Multiple functions of HMGB1 in cancer.

High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.

Causal relationship between circulating cytokines and follicular lymphoma: a two-sample Mendelian randomization study.

Follicular lymphoma (FL), derived from germinal centre (GC) B cells, is a kind of systemic neoplasm. Even though FL is indolent, it remains an incurable haematology Neoplasm. Accumulating evidence has suggested that the circulating cytokine is associated with the development of FL, yet the causal relationship between FL and circulating cytokines remains undetermined. Therefore, we conducted a two-sample Mendelian randomization (MR) to confirm the causal link between FL and levels of circulating cytokines with the use of summary data on circulating cytokines and FL. All these data from genome-wide association study were derived from the Genome-wide pQTL mapping which contains 14,824 individuals. FL data were acquired exclusively from FinnGen, where 218,792 individuals (522 cases vs. 218,270 controls) were involved. Various statistical methods, including the inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model (WM) and MR-Egger, were used to evaluate the potential causal connection between circulating cytokines and FL. Sensitivity analysis, which involves the examination of the heterogeneity, pleiotropy, and leave-one-out method, was also performed to ensure more trustworthy results. A bidirectional MR test was performed to evaluate the direction of causal association between circulating cytokines and FL. Combining all the steps of MR analysis, we revealed four causal cytokines: C-X-C motif chemokine ligand 5 (CXCL5), interleukin-15 receptor A (IL15RA), interleukin-20 (IL20), and neurotrophin-3 (NT-3). The risk of FL may be inversely linked to CXCL5 (OR=0.73, CI: 0.545-0.979, P=0.036), IL-15RA (OR=0.669, CI: 0.451-0.993, P=0.046), and IL-20 (OR=0.565, CI: 0.325-0.981, P=0.043) but positively linked to NT-3 (OR=1.872, CI: 1.063-3.297, P=0.03). In addition, in our study, no causal effect of FL on cytokines was demonstrated and no significant heterogeneity and pleiotropy were found. Our research revealed the causal relationship between cytokines and FL, along with both the anti-protective effect of CXCL5, IL-15RA, and IL-20 and the protective effect of neurotrophin-3 on FL. These findings aim to provide new clues regarding the pathogenesis of FL and to extend the potential of circulating cytokines to therapeutic interventions.

HER2-targeting CAR-T cells show highly efficient anti-tumor activity against glioblastoma both in vitro and in vivo.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options for GBM include surgical resection, radiation, and chemotherapy, which predominantly slow cancer growth and reduce symptoms, resulting in a 5-year survival rate of no more than 10%. Chimeric antigen receptor (CAR) T-cell therapy is a new class of cellular immunotherapy that has made great progress in treating malignant tumors. Human epidermal growth factor receptor 2 (HER2) is overexpressed in GBM and may provide a potential therapeutic target for GBM treatment. In this study, we constructed third-generation CAR-T cells targeting the HER2 antigen in GBM. HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting abilities against GBM cells in vitro. Anti-HER2 CAR-T cells also exhibited increased cytotoxicity with increasing effector-to-target ratios. Anti-HER2 CAR-T cells delivered via peritumoral injection successfully stunted tumor progression in vivo. Moreover, peritumoral intravenous administration of anti-HER2 CAR-T cells resulted in therapeutic improvement against GBM cells compared with intravenous administration. In conclusion, our study shows that HER2 CAR-T cells represent an emerging immunotherapy for treating GBM.

A novel biopsy scheme for prostate cancer: targeted and regional systematic biopsy.

PURPOSE: To explore a novel biopsy scheme for prostate cancer (PCa), and test the detection rate and pathological agreement of standard systematic (SB) + targeted (TB) biopsy and novel biopsy scheme. METHODS: Positive needles were collected from 194 patients who underwent SB + TB (STB) followed by radical prostatectomy (RP). Our novel biopsy scheme, targeted and regional systematic biopsy (TrSB) was defined as TB + regional SB (4 SB-needles closest to the TB-needles). The McNemar test was utilized to compare the detection rate performance for clinical significant PCa (csPCa) and clinical insignificant PCa (ciPCa). Moreover, the accuracy, positive predictive value (PPV) and negative predictive value (NPV) were investigated. The agreement between the different biopsy schemes grade group (GG) and RP GG were assessed. The concordance between the biopsy and the RP GG was evaluated using weighted κ coefficient analyses. RESULTS: In this study, the overall detection rate for csPCa was 83.5% (162 of 194) when SB and TB were combined. TrSB showed better NPV than TB (97.0% vs. 74.4%). Comparing to STB, the TB-detection rate of csPCa had a significant difference (p < 0.01), while TrSB showed no significant difference (p > 0.999). For ciPCa, the overall detection rate was 16.5% (32 of 194). TrSB showed better PPV (96.6% vs. 83.3%) and NPV (97.6% vs. 92.9%) than TB. Comparing to STB, the detection rate of both schemes showed no significant difference (p = 0.077 and p = 0.375). All three schemes GG showed poor agreement with RP GG (TB: 43.3%, TrSB: 46.4%, STB: 45.9%). Using weighted κ, all three schemes showed no difference (TB: 0.48, TrSB: 0.51, STB: 0.51). In our subgroup analysis (PI-RADS = 4/5, n = 154), all three schemes almost showed no difference (Weighted κ: TB-0.50, TrSB-0.51, STB-0.50). CONCLUSION: Our novel biopsy scheme TrSB (TB + 4 closest SB needles) may reduce 8 cores of biopsy compared with STB (standard SB + TB), which also showed better csPCa detection rate than TB only, but the same as STB. The pathological agreement between three different biopsy schemes (TB/TrSB/STB) GG and RP GG showed no difference.

Identification of novel resistance-associated mutations and discrimination within whole-genome sequences of fluoroquinolone-resistant Mycobacterium tuberculosis isolates.

This study aims to elucidate additional mutation loci associated with fluoroquinolone (FQ) resistance and evaluate the discriminatory capacity of mutation loci and allele mutation frequencies in identifying FQ-resistant Mycobacterium tuberculosis (MTB) isolates. A random selection of isolates was extracted from an ongoing collection. Drug resistance was determined using the resazurin microtiter assay (REMA) as the gold standard. Mutation loci and the burden of mutations in the quinolone resistance-determining region (QRDR) were elucidated through whole-genome sequencing (WGS). Novel amino acid mutations, namely, G520D and G520T, were identified in the gyrB and associated with FQ resistance. In the context of distinguishing FQ-resistant isolates, the AUC for the QRDR mutation frequency burden (0.969) surpassed that of the mutation locus (0.929), and this difference was statistically significant (P = 0.03). Furthermore, using the resistance mutation locus as a reference, setting the QRDR mutation frequency burden threshold at 1.31% resulted in a 3.60% increase in the accuracy of classifying FQ-resistant isolates (NRI = 3.60%, P < 0.001). The QRDR mutation frequency burden appears to offer superior diagnostic efficacy in discriminating FQ-resistant isolates compared to qualitative detection of mutant loci.IMPORTANCEFluoroquinolone (FQ) drugs are recommended as second-line drugs for the treatment of multidrug-resistant tuberculosis. With the massive use of FQ drugs in the clinical treatment of tuberculosis (TB), there is an increasing rate of drug resistance to FQ drugs. In this study, we identified and demonstrated novel amino acid mutations associated with FQ resistance in Mycobacterium tuberculosis (MTB), and we quantified the mutation sites and identified the quinolone resistance-determining region (QRDR) mutation frequency burden as a novel diagnostic method for FQ resistance. We hope that the results of this study will provide data support and a theoretical basis for the rapid diagnosis of FQ-resistant MTB.

Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

Risk factors of neonatal stroke from different origins: a systematic review and meta-analysis.

Given the persistent ambiguity regarding the etiology of neonatal stroke across diverse origins, our objective was to conduct a comprehensive evaluation of both qualitative and quantitative risk factors. An exhaustive search of eight databases was executed to amass all pertinent observational studies concerning risk factors for neonatal stroke from various origins. Subsequent to independent screening, data extraction, and bias assessment by two researchers, a meta-analysis was conducted utilizing RevMan and Stata software. Nineteen studies, encompassing a total of 30 factors, were incorporated into this analysis. Beyond established risk factors, our investigation unveiled gestational diabetes (OR, 5.51; P < 0.00001), a history of infertility (OR, 2.44; P < 0.05), placenta previa (OR, 3.92; P = 0.02), postdates (OR, 2.07; P = 0.01), preterm labor (OR, 2.32; P < 0.00001), premature rupture of membranes (OR, 3.02; P = 0.007), a prolonged second stage of labor (OR, 3.94; P < 0.00001), and chorioamnionitis (OR, 4.35; P < 0.00001) as potential risk factors for neonatal cerebral arterial ischemic stroke. Additionally, postdates (OR, 4.31; P = 0.003), preterm labor (OR, 1.60; P < 0.00001), an abnormal CTG tracing (OR, 9.32; P < 0.0001), cesarean section (OR, 4.29; P = 0.0004), male gender (OR, 1.73; P = 0.02), and vaginal delivery (OR, 1.39; P < 0.00001) were associated with an elevated risk for neonatal hemorrhagic stroke. CONCLUSIONS: This study provides a succinct overview and comparative analysis of maternal, perinatal, and additional risk factors associated with neonatal cerebral artery ischemic stroke and neonatal hemorrhagic stroke, furnishing critical insights for healthcare practitioners involved in the diagnosis and prevention of neonatal stroke. This research also broadens the conceptual framework for future investigations. WHAT IS KNOWN: • Research indicates that prenatal, perinatal, and neonatal risk factors can elevate the risk of neonatal arterial ischemic stroke (NAIS). However, the risk factors for neonatal cerebral arterial ischemic stroke remain contentious, and those for neonatal hemorrhagic stroke (NHS) and neonatal cerebral venous sinus thrombosis (CVST) are still not well-defined. WHAT IS NEW: • This study is the inaugural comprehensive review and meta-analysis encompassing 19 studies that explore maternal, perinatal, and various risk factors linked to neonatal stroke of differing etiologies. Notably, our analysis elucidates eight risk factors associated with NAIS: gestational diabetes mellitus, a history of infertility, placenta previa, postdates, preterm birth, premature rupture of membranes, a prolonged second stage of labor, and chorioamnionitis. Furthermore, we identify six risk factors correlated with NHS: postdates, preterm birth, an abnormal CTG, the method of delivery, male gender, and vaginal delivery. Additionally, our systematic review delineates risk factors associated with CVST.

Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) is strongly associated with neuroinflammation, and type I interferons (IFN-I) play a crucial role in regulating immune and inflammatory responses. However, the specific features of IFN in different cell types and the underlying mechanisms of PD have yet to be fully described. In this study, we analyzed the GSE157783 dataset, which includes 39,024 single-cell RNA sequencing results for five PD patients and six healthy controls from the Gene Expression Omnibus database. After cell type annotation, we intersected differentially expressed genes in each cell subcluster with genes collected in The Interferome database to generate an IFN-I-stimulated gene set (ISGs). Based on this gene set, we used the R package AUCell to score each cell, representing the IFN-I activity. Additionally, we performed monocle trajectory analysis, and single-cell regulatory network inference and clustering (SCENIC) to uncover the underlying mechanisms. In silico gene perturbation and subsequent experiments confirm NFATc2 regulation of type I interferon response and neuroinflammation. Our analysis revealed that microglia, endothelial cells, and pericytes exhibited the highest activity of IFN-I. Furthermore, single-cell trajectory detection demonstrated that microglia in the midbrain of PD patients were in a pro-inflammatory activation state, which was validated in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model as well. We identified transcription factors NFATc2, which was significantly up-regulated and involved in the expression of ISGs and activation of microglia in PD. In the 1-Methyl-4-phenylpyridinium (MPP+)-induced BV2 cell model, the suppression of NFATc2 resulted in a reduction in IFN-ß levels, impeding the phosphorylation of STAT1, and attenuating the activation of the NF-κB pathway. Furthermore, the downregulation of NFATc2 mitigated the detrimental effects on SH-SY5Y cells co-cultured in conditioned medium. Our study highlights the critical role of microglia in type I interferon responses in PD. Additionally, we identified transcription factors NFATc2 as key regulators of aberrant type I interferon responses and microglial pro-inflammatory activation in PD. These findings provide new insights into the pathogenesis of PD and may have implications for the development of novel therapeutic strategies.

Recent development and future application of biodegradable ureteral stents.

Ureteral stenting is a common clinical procedure for the treatment of upper urinary tract disorders, including conditions such as urinary tract infections, tumors, stones, and inflammation. Maintaining normal renal function by preventing and treating ureteral obstruction is the primary goal of this procedure. However, the use of ureteral stents is associated with adverse effects, including surface crusting, bacterial adhesion, and lower urinary tract symptoms (LUTS) after implantation. Recognizing the need to reduce the complications associated with permanent ureteral stent placement, there is a growing interest among both physicians and patients in the use of biodegradable ureteral stents (BUS). The evolution of stent materials and the exploration of different stent coatings have given these devices different roles tailored to different clinical needs, including anticolithic, antibacterial, antitumor, antinociceptive, and others. This review examines recent advances in BUS within the last 5 years, providing an in-depth analysis of their characteristics and performance. In addition, we present prospective insights into the future applications of BUS in clinical settings.

The effect of metabolism-related lifestyle and clinical risk factors on digestive system cancers in East Asian populations: a two-sample Mendelian randomization analysis.

Metabolic factors play a critical role in the development of digestive system cancers (DSCs), and East Asia has the highest incidence of malignant tumors in the digestive system. We performed a two-sample Mendelian randomization analysis to explore the associations between 19 metabolism-related lifestyle and clinical risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and pancreatic cancer. The causal association was explored for all combinations of each risk factor and each DSC. We gathered information on the instrumental variables (IVs) from various sources and retrieved outcome information from Biobank Japan (BBJ). The data were all from studies of east Asian populations. Finally, 17,572 DSCs cases and 195,745 controls were included. Our analysis found that genetically predicted alcohol drinking was a strong indicator of gastric cancer (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.93-0.98) and hepatocellular carcinoma (OR = 1.11; 95% CI: 1.05-1.18), whereas coffee consumption had a potential protective effect on hepatocellular carcinoma (OR = 0.69; 95% CI: 0.53-0.90). Triglyceride was potentially associated with a decreased risk of biliary tract cancer (OR = 0.53; 95% CI: 0.34-0.81), and uric acid was associated with pancreatic cancer risk (OR = 0.59; 95% CI: 0.37-0.96). Metabolic syndrome (MetS) was associated with esophageal and gastric cancer. Additionally, there was no evidence for a causal association between other risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels, lipoprotein cholesterol, total cholesterol, glycine, creatinine, gout, and Graves' disease, and DSCs. The leave-one-out analysis revealed that the single nucleotide polymorphism (SNP) rs671 from the ALDH2 gene has a disproportionately high contribution to the causal association between alcohol drinking and gastric cancer and hepatocellular carcinoma, as well as the association between coffee consumption and hepatocellular carcinoma. The present study revealed multiple metabolism-related lifestyle and clinical risk factors and a valuable SNP rs671 for DSCs, highlighting the significance of metabolic factors in both the prevention and treatment of DSCs.

Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

Comparative quantitative analysis of optical coherence tomography angiography in varied morphologies of macular neovascularization following intravitreal conbercept and ranibizumab treatments for neovascular age­related macular degeneration.

The present study aimed to examine the optical coherence tomography angiography (OCTA) parameters associated with macular neovascularization (MNV) in patients diagnosed with neovascular age-related macular degeneration (nAMD) and treated with either intravitreal conbercept (IVC) or ranibizumab (IVR). It enrolled 39 nAMD patients presenting with MNV, including 23 in the IVC group and 16 in the IVR group. All participants were treatment-naïve with intravitreal therapy and they underwent treatment following a '3+PRN' regimen. The MNV patterns identified through OCTA were categorized as Medusa, tangled, seafan and other variations. Key outcome measures encompassed best-corrected visual acuity (BCVA), MNV vascular area (MNV-VA), MNV vascular density (MNV-VD) ratio and central macular thickness (CMT). In the present study, 44 eyes were included, with 28 eyes undergoing treatment with IVC and 18 eyes with IVR. On day 90, there was a statistically significant improvement in mean BCVA from baseline among all patients treated with IVC (P=0.002). Notably, improved outcomes were observed in those with the 'tangled' pattern compared with the other three patterns (P=0.007). CMT exhibited a significant decrease from baseline (P=0.007), with consistent improvement observed across all four patterns (P=0.052) on day 90. The mean MNV-VA decreased in all patients, reaching statistical significance for the Medusa pattern (P=0.008), although the improvement in visual acuity was deemed unsatisfactory. Patients with the seafan pattern treated with IVR improved significantly in BCVA (P=0.042). The mean CMT significantly improved from baseline (P=0.001), consistent across the four patterns (P=0.114). Significant improvements were noted in the mean MNV-VA for the seafan pattern and in the mean MNV-VD ratio for the other patterns. The two regimens had no significant differences regarding BCVA, CMT, and MNV parameters. Conbercept emerged as a viable treatment option for patients presenting with tangled MNV patterns. On the other hand, ranibizumab might be considered an effective intervention for individuals with seafan MNV patterns. Notably, the Medusa MNV pattern was associated with a morphologic configuration indicative of a poor prognosis.

Protein disulfide isomerase 1 is required for RodA assembling-based conidial hydrophobicity of Aspergillus fumigatus.

The hydrophobic layer of Aspergillus conidia, composed of RodA, plays a crucial role in conidia transfer and immune evasion. It self-assembles into hydrophobic rodlets through intramolecular disulfide bonds. However, the secretory process of RodA and its regulatory elements remain unknown. Since protein disulfide isomerase (PDI) is essential for the secretion of many disulfide-bonded proteins, we investigated whether PDI is also involved in RodA secretion and assembly. By gene knockout and phenotypic analysis, we found that Pdi1, one of the four PDI-related proteins of Aspergillus fumigatus, determines the hydrophobicity and integrity of the rodlet layer of the conidia. Preservation of the thioredoxin-active domain of Pdi1 was sufficient to maintain conidial hydrophobicity, suggesting that Pdi1 mediates RodA assembly through its disulfide isomerase activity. In the absence of Pdi1, the disulfide mismatch of RodA in conidia may prevent its delivery from the inner to the outer layer of the cell wall for rodlet assembly. This was demonstrated using a strain expressing a key cysteine-mutated RodA. The dormant conidia of the Pdi1-deficient strain (Δpdi) elicited an immune response, suggesting that the defective conidia surface in the absence of Pdi1 exposes internal immunogenic sources. In conclusion, Pdi1 ensures the correct folding of RodA in the inner layer of conidia, facilitating its secretion into the outer layer of the cell wall and allowing self-assembly of the hydrophobic layer. This study has identified a regulatory element for conidia rodlet assembly.IMPORTANCEAspergillus fumigatus is the major cause of invasive aspergillosis, which is mainly transmitted by the inhalation of conidia. The spread of conidia is largely dependent on their hydrophobicity, which is primarily attributed to the self-assembly of the hydrophobic protein RodA on the cell wall. However, the mechanisms underlying RodA secretion and transport to the outermost layer of the cell wall are still unclear. Our study identified a critical role for Pdi1, a fungal protein disulfide isomerase found in regulating RodA secretion and assembly. Inhibition of Pdi1 prevents the formation of correct S-S bonds in the inner RodA, creating a barrier to RodA delivery and resulting in a defective hydrophobic layer. Our findings provided insight into the formation of the conidial hydrophobic layer and suggested potential drug targets to inhibit A. fumigatus infections by limiting conidial dispersal and altering their immune inertia.

Industrial fluoride emissions and their spatial characteristics in the Nansi Lake Basin, Eastern China.

Excessive fluoride emissions threaten ecological stability and human health. Previous studies have noted that industrial sources could be significant. However, quantifying industrial fluoride emissions has not been yet reported. In this study, both bottom-up and top-down approaches were used to estimate the fluoride emissions in the Nansi Lake Basin. Global and local spatial autocorrelation were adopted to reveal the spatial agglomeration effects. The fluoride emissions calculated by the bottom-up approach were larger than those calculated by the top-down method. The highest fluoride input mainly occurred in Zoucheng and Mudan. The highest fluoride emissions mainly occurred in Zoucheng and Rencheng using the bottom-up approach. The highest fluoride emissions mainly occurred in Zoucheng and Yanzhou using the top-down approach. Mining and washing of bituminous coal and anthracite (BAW) was the most significant source of fluoride input and emissions. A significant spatial agglomeration effect of fluoride emissions was found. These findings could provide a method for accurate industrial fluoride emission estimation, complement the critical data on the fluoride emissions of main industrial sectors, and provide a scientific basis for tracing fluoride sources.

Lifestyle intervention in children with obesity and nonalcoholic fatty liver disease (NAFLD): study protocol for a randomized controlled trial in Ningbo city (the SCIENT study).

BACKGROUND: The increasing prevalence of childhood obesity has become an urgent public health problem, evidence showed that intervention for childhood obesity bring enormous health benefits. However, an effective individualized intervention strategy remains to be developed, and the accompanying remission of related complications, such as nonalcoholic fatty liver disease (NAFLD), needs to be assessed. This study aimed to develop an m-Health-assisted lifestyle intervention program targeting overweight/obese children and assess its effectiveness on indicators of adiposity and NAFLD. METHODS: This is a cluster-randomized controlled trial that conducted in children with overweight/obesity in Ningbo city, Zhejiang Province, China. Students in Grade 3 (8-10 years old) were recruited from six primary schools, with three be randomized to intervention group and three to usual practice group. The intervention program will last for one academic year and consists of health education, dietary guidance, and physical activity reinforcement. This program is characterized by encouraging four stakeholders, including School, Clinic, famIly, and studENT (SCIENT), to participate in controlling childhood obesity, assisted by m-Health technology. Assessments will be conducted at baseline and 3 months, 9 months, 24 months, and 36 months after baseline. The primary outcome will be the differences between the two groups in students' body mass index and fatty liver index at the end of the intervention (9 months after baseline). During the implementation process, quality control methods will be adopted. DISCUSSION: The program will test the effectiveness of the m-Health-assisted lifestyle intervention on children with obesity and NAFLD. The results of this study will provide evidence for establishing effective lifestyle intervention strategy aimed at childhood obesity and NAFLD and may help develop guidelines for the treatment of obesity and NAFLD in Chinese children. TRIAL REGISTRATION: Clinicaltrials.gov NCT05482191. Registered on July 2022.

Risk factors for infant hearing loss: a meta-analysis.

Hearing loss is a common disability in infants that significantly impacts their cognitive, language, and literacy development. This study aimed to systematically assess the risk factors for the early identification and intervention in infant hearing loss. Databases were searched for meta-analyses of observational studies until November 2023. The quality assessment was performed using the Cochrane risk of bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of the evidence. A meta-analysis identified 14 risk factors significantly associated with infant hearing loss. According to the GRADE approach, there were four factors with moderate-certainty evidence (low birth weight(LBW), congenital anomalies, craniofacial anomalies, intracranial hemorrhages), seven factors with low-certainty evidence (ototoxic medications, family history of hearing loss, mechanical ventilation > 5 days, intrauterine infection, admission to neonatal intensive care unit (NICU) > 5 days, mechanical ventilation and asphyxia) and six with extremely-low-certainty evidence (very low birth weight < 1500 g (VLBW), hyperbilirubinemia, sepsis or meningitis, male sex, premature birth, small for gestational age (SGA)). Nevertheless, no significant association was found between infant hearing loss and factors such as small for gestational age (SGA), male sex, and premature birth (P > 0.05).  Conclusion: The identification of these 14 interrelated risk factors can prove advantageous in clinical practice, as these findings could guide hearing screening and parental counseling. Furthermore, prospective research could be conducted to develop risk-based scoring systems based on these factors. What is Known: • Infant hearing loss is a worldwide issue. • Risk factors for this condition are debated. What is New: • This is the first meta-analysis to comprehensively evaluate perinatal and postnatal risk factors for hearing loss in infants. • Intracranial hemorrhage, mechanical ventilation, and low birth weight are associated with infant hearing loss. However, no evidence of an association was found between premature birth, being small for gestational age, or male sex and hearing loss.

Adipocyte­rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator­activated receptor gamma/ABCG2 in epithelial ovarian cancer.

The effects of adipocyte­rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte­rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM­associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator­activated receptor Î³ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3­shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM­educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS-STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1-PMS2), a negative regulator of Exo1. While the HTT-Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT-MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS-STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS-STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.