelination can also undergo cross-modal modulation. Here, we report that while early life short-term whisker deprivation from birth significantly reduces in the number of mature of OLs and the degree of myelination in the primary somatosensory cortex(S1) at postnatal day 14 (P14), it also simultaneously affects the primary visual cortex (V1), but not the medial prefrontal cortex (mPFC) with a similar reduction. Interestingly, when mice were subjected to long-term early whisker deprivation from birth (P0) to P35, they exhibited dramatically impaired myelination and a deduced number of differentiated OLs in regions including the S1, V1, and mPFC, as detected at P60. Meanwhile, the process complexity of OL precursor cells (OPCs) was also rduced, as detected in the mPFC. However, when whisker deprivation occurred during the mid-late postnatal period (P35 to P50), myelination was unaffected in both V1 and mPFC brain regions at P60. In addition to impaired OL and myelin development in the mPFC, long-term early whisker-deprived mice also showed deficits in social novelty, accompanied by abnormal activation of c-Fos in the mPFC. Thus, our results reveal a novel form of cross-modal modulation of myelination by sensory experience that can lead to abnormalities in social behavioral, suggesting a possible similar mechanism underlying brain pathological conditions that suffer from both sensory and social behavioral deficits, such as autism spectrum disorders.

Association of pre-pregnancy body mass index and gestational weight gain on postpartum pelvic floor muscle morphology and function in Chinese primiparous women: A retrospective cohort study.

OBJECTIVE: Our study aimed to investigate the association between maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and impaired pelvic floor muscle (PFM) morphology and function during the early postpartum period. METHODS: This retrospective cohort study was conducted at Shanghai First Maternity and Infant Hospital from December 2020 to December 2022. A total of 1118 primiparous women with singleton pregnancies who underwent vaginal deliveries and participated in postpartum PFM assessments were included. Maternal pre-pregnancy BMI and GWG were considered as exposures. PFM morphology and function impairment were the primary outcomes. PFM morphology impairment, defined as levator ani muscle avulsion, was assessed using transperineal ultrasound. PFM function impairment, manifested as diminished PFM fiber strength, was assessed through vaginal manometry. Multivariable logistic regression analysis was employed to calculate adjusted odds ratios (aOR) with 95% confidence intervals (CI). Restricted cubic spline models were used to validate and visualize the relationship. RESULTS: Women with lower pre-pregnancy BMI were at an increased risk of levator ani muscle avulsion (aOR = 1.73, 95% CI: 1.10-2.70, P = 0.017), particularly when combined with excessive GWG during pregnancy (aOR = 3.20, 95% CI: 1.15-8.97, P = 0.027). Lower pre-pregnancy BMI was also identified as an independent predictor of PFM weakness (aOR = 1.53, 95% CI: 1.08-2.16, P = 0.017 for type I fiber injuries). Notably, regardless of the avulsion status, both underweight and overweight/obese women faced an elevated risk of reduced PFM strength (aOR = 1.74, 95% CI: 1.17-2.59, P = 0.006 for underweight women with type I fiber injuries; aOR = 1.67, 95% CI: 1.06-2.64, P = 0.027; and aOR = 1.73, 95% CI: 1.09-2.76, P = 0.021 for overweight/obese women with type I and type II fibers injuries, respectively). CONCLUSIONS: Both lower and higher pre-pregnancy BMI, as well as excessive GWG, were strongly associated with PFM impairments. These findings highlighted the critical importance of comprehensive weight management throughout pregnancy to effectively promote women's pelvic health.

A surgical alternative of fusiform penetrating keratoplasty for the management of severe infectious keratitis.

AIM: To describe the surgical procedure of fusiform penetrating keratoplasty (FPK) using multiple trephines of different sizes for treating patients with severe infectious keratitis. METHODS: Fourteen eyes underwent FPK, and 15 eyes received conventional penetrating keratoplasty (PK) were included in the study. The best-corrected visual acuity (BCVA), refractive outcomes, endothelial cell density, and postoperative complications were recorded. RESULTS: The FPK group was followed for an average of 15.3±2.1mo, whereas the PK group was followed for 16.1±1.9mo. The corneal ulcers were elliptical-shaped in all 14 eyes in the FPK group. The mean BCVA (logMAR, 0.26±0.13) showed no statistically significant differences from that in the PK group (logMAR, 0.21±0.12, P>0.05) at 1y after surgery. But the mean curvature, mean astigmatism, and mean spherical equivalent in the FPK group were lower than those in the PK group (P<0.05). Peripheral anterior synechia was observed in one patient in the FPK group, whereas 6 patients in the PK group. Suture loosening and neovascularization were observed in 4 and 5 eyes in the PK group, respectively. No graft immune rejection or elevation of intraocular pressure was observed in the two groups. CONCLUSION: For patients with elliptical-shaped corneas or corneal ulcers, FPK can avoid disrupting of corneal limbus, reduce the risk of postoperative complications, and can result in satisfactory visual quality.

Binary ruthenium dioxide and nickel oxide ultrafine particles loaded on carbon nanotubes for high-stability oxygen evolution reaction at high current densities.

RuO2 is an efficient electrocatalyst for the oxygen evolution reaction (OER). However, during the OER process, RuO2 is prone to oxidation into Rux+ (x > 4), leading to its dissolution in the electrolyte and resulting in poor stability of RuO2. Here, we report a bicomponent electrocatalyst, NiO and RuO2 co-loaded on carbon nanotubes (RuO2/NiO/CNT). The results demonstrate that the introduction of NiO suppresses the over-oxidation of RuO2 during the OER process, not only inheriting the excellent catalytic performance of RuO2, but also significantly enhancing the stability of the catalyst for OER at high current densities. In contrast to RuO2/CNT, RuO2/NiO/CNT shows no significant change in activity after 150 h of OER at a current density of 100 mA cm-2. Density functional theory (DFT) calculations indicate that NiO transfers a large number of electrons to RuO2, thereby reducing the oxidation state of Ru. In conclusion, this study provides a detailed analysis of the phenomenon where low-valent metal oxides have the ability to enhance the stability of RuO2 catalysts.

Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism.

BACKGROUND: The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear. AIM: To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation. METHODS: A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH. RESULTS: MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones. CONCLUSION: MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

A sarcomatoid malignancy originating in the right cervical lymph nodes with atypical pathological characteristics: a case report of an incidental finding.

Background: Primary malignancies of the cervical lymph nodes with special pathological characteristics are relatively uncommon in clinical settings, and there have been few reports on these tumors. The precise basis for their pathogenesis is poorly understood, and their diagnosis can be challenging. In addition, no clinically validated treatments have been established to date for affected patients. Case Description: Here, we describe a case of a 65-year-old male patient who exhibited the enlargement of several lateral and supraclavicular lymph nodes on the right side of his neck that presented as a large mass associated with a high fever and benign leukocytosis. He did not exhibit any relevant prior history. Radiological assessment revealed that this lesion was the primary tumor and that it has since spread to the liver. Histological assessment was unable to definitively classify the pathological characteristics of this tumor. Without any relevant morphological findings, immunohistochemical outcomes were not sufficiently specific to clarify the origin of these cells. When distinguishing it from similar sarcomas of the lymphohematopoietic system, it was found to not be typical of a histiocytic or dendritic cell tumor. Treatment to this patient was performed following multidisciplinary consultation and consisted of one course of a cyclophosphamide plus doxorubicin, vincristine, and dexamethasone regimen and two courses of the cyclophosphamide plus pirarubicin, vincristine, and dexamethasone regimen. However, the tumor exhibited minimal response to such treatment. While radiotherapy was proposed, the patient lacked confidence in the approach and declined treatment. He eventually developed severe tumor-associated complications. In the discussion section of this report, we detail and analyze the pathogenesis, diagnosis, and referential treatments of this rare malignancy. Conclusions: This is the first report describing such a malignancy, and we hope that the publication of these findings can lead to the recognition of this tumor while supporting efforts to acquire greater experience in the diagnosis and treatment of affected patients.

Predictive role of oxidative stress-related genes in colon cancer: a retrospective cohort study based on The Cancer Genome Atlas.

PURPOSE: This study aimed to elucidate the predictive role of an oxidative stress-related genes (OSRGs) model in colon cancer. MATERIALS AND METHODS: First, OSRGs that were differentially expressed between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA)-(Colorectal Adenocarcinoma) COAD dataset. Then, Lasso COX regression was performed to develop an optimal prognostic model patients were stratified into high- and low-risk groups based on the expression patterns of these genes. The model's validity was confirmed through Kaplan-Meier survival curves and receiver operating characteristic curve (ROC) analysis. Additionally, enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to uncover underlying mechanisms. RESULTS: A totally of 115 differentially expressed OSRGs were identified within the TCGA cohort, with 17 significantly linked to overall survival. These 17 genes were used to formulate a prognostic model that differentiated patients into distinct risk groups, with the high-risk group demonstrating a notably inferior overall survival rate. The risk score, when integrated with clinical and pathological data, emerged as an independent prognostic indicator of colon cancer. Further analyses revealed that the disparity in prognostic outcomes between risk groups could be attributed to the reactive oxygen species pathway and the p53 signaling pathway. CONCLUSION: A new prediction model was established based on OSRGs. CYP19A1, NOL3 and UCN were found to be highly expressed in tumor tissues and substantial clinical predictive significance. These findings offer new insights into the role of oxidative stress in colon cancer.

Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration.

BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.

Epidemiological characteristics and clinical antibiotic resistance analysis of Ureaplasma urealyticum infection among women and children in southwest China.

BACKGROUND: The aim of this study was to investigate the epidemiological characteristics and antibiotic resistance patterns of Ureaplasma urealyticum (UU) infection among women and children in southwest China. METHODS: A total of 8,934 specimens, including urogenital swabs and throat swabs were analyzed in this study. All samples were tested using RNA-based Simultaneous Amplification and Testing (SAT) methods. Culture and drug susceptibility tests were performed on UU positive patients. RESULTS: Among the 8,934 patients, the overall positive rate for UU was 47.92%, with a higher prevalence observed among women of reproductive age and neonates. The majority of UU positive outpatients were women of reproductive age (88.03%), while the majority of UU positive inpatients were neonates (93.99%). Overall, hospitalization rates due to UU infection were significantly higher in neonates than in women. Further analysis among neonatal inpatients revealed a higher incidence of preterm birth and low birth weight in UU positive inpatients (52.75% and 3.65%, respectively) than in UU negative inpatients (44.64% and 2.89%, respectively), especially in very preterm and extremely preterm neonates. Moreover, the incidence rate of bronchopulmonary dysplasia (BPD) among hospitalized neonatal patients was significantly higher in the UU positive group (6.89%) than in the UU negative group (4.18%). The drug susceptibility tests of UU in the neonatology, gynecology and obstetrics departments exhibited consistent sensitivity patterns to antibiotics, with high sensitivity to tetracyclines and macrolides, and low sensitivity to fluoroquinolones. Notably, UU samples collected from the neonatology department exhibited significantly higher sensitivity to azithromycin and erythromycin (93.8% and 92.9%, respectively) than those collected from the gynecology and obstetrics departments. CONCLUSIONS: This study enhances our understanding of the current epidemiological characteristics and antibiotic resistance patterns of UU infection among women and children in southwest China. These findings can aid in the development of more effective intervention, prevention and treatment strategies for UU infection.

Design of a double-layered material as a long-acting moisturizing hydrogel-elastomer and its application in the field protection of elephant ivories excavated from the Sanxingdui Ruins.

The sudden change in the environment from a dark, low-oxygen, low-temperature, high-humidity underground stable environment to an environment with much-improved temperature and humidity, a high oxygen content, enhanced light exposure, and increased harmful organisms has greatly affected the stability of the ivory unearthed from the Sanxingdui site. Therefore, the implementation of an effective emergency protection strategy for ivory excavated at Sanxingdui is imperative and urgently needed. However, the current gauze technique used at many archaeological sites suffers from short timescales, poor transparency of the material, and susceptibility to reverse osmosis of the ivory. Therefore, in this study, a transparent poly(acrylamide-acrylic acid) (P(AM-AA)) hydrogel-poly(dimethylsiloxane) (PDMS) elastomer bilayer was designed for the effective protection of excavated ivory. In this system, a hydrophobic PDMS elastomer was constructed on the surface of the hydrogel by the introduction of a silane coupling agent to inhibit the loss of water from the hydrogel to the external environment, thus prolonging the preservation of ivory by the protective material. The covalent interface between the hydrogel and the elastomer allowed the double-layer composite to exhibit excellent interfacial bonding. In addition, the double-layer material demonstrated a high mechanical strength of 1.2 MPa and a water binding ratio of ∼31%, which allowed it to form strong hydrogen bonds with the silanol structure. When the hydrogel was placed in an air environment (temperature: 25 °C; relative humidity: 65% RH), the water-retention rate of the double-layer material was still more than 60% after 5 days, thus the double-layer material showed excellent performance. Meanwhile, the double-layer material had a transmittance of more than 90% and exhibited a high degree of transparency, which makes it possible to promptly observe the changes occurring on the surface of the ivory. The combination of the aforementioned properties makes the bilayer a promising material for moisturizing and protecting excavated ivory in situ. Based on these properties, we used the prepared P(AM-AA)/PDMS double-layer material directly for wrapping the K8 ivory with the highest water content at Sanxingdui. The weight retention rate of the ivory was around 70% after 50 days of placement (temperature: 25 °C; relative humidity: 60% RH), the macroscopic morphology did not change significantly and the mechanical properties of the wrapped ivory were basically unchanged, which indicated that the double-layer material has an excellent on-site protection effect on the ivory excavated from Sanxingdui. This work provides new ideas and methods for the temporary conservation of wet heritage.

tRNA-m1A methylation controls the infection of Magnaporthe oryzae by supporting ergosterol biosynthesis.

Ergosterols are essential components of fungal plasma membranes. Inhibitors targeting ergosterol biosynthesis (ERG) genes are critical for controlling fungal pathogens, including Magnaporthe oryzae, the fungus that causes rice blast. However, the translational mechanisms governing ERG gene expression remain largely unexplored. Here, we show that the Trm6/Trm61 complex catalyzes dynamic N1-methyladenosine at position 58 (m1A58) in 51 transfer RNAs (tRNAs) of M. oryzae, significantly influencing translation at both the initiation and elongation stages. Notably, tRNA m1A58 promotes elongation speed at most cognate codons mainly by enhancing eEF1-tRNA binding rather than affecting tRNA abundance or charging. The absence of m1A58 leads to substantial decreases in the translation of ERG genes, ergosterol production, and, consequently, fungal virulence. Simultaneously targeting the Trm6/Trm61 complex and the ergosterol biosynthesis pathway markedly improves rice blast control. Our findings demonstrate an important role of m1A58-mediated translational regulation in ergosterol production and fungal infection, offering a potential strategy for fungicide development.

Vonoprazan and amoxicillin dual therapy for 14 days as the first-line treatment of Helicobacter pylori infection: A non-inferiority, randomized clinical trial.

BACKGROUND: We previously optimized the duration and dose of vonoprazan and amoxicillin dual therapy in China. The efficacy of vonoprazan with b.i.d. amoxicillin in comparison with vonoprazan-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection has not been adequately evaluated. METHODS: In a non-inferiority, randomized clinical trial, H. pylori infected and treatment-naïve patients were randomly assigned to receive 14 days of either vonoprazan dual (vonoprazan 20 mg and amoxicillin 1 g twice daily) or quadruple therapy (vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth potassium citrate 600 mg twice daily). H. pylori status was confirmed using 13C-urea breath tests or fecal antigen test. The primary outcome was the H. pylori eradication rate following vonoprazan dual and quadruple therapy at 4-12 weeks. We also compared drug compliance to either regimen and documented their side effect. RESULTS: A total of 190 subjects were randomized. The eradication rate of vonoprazan dual and quadruple therapy were 87.4% and 92.6% (p = 0.23) by intention-to-treat analysis, respectively, and 96.5% and 97.7% (p = 0.63) by per-protocol analysis, respectively. The efficacy of vonoprazan dual therapy was non-inferior to vonoprazan-containing quadruple therapy in per-protocol analysis (p < 0.001; difference: -1.2%; 90% confidence interval: -5.4% to 3.0%). CONCLUSION: Vonoprazan with b.i.d. amoxicillin for 14 days provided similar satisfactory efficacy with vonoprazan-containing quadruple therapy as a first-line H. pylori treatment in China.

Dapagliflozin alleviates right heart failure by promoting collagen degradation by reducing ROS levels.

BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-ß) to investigate the effect of DAPA. RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Assessment of heavy metal(oid) pollution and related health risks in agricultural soils surrounding a coal gangue dump from an abandoned coal mine in Chongqing, Southwest China.

The coal gangue dump may introduce heavy metal(oid)s (HMs) into surrounding agricultural soils, posing potential health risks to nearby communities. This study evaluated heavy metal(oid) pollution in agricultural soils adjacent to a gangue dump at an abandoned coal mine in Chongqing, Southwest China. The concentrations of HMs (As, Cd, Cr, Cu, Ni, Pb, and Zn) were quantified using ICP-MS, and the contamination status was assessed using the Geoaccumulation Index (Igeo), Contamination Factor (CF), Pollution Load Index (PLI), and Potential Ecological Risk Index (RI). Heavy metal(oid) contamination was detected in soils across a depth of 0-30 cm, particularly pronounced in the topsoil layer (0-10 cm and 10-20 cm depths). Cu emerged as the predominant contaminant across all examined depths, with average Igeo values of 1.20, 1.21, and 1.16 for the 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively, indicating moderate contamination. The CF for Cu was 3.55, 3.55, and 3.50 for these respective depths, classifying it as considerable contamination. The PLI values ranged from 1.61 to 2.50, with a mean value of 2.12, indicating overall contamination. The ecological risk assessment indicated that the soil's ecological risk was low at all depths. Cd was the major contributor to the RI, accounting for 48%, 47%, and 42% at 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively. Health risk assessments revealed significant non-carcinogenic risks to children (mean HI = 1.30) and unacceptable carcinogenic risks to both adults and children (mean TCR = 3.26 × 10-4 and 1.53 × 10-3, respectively). This study underscores the critical need for comprehensive risk assessments using multiple indicators to prioritize remediation efforts for HMs, providing a scientific basis for effective environmental management and public health protection in the Three Gorges Reservoir Area.

SARS-CoV-2 reinfection broadens the antibody responses and promotes the phenotypic differentiation of virus-specific memory T cells in adolescents.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants raises concerns regarding the effectiveness of immunity acquired from previous Omicron subvariants breakthrough infections (BTIs) or reinfections (RIs) against the current circulating Omicron subvariants. In this study, we prospectively investigate the dynamic changes of virus-specific antibody and T cell responses among 77 adolescents following Omicron BA.2.3 BTI with or without subsequent Omicron BA.5 RI. Notably, the neutralizing antibodies (NAbs) titers against various detected SARS-CoV-2 variants, especially the emerging Omicron CH.1.1, XBB.1.5, XBB.1.16, EG.5.1, and JN.1 subvariants, exhibited a significant decrease along the time. A lower level of IgG and NAbs titers post-BTI was found to be closely associated with subsequent RI. Elevated NAbs levels and shortened antigenic distances were observed following Omicron BA.5 RI. Robust T cell responses against both Omicron BA.2- and CH.1.1-spike peptides were observed at each point visited. The exposure to Omicron BA.5 promoted phenotypic differentiation of virus-specific memory T cells, even among the non-seroconversion adolescents. Therefore, updated vaccines are needed to provide effective protection against newly emerging SARS-CoV-2 variants among adolescents.

Finite immune imprinting on neutralizing antibody responses to Omicron subvariants by repeated vaccinations.

OBJECTIVE: To investigate the effects of repeated vaccination with ancestral SARS-CoV-2 (Wuhan-hu-1)-based inactivated, recombinant protein subunit or vector-based vaccines on the neutralizing antibody response to Omicron subvariants. METHODS: Individuals who received four-dose vaccinations with the Wuhan-hu-1 strain, individuals who were infected with the BA.5 variant alone without prior vaccination, and individuals who experienced a BA.5 breakthrough infection following receiving 2-4 doses of the Wuhan-hu-1 vaccine were enrolled. Neutralizing antibodies against D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 were detected using a pseudovirus-based neutralization assay. Antigenic cartography was used to analyze cross-reactivity patterns among D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 and sera from individuals. RESULTS: The highest neutralizing antibody titers against D614G were observed in individuals who only received four-dose vaccination and those who experienced BA.5 breakthrough infection, which was also significantly higher than the antibody titers against XBB.1.5, EG.5.1, and BA.2.86. In contrast, only BA.5 infection elicited comparable neutralizing antibody titers against the tested variants. While neutralizing antibody titers against D614G or BA.5 were similar across the cohorts, the neutralizing capacity of antibodies against XBB.1.5, EG.5.1, and BA.2.86 was significantly reduced. BA.5 breakthrough infection following heterologous booster induced significantly higher neutralizing antibody titers against the variants, particularly against XBB.1.5 and EG.5.1, than uninfected vaccinated individuals, only BA.5 infected individuals, or those with BA.5 breakthrough infection after primary vaccination. CONCLUSIONS: Our findings suggest that repeated vaccination with the Wuhan-hu-1 strain imprinted a neutralizing antibody response toward the Wuhan-hu-1 strain with limited effects on the antibody response to the Omicron subvariants.

[Ecological Transition from Micro-remediation to Ecological Regulation of Petroleum Pollution].

Petroleum pollution has become a prominent global environmental problem, restricting the coordinated development of the economy and the ecological environment. Although bioremediation has the advantages of low carbon, high efficiency, and safety, the complexity and severity of the pollution makes it difficult to achieve the remediation purpose with a single bioremediation. Ecological remediation based on bioremediation can integrate carbon neutrality and ecological environmental protection, synergistically promote pollution reduction and carbon reduction, ensure the sustainability of soil and sediment to fulfil ecosystem service functions, and ultimately achieve soil health and sediment health. Therefore, the transition from bioremediation to ecological restoration is the optimal choice for environmental management and ecosystem maintenance at this stage. Here, we first analyzed the micro-removal mechanism of petroleum hydrocarbons in different bioremediation techniques and discussed the types and characteristics of different bioremediation techniques from an ecological point of view. Based on this, the necessity of bioremediation for ecological restoration was analyzed in detail. Finally, a reasonable outlook on the development of ecological remediation is given to provide theoretical support for optimizing ecological remediation of petroleum pollution.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.