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Background: The relationship between serum folate status and cognitive functions is still controversial. Objective: To evaluate the association between serum tetrahydrofolate and cognitive functions. Methods: A total of 3,132 participants (60–80 years old) from the 2011–2014 NHANES were included in this cross-sectional study. The primary outcome measure was cognitive function assessment, determined by the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning Test (CERAD-WL), CERAD-Delayed Recall Test (CERAD-DR), Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), and global cognitive score. Generalized linear model (GLM), multivariate logistic regression models, weighted generalized additive models (GAM), and subgroup analyses were performed to evaluate the association between serum tetrahydrofolate and low cognitive functions. Results: In GLM, and the crude model, model 1, model 2 of multivariate logistic regression models, increased serum tetrahydrofolate was associated with reduced cognitive functions via AF, DSST, CERAD-WL, CERAD-DR, and global cognitive score (p

Some patients with cancer treated with programmed death 1 (PD-1) inhibitors experience immune-related severe adverse events (ir-SAEs), however, predictors are limited. The objective was to identify clinicopathologic features that may be associated with a higher ir-SAE risk. This was a nested case-control study. After screening a total of 832 PD-1 inhibitor-treated patients, we identified 42 ir-SAE cases. According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, ir-SAEs were defined as grade ≥3 toxic effects associated with immunotherapy. A total of 126 controls were matched. The crude and adjusted risks of ir-SAEs were estimated by odds ratio (ORs) and 95% CIs using multivariate logistic regression models. Baseline neutrophil-to-lymphocyte ratio (NLR) [per SD increment-adjusted (aOR): 1.16], lactate dehydrogenase (LDH) ≥245 U/L (aOR: 2.39), and antibiotic exposure (aOR: 4.39) were associated with a higher risk of ir-SAEs. When NLR was categorized in 3 groups, significantly higher risks of ir-SAEs (aOR: 4.95) were found in participants in group 3 (6) than in those in group 1 (3). Furthermore, NLR (per SD increment-adjusted hazard ratio:1.08) were also significantly associated with shorter overall survival (OS). Baseline LDH ≥245 U/L and antibiotic exposure were no significant association with OS. In conclusion, ir-SAEs were associated between baseline NLR, LDH ≥245 U/L and antibiotic exposure. Lower NLR was correlated with longer OS for cancer.

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients' kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell's C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II-IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.

To investigate the prognostic value of metabolic syndrome (MetS) and its relationship with renal structure changes in patients with type 2 diabetes and associated diabetic nephropathy (DN).411 Chinese patients with type 2 diabetes and biopsy-confirmed DN were enrolled in this retrospective study. MetS was defined according to the modified criteria of the 2005 International Diabetes Federation. Baseline demographics and clinical information at the time of renal biopsy were extracted from the hospital's electronic medical records system. Renal pathological findings were assessed according to Renal Pathology Society system. Univariate and multivariate logistic regression analyses were performed to define the pathological covariates associated with MetS. A competing risk model, with death as the competing risk, was used to estimate the sub-distribution hazard ratio (SHR) of MetS for end-stage kidney disease (ESKD).224 (55%) patients had MetS. Patients with MetS had poor renal function and more severe interstitial fibrosis tubular atrophy scores (IFTA) than those without MetS. Multivariate logistic regression analysis revealed that IFTA was significantly associated with MetS (odds ratio per score increase 1.45, 95% confidence interval [CI] 1.02-2.05). Of the patients with DN at risk, 40% of patients progressed to ESKD. After adjusting for renal function and pathological parameters, the presence of MetS was an independent predictor for progression to ESKD (SHR 1.93, 95% CI 1.34-2.79). The SHRs for progression to ESKD also increased as the number of MetS components increased. Additionally, adding the IFTA scores improved the prognostic power of a model that only contained MetS and clinical covariates for predicting future ESKD.MetS is an independent prognostic predictor of ESKD in patients with T2D and DN, while adding the IFTA scores increased the prognostic value of MetS for renal outcome.

Nasopharyngeal carcinoma (NPC) is a typical type of malignant tumor. This research paper aims to study the function and mechanism of long non-coding RNA lung adenocarcinoma-related transcript 1 (lncRNA-LUADT1) in the progression of NPC. In this study, the expressions of lncRNA-LUADT1, miR-1207-5p, and TEAD1 in NPC tissues and cell lines were detected by RT-qPCR. Initially, the expression of lncRNA-LUADT1 and TEAD1 were significantly up-regulated in NPC tissues and cells, while miR-1207-5p was significantly down-regulated. Next, miR-1207-5p was confirmed to bind to lncRNA-LUADT1 or TEAD1 by bioinformatics and luciferase reporter assay. In addition, after interfering with lncRNA-LUADT1 expression, experiments of CCK8, EDU staining, and Transwell invasion were used to detect proliferation, invasion, and migration of NPC cells. The results showed that interfering with lncRNA-LUADT1 expression could inhibit the proliferation, invasion, and migration of NPC cells. Western blot showed that lncRNA-LUADT1 knockdown significantly decreased the expression of Hippo/YAP pathway protein (YAP1 and TAZ). However, interfering with the expression of miR-1207-5p reversed these results. In addition, the nude mouse tumor formation experiment suggested that low-expressed lncRNA-LUADT1 reduced the volume and weight of tumor tissues. In summary, lncRNA-LUADT1 down-regulation could inhibit NPC cell proliferation and invasion, which may be achieved through regulating miR-1207-5p expression and affecting TEAD1 expression, thus inhibiting the activation of Hippo/YAP signaling pathway.

BackgroundThere is great mental stress due to the coronavirus disease 2019 (COVID-19) pandemic. However, there are no detailed psychological studies of the children with chronic kidney disease (CKD) and their guardians during the COVID-19 pandemic.ObjectiveThis study explores the psychological pressure on children with CKD and their guardians.MethodsAn online survey was conducted at 20 of the largest pediatric nephropathy departments in China, including the Rutter Parent Questionnaire, Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS). Overall, 885 children (589 children with CKD associated with 296 children of the control group) completed the survey together with their guardians.ResultsThere was no statistical difference between CKD children and control children regarding their Rutter behavior scores and abnormal behaviors. Nevertheless, the abnormal behavior of children might aggravate the anxiety and depression of guardians in both CKD and control groups (p < 0.05). We confirmed that the anxiety and depression of guardians in the CKD group were both significantly higher than those in the control group (p < 0.05). The guardians in the CKD group with lower annual income were more likely to experience anxiety (p < 0.05). Furthermore, the guardians whose children were older than 11 years old might be more anxious than those who were 6–11 years old. Besides, the guardians in the CKD group who watched the news for 30–60 min daily were less likely to have depression than those who watched < 10 min (p < 0.05). The subgroup results showed that the gender, the time of watching the news, the annual income of guardians, and children's age might be the most critical factors influencing guardians' psychological burden.ConclusionThe guardians in the CKD group have more severe anxiety and depression during the pandemic. The children's abnormal behavior, adolescents' pressure, low household income, and the panic about the pandemic may be the main reasons for the anxiety and depression of guardians.

To summarize the design and methodology of a trial designed to evaluate the efficacy and safety of low dose laser cycloplasty (LCP) in treating malignant glaucoma.Prospective, multicentre, non-controlled clinical trial. Subjects were recruited from eight ophthalmic centers in China. The target sample size was 34. Patients aged18 years with a clinical diagnosis of malignant glaucoma inadequately controlled on medical therapy or malignant glaucoma recurrence after topical cycloplegics withdrawal were enrolled. All patients underwent LCP under retrobulbar anesthesia or sub-Tenon anesthesia. LCP is a treatment adopting few laser points (1100-2000 mW energy, 2000 milliseconds duration) that cauterizes and remodels the ciliary body over two clock hour-positions, which may relieve the ciliary ring block. Follow-up is planned for a period of 12 months. The primary outcome is the resolution of malignant glaucoma which is defined as central anterior chamber deepening after LCP.The Malignant Glaucoma Treatment trial (MGTT) will be the first prospective trial providing evidence of a treatment for malignant glaucoma. It intends to provide clinicians an optional, easy and convenient treatment for malignant glaucoma patients. Detailed morphological and biometric information collected during the study period will also help provide experience for the outcomes of malignant glaucoma.ChiCTR1800017960.

PurposeTo assess the prevalence of refractive errors (REs) in school children aged 6–18 years in urban and rural settings in Dalian, Northeast of China.MethodsThis is a school-based cross-sectional survey using multi-stage randomization technique. Six- to eighteen-year-old school children from elementary schools, junior and senior high schools from a rural area and an urban area in Dalian were included in December 2018. All subjects underwent a comprehensive questionnaire and eye examination.ResultsA total of 4,522 school children with 6–18 years of age were investigated. The age, gender-adjusted prevalence of myopia, and anisometropia were 82.71 and 7.27% among the urban students as compared to 71.76% and 5.41% among the rural ones (OR = 1.80, 95 % CI = 1.53 - 2.11, P < 0.001; OR = 1.29, 95 % CI = 1.00–1.67, P = 0.049), respectively. The hyperopia was less common in urban students than in rural ones (5.63 vs. 10.21%; OR = 0.54, 95 % CI: 0.43–0.67, P < 0.001). However, there was no significant difference in prevalence of astigmatism between urban (46.07%) and rural (44.69%) participants (OR = 0.96, 95 % CI: 0.84–1.10, P = 0.559). The differences on prevalence of REs were attributed to different social-demographic and physiologic factors.ConclusionsThe students from urban settings are more likely to have myopia and anisometropia but less likely to have hyperopia than their rural counterparts. Although considerable attention had been paid to controlling REs, it is necessary to further consider the urban-rural differences in REs.

The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell−specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell−redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.

Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.

BACKGROUND Primary insomnia is a worldwide problem and it has a considerable negative impact on one's physical and mental health. Studies have shown that non-synonymous Single-nucleotide polymorphisms in 5-hydroxytryptamine (serotonin or 5-HT) are related to primary insomnia. Previous studies have shown that 5-HT polymorphism (rs140700) is related to depression, and insomnia is often accompanied by depression and anxiety. The relationship between this site and primary insomnia is unknown. We speculated that this site may be related to primary insomnia, so we investigated the relationship between rs140700 and primary insomnia. AIMS To explore the relationship between the 5-HT gene polymorphism rs140700 and primary insomnia. METHODS In this study, we included 57 patients with primary insomnia and 54 age- and gender-matched normal controls. The subjects who belonged to the Chinese population were subjected to polysomnography for three consecutive nights. Their sleep quality was assessed, and the genotypes of the 5-hydroxytryptamine (5-HT) gene polymorphism rs140700 were determined by the flight mass spectrometry. RESULTS The genotype distributions of the 5-HT gene polymorphism rs140700 were in Hardy-Weinberg equilibrium in both patients and controls (P > 0.05). The allele and genotype distributions of this variant were comparable between the patients and controls in all subjects and between genders (all P > 0.05). The influence of rs140700 on percentage of stage 1 (P = 0.015) change and arousal index (P = 0.028) of primary insomnia was statistically significant. The logistic multi-factor regression analysis results revealed that 5-HT gene polymorphism rs140700 was not a risk factor for primary insomnia in the Chinese population (P = 0.589). CONCLUSIONS The 5-HT gene polymorphism rs140700 may not be a susceptibility locus for primary insomnia in the Chinese population.

Colon cancer is the third most common malignant tumor and its mortality rate ranks fourth among all malignant tumor types. Bioinformatics analysis has shown that GSPT1 is dysregulated in colon cancer and is associated with tumor progression. However, the underlying mechanism remains unclear. To address this research gap, we examined the impact of GSPT1 on cell proliferation, apoptosis, migration, and invasion in vitro as well as tumor growth in vivo in colon cancer by using a Cell Counting Kit-8 assay, flow cytometry, transwell migration assay, transwell invasion assay, and tumor xenograft model-based analysis, respectively. GSPT1 was significantly up-regulated in colon cancer tissues and cell lines. High GSPT1 expression was correlated with a larger tumor size. Depletion of GSPT1 suppressed cell proliferation, migration, and invasion-induced colon cancer cell apoptosis in vitro and restrained tumorigenicity in vivo in HCT116 colon cancer cells. Taken together, our findings suggest that the GSPT1/GSK pathway exerts tumor-promoting actions in colon cancer oncogenesis and progression. The GSPT1/GSK pathway may thus be an effective target for controlling colon cancer.

Several studies show that patients with early-onset diabetes have higher risk of diabetic complications than those diagnosed in middle age. However, whether early-onset of type 2 diabetes mellitus (T2DM) is a risk factor for diabetic nephropathy (DN) progression remains unclear, especially a lack of data in biopsy-confirmed cohort. In This study, we enrolled 257 patients with T2DM and biopsy-confirmed DN to investigate the role of early-onset T2DM in DN progression. Participants were divided into two groups according to the age of T2DM diagnosis: early-onset group (less than 40 years) and later-onset group (40 years or older). We found that patients with early-onset T2DM had higher glomerular grades and arteriolar hyalinosis scores than those in later-onset group. After adjusted for confounding factors, early-onset of T2DM remained an independent predictor of end-stage renal disease (ESRD) for patients with DN. In conclusion, although with the comparable renal function and proteinuria, patients with early-onset T2DM and DN had worse renal pathological changes than those with later-onset. Early-onset of T2DM might be an important predictor of ESRD for patients with DN, which called more attention to early supervision and prevention for patients with early-onset T2DM and DN.

Background Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear. Methods This retrospective study enrolled 218 adult patients with type 2 diabetes mellitus and biopsy-proven DKD, and without known cardiovascular diseases. These patients were followed up at least 1 year. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was further analyzed with logistic regression and Cox proportional hazard analysis. Results Among all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively (P = 0.268). Compared with patients with lower ASCVD risk(༜14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk(> 14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis(odds ratio [OR], 3.997; 95% confidence interval [CI], 1.385–11.530;P = 0.010). However, univariate and multivariate COX proportional hazard analysis showed the 10-year ASCVD risk score failed to be an independent risk factor for ESRD in patients with type 2 diabetes mellitus. Conclusions PCE can estimate ASCVD risk in patients with DKD, and DKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.

Rationale: Therapeutic antibody conjugates allow for the specific delivery of cytotoxic agents or immune cells to tumors, thus enhancing the antitumor activity of these agents and minimizing adverse systemic effects. Most current antibody conjugates are prepared by nonspecific modification of antibody cysteine or lysine residues, inevitably resulting in the generation of heterogeneous conjugates with limited therapeutic efficacies. Traditional strategies to prepare homogeneous antibody conjugates require antibody engineering or chemical/enzymatic treatments, processes that often affect antibody folding and stability, as well as yield and cost. Developing a simple and cost-effective way to precisely couple functional payloads to native antibodies is of great importance. Methods: We describe a simple proximity-induced antibody conjugation method (pClick) that enables the synthesis of homogeneous antibody conjugates from native antibodies without requiring additional antibody engineering or post-synthesis treatments. A proximity-activated crosslinker is introduced into a chemically synthesized affinity peptide modified with a bioorthogonal handle. Upon binding to a specific antibody site, the affinity peptide covalently attaches to the antibody via spontaneous crosslinking, yielding an antibody molecule ready for bioorthogonal conjugation with payloads. Results: We have prepared well-defined antibody-drug conjugates and bispecific small molecule-antibody conjugates using pClick technology. The resulting conjugates exhibit excellent in vitro cytotoxic activity against cancer cells and, in the case of bispecific conjugates, superb antitumor activity in mouse xenograft models. Conclusions: Our pClick technology enables efficient, simple, and site-specific conjugation of various moieties to the existing native antibodies. This technology does not require antibody engineering or additional UV/chemical/enzymatic treatments, therefore providing a general, convenient strategy for developing novel antibody conjugates.

Background Haemophilus influenzae was the most aggressive pathogen and formed a major cause of bacterial meningitis and pneumonia in young children and infants, which need medical emergency requiring immediate diagnosis and treatment. However, From isolation to identification of H. influenzae, the traditional diagnose strategy was time-consuming and expensive. Therefore, the establishment of a convenient, highly sensitive, and stable detection system is urgent and critical. Results In this study, we used a combined method to detect H. influenzae. Six specific primers were designed on the basis of outer membrane protein P6 gene sequence of H. influenzae. The reaction condition such as the optimum temperature was 65℃, and the optimum reaction time was 30 min, respectively. Through the loop-mediated isothermal amplification (LAMP) in combination with nanoparticle-based lateral flow biosensor (LFB), the sensitivity of LAMP-LFB showed 100 fg was the lowest genomic DNA templates concentration in the pure cultures. Meanwhile, the specificity of H. influenzae-LAMP-LFB assay showed the exclusive positive results, which were detected in H. influenzae templates. In 55 clinical sputum samples, 22 samples were positive with LAMP-LFB method, which was in accordance with the traditional culture and Polymerase Chain Reaction (PCR) method. The accuracy in diagnosing H. influenzae with LAMP-LFB could reach 100%, compared to culture and PCR method, indicating the LAMP-LFB had more advantages in target pathogen detection. Conclusions Taken together, LAMP-LFB could be used as an effective diagnostic approach for H. influenzae in the conditions of basic and clinical labs, which would allow clinicians to make better informed decisions regarding patient treatment without delay.

The pathological features of PDD are represented by dopaminergic neuronal death and intracellular α-synuclein (α-syn) aggregation. The interaction of iron accumulation with α-syn and tau was further explored as an essential pathological mechanism of PDD. However, the links and mechanisms between these factors remain unclear. Studies have shown that the occurrence and development of neurodegenerative diseases such as PDD are closely related to the separation of abnormal phases. Substances such as proteins can form droplets through liquid-liquid phase separation (LLPS) under normal physiological conditions and even undergo further liquid-solid phase transitions to form solid aggregates under disease or regulatory disorders, leading to pathological phenomena. By analyzing the existing literature, we propose that LLPS is the crucial mechanism causing abnormal accumulation of α-syn, tau, and other proteins in PDD, and its interaction with iron metabolism disorder is the key factor driving ferroptosis in PDD. Therefore, we believe that LLPS can serve as one of the means to explain the pathological mechanism of PDD. Determining the significance of LLPS in neurodegenerative diseases such as PDD will stimulate interest in research into treatments based on interference with abnormal LLPS.

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) and is associated with increased morbidity and mortality in patients with diabetes. Identification of risk factors involved in the progression of DKD to ESRD is expected to result in early detection and appropriate intervention and improve prognosis. Therefore, this study aimed to establish a risk prediction model for ESRD resulting from DKD in patients with type 2 diabetes mellitus (T2DM).Between January 2008 and July 2019, a total of 390 Chinese patients with T2DM and DKD confirmed by percutaneous renal biopsy were enrolled and followed up for at least 1 year. Four machine learning algorithms (gradient boosting machine, support vector machine, logistic regression, and random forest (RF)) were used to identify the critical clinical and pathological features and to build a risk prediction model for ESRD.There were 158 renal outcome events (ESRD) (40.51%) during the 3-year median follow up. The RF algorithm showed the best performance at predicting progression to ESRD, showing the highest AUC (0.90) and ACC (82.65%). The RF algorithm identified five major factors: Cystatin-C, serum albumin (sAlb), hemoglobin (Hb), 24-hour urine urinary total protein, and estimated glomerular filtration rate. A nomogram according to the aforementioned five predictive factors was constructed to predict the incidence of ESRD.Machine learning algorithms can efficiently predict the incident ESRD in DKD participants. Compared with the previous models, the importance of sAlb and Hb were highlighted in the current model.Highlights

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD). Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD. Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions. Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria. Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor.

Objective: Our study sought to investigate the clinicopathologic features and renal prognosis of patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in different age groups. Methods: A total of 315 patients with T2DM and biopsy-proven DN were enrolled and divided into three groups by age: the Youth group (≤44 years old), the Middle-aged group (45 to 59 years old), and the Elderly group (≥60 years old). Results: The Youth group, Middle-aged group, and Elderly group accounted for 19.05% (60/315), 59.37% (187/315), and 21.59% (68/315) of the patients in our study, respectively. The patients in the Youth group had a higher estimated glomerular filtration rate (calculated using the Chronic Kidney Disease–Epidemiology collaboration formula) (P .05). Conclusion: This study indicated that there were different clinicopathologic features among Chinese DN patients in different age groups. Although the Youth group had a relatively lower rapid kidney disease progression rate, there were no significant differences in renal survival rate among the three groups, which calls more attention to early supervision and prevention for younger DN patients. Abbreviations: CKD = chronic kidney disease; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; GY IFTA = interstitial fibrosis and tubular atrophy; T2DM = type 2 diabetes mellitus

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patient

Adult brainstem gliomas are characterized into subtypes depending on clinicopathologic and radiographic characteristics. Among them, brainstem glioblastoma is the most malignant and has the poorest prognosis, with surgical resection for this condition posing a great challenge and risk. Postoperative synchronous radiotherapy and temozolomide (TMZ) chemotherapy, or "Stupp's regimen", is the standard of care for glioblastomas. However, antiangiogenic therapy, which is widely used for different cancers, is now an alternative treatment for malignant tumors. Angiogenesis is one of the pathological features of glioblastoma and is involved in tumor progression and metastasis. Besides, previous studies suggested a better response to antiangiogenic therapy in some solid tumors with TP53 mutation than TP53 wide-type. Apatinib is a novel, oral, small-molecule tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit angiogenesis. In addition, apatinib can cross the blood-brain barrier and improve encephaledema. This report describes the use of concurrent apatinib and dose-dense TMZ in a clinically inoperable patient who had a refractory brainstem glioblastoma with a TP53 germline mutation. He obtained an ongoing progression free survival (PFS) of nearly 16.0 months after resistance to TMZ maintenance. Due to the patient's circumstances, apatinib and TMZ was considered an effective and safe treatment method.

Immunoglobulin G (IgG) molecules modulate an immune response. However, site-specific

Background Human papillomavirus (HPV) infection can cause cervical and other cancers, including vulva, vagina, penis, anus, or oropharynx. However, in China's northern Henan Province, data on the prevalence and genotype distribution of HPV among women attending gynecology clinics is limited. This study aimed to investigate the current prevalence and genotype distribution of HPV among women attending gynecology clinics in northern Henan Province. Methods This study included 15,616 women aged 16–81 years old who visited the Xinxiang central hospital's gynecology department between January 2018 and December 2019. HPV DNA was detected by a conventional PCR method followed by HPV type-specific hybridization, which was designed to detect 17 high-risk HPV (HR-HPV) genotypes and 20 low-risk HPV (LR-HPV) genotypes. HPV prevalence and corresponding 95% confidence intervals (95% CI) were calculated using SPSS 18.0. Results The overall HPV prevalence was 19.7% among women in northern Henan Province. Single, double, and multiple HPV infections accounted for 13.7%, 4.3%, and 1.8% of the total cases. Most infections were caused by HR-HPV (71.8%), and single genotype HPV infection (13.7%) was the most common pattern. The most common HR-HPV genotype was HPV16 (4.3%), followed by HPV52 (3.5%) and HPV58 (2.0%). The most common LR-HPV genotype was HPV6 (1.4%), followed by HPV61 (1.1%) and HPV81 (1.1%). Conclusions HPV infection is high among women attending gynecology clinics in northern Henan Province. The highest prevalence was found in women less than 20 years old. In northern Henan Province, the 9-valent HPV vaccine is strongly recommended for regular immunization.

Background: Prostate cancer (PCa) is the fifth leading cause of death from cancer in men worldwide. Its treatment remains challenging due to the heterogeneity of the tumor, mainly because of the lack of effective and targeted prognostic markers at the system biology level.Methods: First, samples of PCa were retrieved from UCSC Xena data, and valid samples were obtained by consistent clustering and principal component analysis; next, key genes were analyzed for prognosis of PCa using WGCNA, MEGENA, and LASSO Cox regression model analysis, while key genes were screened based on disease-free survival (DFS) significance. Finally, TIMER data were selected to explore the relationship between genes and tumor immune infiltration, and GSCAlite was used to explore the small-molecule targeted drugs that act with them.Results: In this study, we used tumor subtype analysis and an energetic co-expression network algorithm of WGCNA and MEGENA to identify a signal dominated by the ROMO1 tag to predict PCa prognosis. Cox regression analysis of this signal was an independent influence, and the prognostic value of this biomarker was validated in the training set, the validated data itself, and external data, respectively. This biomarker correlates with tumor immune infiltration and has a high degree of infiltration, poor prognosis, and strong correlation with CD8+ T cells. Gene function annotation and other analyses also implied a potential molecular mechanism for ROMO1.Conclusions: In conclusion, our study suggests ROMO1 as a portal key prognostic gene for the diagnosis and prognosis of PCa. Moveover, we identify nutlin-3, fluorouracil, and other drugs as possible key drugs for diagnosis and prognosis, which provide new insights into the diagnosis and treatment of prostate cancer.

Objective: We sought to examine the effects of 8 wk of time-restricted eating (TRE) on glucose metabolism and the adipose tissue transcriptome during a metabolic ward stay in men with obesity. Methods: In a single-arm, pre-post trial, 15 men (ages 63 § 4 y, body mass index = 30.5 § 2.4 kg/m2, waist circumference = 113 § 4 cm) with obesity but no history of diabetes were enrolled and underwent 2 wk of baseline monitoring before they were instructed to eat their regular diets within a contiguous 10-h time frame each day for 8 wk. Metabolic testing was performed at baseline and week 8 during a 35-h metabolic ward stay, during which all food intake was strictly timed and controlled. Identical meal-tolerance tests were performed at breakfast and dinner. Blood glucose, glucoregulatory hormones, and subjective appetite score were measured. Subcutaneous adipose tissue biopsies were performed and the transcriptome was assessed. Results: The primary outcome, plasma glucose area under the curve, was altered by TRE, being unchanged at breakfast but increased at dinner. However, TRE reduced fasting glucose, glycated hemoglobin, body weight, and body fat, and increased glucose-dependent insulinotropic peptide area under the curve at dinner. In subcutaneous adipose tissue, 117 genes were up-regulated and 202 genes down-regulated by TRE. Pathway analysis revealed down-regulation of genes involved in proteasome function and mitochondrial regulation. Conclusions: TRE had a net effect of reducing glycemia and dampening energy-consuming pathways in adipose tissue. Refereed/Peer-reviewed

The aim of the present study was to identify the function of long non‑coding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) and examine its effects on non‑small cell lung cancer (NSCLC). A series of in vitro experiments were employed to evaluate the effects of SNHG3 on the progression of NSCLC, including Cell Counting Kit‑8, 5‑Ethynyl‑2'‑deoxyuridine, flow cytometry, wound healing, Transwell, western blotting and reverse transcription‑quantitative PCR assays. Bioinformatics analyses and a luciferase reporter assay were performed to identify the target gene of SNHG3 and microRNA (miR)‑1343‑3p. Finally, recuse experiments were conducted to verify the effect of SNHG3 and its target gene on proliferation, apoptosis, migration and invasion. The findings indicated that lncRNA SNHG3 was highly expressed in NSCLC tissues and cell lines. Knockdown of lncRNA SNHG3 inhibited cell proliferation, migration and invasion, and accelerated cell apoptosis in NSCLC cell lines. The results of the bioinformatics analysis and the luciferase reporter assay indicated that lncRNA SNHG3 directly bound to miR‑1343‑3p and that it could downregulate the expression levels of miR‑1343‑3p to promote the progression of NSCLC. Rescue experiments indicated that lncRNA SNHG3 increased nuclear factor IX (NFIX) expression by sequestering miR‑1343‑3p in NSCLC. These results suggested that the SNHG3/miR‑1343‑3p/NFIX axis may serve as a novel prognostic biomarker and therapeutic target for NSCLC.

To determine the prevalence of diabetic nephropathy (DN) and non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (T2DM), and the important clinical predictors of renal outcome and clinical course. We conducted a retrospective analysis of clinical, laboratory, and histopathologic data from T2DM patients with renal involvement confirmed by renal biopsy (n = 505). The outcome was defined as the progression to end-stage renal disease (ESRD). Renal biopsy revealed that 302 patients (59.8%) had DN, 174 (34.5%) had NDRD, and 29 (5.7%) had NDRD superimposed on DN. In multivariate analysis, the absence of diabetic retinopathy (DR) (odds ratio (OR) 4.171, 95% confidence interval (CI) 1.810–9.612; P = 0.001), absence of hypertension (OR 2.412, 95% CI 1.095–5.315; P = 0.029), shorter duration of diabetes (OR 1.015, 95% CI 1.008–1.022; P

Nasopharyngeal carcinoma (NPC) is prevalent in certain areas, such as South China, Southeast Asia, and the Middle East. Radiation therapy is the most efficient means to treat this malignant tumor. Positron emission tomography-computed tomography (PET-CT) is a suitable imaging technique to assess this disease. However, the large amount of data produced by numerous patients causes traditional manual delineation of tumor contour, a basic step for radiotherapy, to become time-consuming and labor-intensive. Thus, the demand for automatic and credible segmentation methods to alleviate the workload of radiologists is increasing. This paper presents a method that uses fully convolutional networks with auxiliary paths to achieve automatic segmentation of NPC on PET-CT images. This work is the first to segment NPC using dual-modality PET-CT images. This technique is identical to what is used in clinical practice and offers considerable convenience for subsequent radiotherapy. The deep supervision introduced by auxiliary paths can explicitly guide the training of lower layers, thus enabling these layers to learn more representative features and improve the discriminative capability of the model. Results of threefold cross-validation with a mean dice score of 87.47% demonstrate the efficiency and robustness of the proposed method. The method remarkably outperforms state-of-the-art methods in NPC segmentation. We also validated by experiments that the registration process among different subjects and the auxiliary paths strategy are considerably useful techniques for learning discriminative features and improving segmentation performance.

Although several studies indicate that RNA-binding proteins (RBPs) contribute to key steps in a variety of physiological processes and cancer, the detailed biological functions and mechanisms remain to be determined. By performing bioinformatics analysis using well-established hepatocellular carcinoma (HCC) datasets, we identified a set of HCC progression-associated RBPs (HPARBPs) and found that the global expression of HPARBPs was significantly correlated with patient prognosis. Among the 42 HPARBPs, human ribosomal protein S3 (RPS3) was one of the most abundant genes whose role remains uncharacterized in HCC. Gain- and loss-of-function analyses demonstrated that RPS3 promoted HCC tumorigenesis both in vitro and in vivo. Mechanistically, we revealed that silent information regulator 1 (SIRT1) was a critical target of RPS3 and was essential for sustaining the RPS3-induced malignant phenotypes of HCC cells. RPS3 stabilized SIRT1 mRNA by binding to AUUUA motifs in the 3448–3530 region of the 3′ untranslated region (UTR) of SIRT1 mRNA. In addition, we found that (5-formylfuran-2-yl) methyl 4-hydroxy-2-methylenebutanoate (FMHM) inhibited HCC progression by repressing the RPS3/SIRT1 pathway. Our study unveils a novel extra-ribosomal role of RPS3 in facilitating hepatocarcinogenesis via the post-transcriptional regulation of SIRT1 expression and proposes that the RPS3/SIRT1 pathway serves as a potential therapeutic target in HCC.

Glucose metabolism is under circadian regulation, with insulin secretion and sensitivity being highest in the morning as compared to the evening. The present review will discuss the existing evidence for the role of meal and macronutrient timing to improve glucose metabolism and reset circadian clocks, with a focus on the evidence in humans.Shortening the daily eating window (also known as time-restricted eating), or skewing food intake towards breakfast and away from the evening meal both improve glucose control in people with impaired glucose metabolism. Insulin is recently purported to be a zeitgeber and thus an important reset signal for peripheral circadian clocks in vitro and in mice. Although few studies have tested the impact of macronutrient timing in humans, eating a greater proportion of carbohydrates earlier, rather than later, in the day is associated with better glucose control.The impact of carbohydrate intake timing on endogenous central and peripheral clocks, and its potential to optimize circadian regulation and improve glycaemic control, are not well understood but are currently under intense exploration.

Various antibody-redirected immunotherapeutic approaches, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor-T (CAR-T) cells, have been devised to produce specific activity against various cancer types. Using genetically encoded unnatural amino acids, we generated a homogeneous Her2-targeted ADC, a T cell-redirected bsAb, and a FITC-modified antibody capable of redirecting anti-FITC CAR-T (switchable CAR-T; sCAR-T) cells to target different Her2-expressing breast cancers. sCAR-T cells showed activity against Her2-expressing tumor cells comparable to that of conventional anti-Her2 CAR-T cells and superior to that of ADC- and bsAb-based approaches. To prevent antigen escape, we designed bispecific sCAR-T cells targeting both the Her2 receptor and IGF1R, which showed an overall improved activity against cancer cells with low Her2 expression. This study increases our understanding of various explored cancer therapeutics and underscores the efficient application of sCAR-T cells as a promising therapeutic option for breast cancer patients with low or heterogeneous antigen expression.

Few histological prognostic indicators for end-stage renal disease (ESRD) have been validated in diabetic patients. This biopsy-based study aimed to identify nephropathological risk factors for ESRD in Chinese patients with type 2 diabetes. Histological features of 322 Chinese type 2 diabetic patients with biopsy-confirmed diabetic nephropathy (DN) were retrospectively analysed. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) for ESRD. Single glomerular proteomics and immunohistochemistry were used to identify differentially expressed proteins and enriched pathways in glomeruli. During the median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society classification failed to predict ESRD, although the solidified glomerulosclerosis (score 1: HR 1.65, 95% confidence interval [CI] 1.04–2.60; score 2: HR 2.48, 95% CI 1.40–4.37) and extracapillary hypercellularity (HR 2.68, 95% CI 1.55–4.62) were identified as independent risk factors. Additionally, single glomerular proteomics, combined with immunohistochemistry, revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis. Therefore, solidified glomerulosclerosis and extracapillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathological change that may be associated with complement overactivation and abnormal lipid metabolism.

Background To address the prognostic value of combining tubular basement membrane (TBM) and glomerular basement membrane (GBM) thickness in diabetic nephropathy (DN). Methods This retrospective study enrolled 110 patients with type 2 diabetes and biopsy‐proven DN from 2011 to 2018. The pathological findings were confirmed according to the Renal Pathology Society classifications. GBM and TBM thicknesses were determined using the Haas' direct measurement/arithmetic mean method and orthogonal intercept method, respectively. Cox proportional hazard models were used to investigate the hazard ratios (HRs) for the influence of combined GBM and TBM thickness for predicting end‐stage renal disease (ESRD). Results Patients were assigned to three groups according to the median GBM and TBM thickness: GBMloTBMlo (GBM, Highlights The prognostic value of combining tubular basement membrane (TBM) and glomerular basement membrane (GBM) in diabetic nephropathy (DN) was lacking.TBM thickness was strongly correlated with GBM thickness, baseline estimated glomerular filtration rate, and proteinuria.The degree of TBM thickness provided additional value to GBM thickness for predicting end‐stage renal disease progression in patients with type 2 diabetes and biopsy‐proven DN.

Zhao, Lijun, Xi Wang, Tingli Wang, Wenxin Fan, Honghong Ren, Rui Zhang, Yutong Zou, Huan Xu, Jie Zhang, Yunhong Wu, and Fang Liu. Associations between high-altitude residence and end-stage kidney disease in Chinese patients with type 2 diabetes.

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

This retrospective study included 299 patients with type 2 diabetes mellitus and biopsy-confirmed diabetic nephropathy (DN) to investigate the prognostic value of alkaline phosphatase (ALP) for renal outcome. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for the serum ALP level on renal outcome, which was defined as end-stage renal disease (ESRD) or a 50% decline in estimated glomerular filtration rate (eGFR) from baseline. The median baseline ALP was 80 IU/L with an interquartile range of 64–97 IU/L. Serum ALP was negatively associated with eGFR but positively associated with proteinuria and renal interstitial fibrosis. During a median follow-up period of 23 months, ESRD or a 50% declined in the eGFR occurred in 156 (52.2%) patients. The highest quartile of ALP was significantly associated with poor renal outcome, as defined above (HR 2.38, 95% confidence interval [CI] 1.09–5.17), when adjusted for sociodemographics, baseline eGFR, proteinuria, liver function parameters, parathyroid hormone levels, and renal pathological findings. Each standard deviation higher in the natural log-transformed ALP was associated with a 25% increased risk for poor renal outcome. Additionally, there was a graded increase in the risk for poor renal outcome with higher ALP in patients with nephrotic-range proteinuria. However, no significant associations were observed between serum ALP levels and renal outcome in patients with non-nephrotic-range proteinuria. In conclusion, an elevated ALP level was independently associated with poor renal outcome in patients with type 2 diabetes mellitus and nephrotic-range proteinuria after multivariate adjustment.

The roles of genital mycoplasmas including Mycoplasma genitalium (M. genitalium), Mycoplasma hominis (M. hominis), Ureaplasma urealyticum (U. urealyticum), and Ureaplasma parvum (U. parvum) in reproductive diseases are equivocal. To investigate whether genital mycoplasmas are risk factors of female infertility and adverse pregnancy outcomes, we performed a systematic review and meta-analysis. Electronic databases were searched for related studies. A random-effects model or fixed-effects model was employed to generate forest plots. Pooled odd ratios (ORs) with 95% confidence intervals (CIs) were applied to measure the strength of associations. Meanwhile, heterogeneity was evaluated by H statistic and I

The older population has increased sharply in China. However, renal clinical and histopathological data in this population are lacking. This study investigated the clinicopathologic features and the related risk factors for long-term renal survival in older patients with diabetic nephropathy (DN). In this retrospective observational study, 74 older patients (≥ 60 years old) with type 2 diabetes mellitus and biopsy-proven DN from 2007 to 2019 were included. Clinical data were extracted from electronic records. Renal biopsy specimens were semiquantitatively evaluated using the Renal Pathology Society (RPS) classification system. Cox proportional hazard analysis was used to estimate hazard ratios (HRs) for progression to end-stage renal disease (ESRD). During the median follow-up period of 22 months, 24 (32%) older patients progressed to ESRD. Older patients who progressed to ESRD had poorer renal function, lower hemoglobin and albumin concentrations, more severe glomerular lesions, and higher percentages of Kimmelstiel–Wilson lesions than those who did not progress to ESRD. After adjusting for age, sex, baseline renal function, and pathological parameters, multivariate Cox proportional hazard analysis showed that RPS glomerular classification (HR 2.49, 95% confidence interval [CI] 1.03–6.04), estimated glomerular filtration rate (eGFR) (HR 0.76, 95% CI 0.58–0.99), and proteinuria (HR 3.85, 95% CI 1.44–10.27) were independent risk factors for progression to ESRD. Lower eGFR, heavier proteinuria, and more severe RPS glomerular lesions were associated with ESRD in older patients with type 2 diabetes mellitus and DN.

The exposure/biotransformation of inorganic arsenic (iAs) may perturb DNA methylation patterns and subsequently influence disease risk by altering the expression of key genes. Interindividual variation in patterns of DNA methylation can be explained by the influence of environmental, genetic, and stochastic factors. Here, we examined promoter DNA methylation levels with urinary arsenical concentrations and investigated the genetic and nongenetic determinants of DNA methylation in 105 samples collected from populations in Shanxi Province, China, with high levels of arsenic in drinking water. Arsenic concentrations in water were determined by atomic absorption spectrophotometry (AA-6800, Shimadzu Co., Kyoto, Japan). Urine samples were measured using an atomic absorption spectrophotometer with an arsenic speciation pretreatment system (ASA-2sp, Shimadzu Co. Kyoto, Japan) for detection. Gene-specific (CDH1, EREG, ERCC2, GSTP1, and MGMT) DNA methylation was quantified by targeted bisulfite sequencing. Single-nucleotide polymorphism (SNP) genotyping was performed using a custom-by-design 2 × 48-Plex SNPscan™ Kit. These results revealed CDH1 with promoter DNA methylation levels associated with iAs. After the exclusion of confounding factors, age was correlated with increased methylation of the CDH1 gene. The susceptibility of the CDH1 and GSTP1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs2424932) GA genotype, and the susceptibility of the CDH1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs6087990) TC genotype. Although the above results must still be replicated in larger samples, the findings improve our understanding of the pathogenesis of arsenic and may highlight certain DNA methylation markers as attractive surrogate markers for prevention research.

Ethnopharmacological relevance Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear. Aim of the study: To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms. Materials and methods We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague–Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS. Results Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis. Conclusion Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.

Objective To clarify the urinary arsenic metabolism characteristics in individuals with essential hypertension and to analyze the relationship between lipid metabolism gene polymorphisms and susceptibility to essential hypertension in individuals in high-arsenic areas in western China. Methods A case-control study was conducted and involved individuals exposed to high arsenic levels (in this study, the arsenic content in the pressurized well water was 0–510.2 μg/L, and that in the mechanical well water was 167 μg/L) in two adjacent high-arsenic areas in Shanxi Province and the Inner Mongolia Autonomous Region, China. A total of 699 samples were collected, including 192 case samples (patients with hypertension) and 507 control samples (no hypertension). Blood pressure measurement data obtained from an epidemiological survey were used to determine whether the subjects had hypertension, and a logistic regression model was used to analyze the association between lipid metabolism gene polymorphisms and hypertension susceptibility. Blood and urine samples were collected based on epidemiological methods, single nucleotide polymorphisms (SNPs) were genotyped using a SNPscan™ multiple SNP typing kit, and urinary arsenic concentrations were determined using the hydride generation atomic fluorescence method (HG-AFS). Results ADIPOQ/rs266729 was the dominant genetic model [(GC + GG) vs CC = 0.686:1, 95 % CI = 0.478−0.983], and FABP2/rs1799883 was the recessive genetic model [TT vs (CC + TC) = 1.690:1, 95 % CI = 1.014–2.816]. The distribution of the urinary arsenic secondary methylation ratio (SMR) [dimethylated arsenic (DMA)/monomethylated arsenic (MMA)] was different between hypertensive patients and controls. Conclusion ADIPOQ/rs266729 and FABP2/rs1799883 polymorphisms affect susceptibility to essential hypertension in individuals exposed to high levels of arsenic; there was a clear difference in the urinary arsenic metabolism pattern between hypertensive patients and controls.

A series of novel 4-anilinoquinazoline derivatives with ( E )-propen-1-yl moiety were designed, synthesized and evaluated for biological activities in vitro . Most compounds exhibited highly antiproliferative activities against all tested tumor cell lines including A431, A549, NCI-H1975 and SW480 cells. Especially, compound 6e not only presented strong antiproliferative activities against the tested four tumor cell lines (IC 50 of 1.35, 8.83, 5.53 and 6.08 μM, respectively) which expressed wild type or L858R/T790M double mutant epidermal growth factor receptor (EGFR), but also showed potent inhibitory activity against wild type EGFR (IC 50 = 20.72 nM). The result of molecular docking with EGFR suggested the binding mode of 6e was similar to gefitinib, but different from lapatinib. Additionally, western blot analysis showed that 6e inhibited the phosphorylation of EGFR and its downstream signaling proteins in lung cancer cells. The work could be very useful starting point for developing a new series of tyrosine kinase inhibitors targeting EGFR.

Background Splenic artery embolization (SAE) has been an effective adjunct to the Non-operative management (NOM) for blunt splenic injury (BSI). However, the optimal embolization techniques are still inconclusive. To further understand the roles of different embolization locations and embolic materials in SAE, we conducted this system review and meta-analyses. Methods Clinical studies related to SAE for adult patients were researched in electronic databases, included PubMed, Embase, ScienceDirect and Google Scholar Search (between October 1991 and March 2013), and relevant information was extracted. To eliminate the heterogeneity, a sensitivity analysis was conducted on two reduced study sets. Then, the pooled outcomes were compared and the quality assessments were performed using Newcastle-Ottawa Scale (NOS). The SAE success rate, incidences of life-threatening complications of different embolization techniques were compared by χ 2 test in 1st study set. Associations between different embolization techniques and clinical outcomes were evaluated by fixed-effects model in 2nd study set. Results Twenty-three studies were included in 1st study set. And then, 13 of them were excluded, because lack of the necessary details of SAE. The remaining 10 studies comprised 2nd study set, and quality assessments were performed using NOS. In 1st set, the primary success rate is 90.1% and the incidence of life-threatening complications is 20.4%, though the cases which required surgical intervention are very few (6.4%). For different embolization locations, there was no obvious association between primary success rate and embolization location in both 1st and 2nd study sets (P > 0.05). But in 2nd study set, it indicated that proximal embolization reduced severe complications and complications needed surgical management. As for the embolic materials, the success rate between coil and gelfoam is not significant. However, coil is associated with a lower risk of life-threatening complications, as well as less complications requiring surgical management. Conclusions Different embolization techniques affect the clinical outcomes of SAE. The proximal embolization is the best option due to the less life-threatening complications. For commonly embolic material, coil is superior to gelfoam for fewer severe complications and less further surgery management.

A series of novel 4-arylamino-6-(5-substituted furan-2-yl)quinazoline derivatives were designed, synthesized and evaluated on biological activities in vitro. Compound 2a, 3a and 3c exhibited highly anti-proliferation activities on all tested tumor cell lines including SW480, A549, A431 and NCI-H1975 cells. Especially, compound 2a not only exhibited strong anti-proliferation activities against the tumor cell lines which expressed wild type or mutant EGFRL858R/T790M, but also showed the most potent inhibitory activity toward wild type EGFR (IC50=5.06nM). The result of docking with EGFR suggested the binding mode of 2a was similar to that of lapatinib. While Western-blot analyses showed 2a obviously inhibited the activation of EGFR, Akt and Erk1/2 in lung cancer cells at indicated concentration. It is believed that this work would be very useful for developing a new series of TKIs targeting EGFR.

Objective This study aimed to examine the effects of intermittent fasting (IF) on mRNA levels of peripheral clock genes in skeletal muscle and subcutaneous adipose tissue (SAT) in women with obesity. Methods Women were randomized to one of two IF protocols and provided with all foods at 100% or 70% of calculated weekly energy requirements for 8 weeks. Breakfast was consumed before a 24-hour fast, which was initiated on three nonconsecutive days per week. Muscle and SAT biopsies were performed at 8 am after an overnight fast at baseline and at week 8 on a refed day and again following a 24-hour fast at week 8 for analysis of the mRNA levels of key genes involved in circadian regulation. Results A group-by-time interaction was observed in Per2 in muscle (F = 3.497, P = 0.044) and SAT (F = 6.686, P = 0.008), but significance was lost upon post hoc adjustment. A time effect was observed in Rorα in muscle, which was decreased by refeeding in both groups (F = 7.225, P = 0.003). Conclusions There was no universal effect of IF to alter peripheral clocks, which may be partly because of the alignment of the fasting/feeding cycle with the biological clock. Optimizing intermittent fasting protocols could be important to prevent circadian misalignment in humans.

In this report, we provided an overview of the prevalence, control, and prevention of water-borne arsenicosis in China during 2001-2016. Random sampling was continuously performed during 2001-2010 to find villages having high levels of arsenic (50 µg/L) in drinking water. The high-arsenic-exposure villages with more geographically dispersed water supplies were subsequently analyzed for characteristics of arsenic distribution, and villages with relatively large populations were investigated for arsenicosis. The results showed that among 32,673,677 inhabitants in 36,820 villages, 1,894,587 inhabitants in 2,476 villages were at risk of high arsenic exposure. Among the 33,318 drinking water sources surveyed in 625 high-arsenic-exposure villages, 9,807 drinking water sources that contained high levels of arsenic (50 µg/L) were identified. The overall prevalence rate of arsenicosis was 1.93%. Further, some representative villages were chosen to monitor arsenicosis annually, showing that the prevalence rate of arsenicosis was lower in villages with arsenic-safe water supplies than in villages without arsenic-safe water supplies. To the best of our knowledge, this report provides the most comprehensive assessment of the distribution of high arsenic exposure and arsenicosis in China until now.

Objective: Hepatocellular carcinoma (HCC) is a severely lethal cancer that usually originates from chronic liver injury and inflammation. Although progress on diagnosis and treatment is obvious, the cause of HCC remains unclear. In this study, we sought to determine key genes in HCC development. Methods: To identify key regulators during HCC progression, we performed transcriptome sequencing to obtain time series gene expression data from a mouse model with diethylnitrosamine-induced liver tumors and further verified gene expression and function in vitro and in vivo. Results: Among the differentially expressed genes, Cyp2c29 was continuously downregulated during HCC progression. Overexpression of Cyp2c29 suppressed NF-κB activation and proinflammatory cytokine production by increasing the production of 14,15-epoxyeicosatrienoic acid in vitro. Furthermore, overexpression of Cyp2c29 in vivo protected against liver inflammation in mouse models of liver injury induced by both acetaminophen and CCl4. Two human homologs of mouse Cyp2c29, CYP2C8 and CYP2C9, were found to be downregulated in human HCC progression, and their expression was positively correlated with overall survival in patients with HCC (significance: P = 0.046 and 0.0097, respectively). Conclusions: Collectively, through systematic analysis and verification, we determined that Cyp2c29 is a novel gene involved in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis determination.

Purpose To assess the survival, local and distant control, and toxicity in patients with unresectable locally advanced non-small cell lung cancer treated with radical-intent hypofractionated radiation therapy delivering approximately 60 Gy in 4-Gy fractions. Methods and Materials Consecutive patients with unresectable stage III non-small cell lung cancer (n = 42) who received hypofractionated intensity modulated radiation therapy were retrospectively analyzed (2012-2016). Treatments consisted of first-line platinum-based doublet induction chemotherapy followed by an intended dose of 60 Gy in 15 fractions. Results During a median follow-up period of 46 months (95% confidence interval, 41-59) the median overall survival was 47 months (95% confidence interval, 31 to not reached). The 1-, 2-, 3-, and 5-year overall survival rates were 81%, 69%, 64%, and 32%, respectively. The 1-, 2-, 3-, and 5-year progression-free survival rates were 58%, 35%, 25%, and 25%, respectively. An isolated locoregional recurrence was seen in 12% of the patients (n = 5). The incidence of grade (G) 3 or higher treatment-related lung toxicity was 14% (n = 6), among which G3 toxicity was 9.5% (n = 4) and G5 toxicity was 4.8% (n = 2). Twelve percent of patients (n = 5) experienced G3 radiation esophagitis, and 2% (n = 1) had G4 esophageal toxicity. Conclusions Patients with unresectable locally advanced non-small cell lung cancer treated with hypofractionated intensity modulated radiation therapy in doses up to 60 Gy at 4 Gy per fraction had promising survival, although high-grade esophageal and lung toxicities were seen. Our findings deserve further evaluation in prospective studies.