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Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1β release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, in vivo and in vitro. Notably, Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.

Objective This study was aimed to compare different stenting techniques for coronary bifurcation disease (CBD). Background Percutaneous coronary intervention (PCI) remains controversial for CBD; over the years, several stent techniques for bifurcation lesions have been used. Current guidelines recommend a provisional single-stent strategy as the preferred method for coronary artery bifurcation lesions. However, several randomized controlled trials (RCT) indicated that two-stent techniques showed better clinical outcomes. Methods We systematically searched Embase, PubMed, and Web of Science to include RCTs. The primary endpoint was the major adverse cardiovascular event (MACE). Secondary outcomes were cardiac death, myocardial infarction (MI), target-lesion or target-vessel revascularization (TLR or TVR), and definite or probable stent thrombosis (ST). Finally, we used 26 RCTs and a total of 7257 individuals were randomly assigned to one of the 6 stent techniques and included in this network meta-analysis. Results In our network meta-analysis, double-kissing (DK) crush was significantly more superior to other 5 stent techniques in MACEs: OR vs. provisional 0.40 (95% CI 0.28–0.55); vs. culotte 0.40 (95% CI 0.26–0.60). DK crush ranked the most effective treatment for MACE (100%), MI (75%), ST (83%), and TLR (100%) in the rank probabilities analysis. In patients with complex bifurcation lesion defined by DEFINITION criteria, DK crush was notably more efficacious than provisional, culotte, and T-stenting/T-stenting and protrusion (TAP) in MACEs (OR vs. provisional 0.26, 95% CI 0.13–0.52) and TLR (OR vs. provisional 0.24, 95% CI 0.10–0.58). Conclusion Compared with other stenting techniques, DK crush had a lower incidence of MACEs in CBD. DK crush was significantly associated with a lower rate of MACEs in patients with complex bifurcation lesions defined by the DEFINITION criterion. Graphical abstract

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p., Graphical abstract, Transcription factor SRF and NF-κB p65 regulate the co-expression of miR-199a-5p and -3p by positive feedback in the pathological cardiac remodeling. Ppargc1a and Sirt1, Rb1 and Smad1 mediate the pathological role of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively.

The derivation of mature functional cholangiocytes from human pluripotent stem cells (hPSCs) provides a model for studying the pathogenesis of cholangiopathies and for developing therapies to treat them. Current differentiation protocols are not efficient and give rise to cholangiocytes that are not fully mature, limiting their therapeutic applications. Here, we generate functional hPSC-derived cholangiocytes that display many characteristics of mature bile duct cells including high levels of cystic fibrosis transmembrane conductance regulator (CFTR) and the presence of primary cilia capable of sensing flow. With this level of maturation, these cholangiocytes are amenable for testing the efficacy of cystic fibrosis drugs and for studying the role of cilia in cholangiocyte development and function. Transplantation studies show that the mature cholangiocytes generate ductal structures in the liver of immunocompromised mice indicating that it may be possible to develop cell-based therapies to restore bile duct function in patients with biliary disease., Current protocols to generate cholangiocytes from human pluripotent cells produce immature cells. Here the authors identify retinoic acid, BMP, cAMP and Rho kinase pathways as regulators of cholangiocyte maturation, and generate ciliated cholangiocytes expressing high levels of CFTR that form ductal structures in vivo.

Summary For those people with cystic fibrosis carrying rare CFTR mutations not responding to currently available therapies, there is an unmet need for relevant tissue models for therapy development. Here, we describe a new testing platform that employs patient-specific induced pluripotent stem cells (iPSCs) differentiated to lung progenitor cells that can be studied using a dynamic, high-throughput fluorescence-based assay of CFTR channel activity. Our proof-of-concept studies support the potential use of this platform, together with a Canadian bioresource that contains iPSC lines and matched nasal cultures from people with rare mutations, to advance patient-oriented therapy development. Interventions identified in the high-throughput, stem cell-based model and validated in primary nasal cultures from the same person have the potential to be advanced as therapies., Highlights • A Canadian resource (CFIT) has CF donor-matched iPSCs and nasal epithelial cells • Lung progenitor cells (LPCs) differentiated from iPSCs express CFTR • LPCs from people with rare CFTR mutations enable high-throughput therapy testing • Matching nasal cultures can validate patient-specific drug responses in LPCs, Bear and colleagues show that lung progenitor cells (LPCs) differentiated from cystic fibrosis (CF) iPSCs recapitulate the primary defects conferred by different types of CF mutations. LPCs enable high-throughput testing of interventions, and pilot studies show that responses in LPCs can be validated in patient-matched primary nasal epithelial cultures, confirming the potential utility of LPCs in precision CF therapy development.

Aim This study investigated the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on renal outcomes in Asian patients with type 2 diabetes mellitus (T2DM). Materials and methods We searched Medline, EMBASE, and the Cochrane Library to identify randomized controlled trials published up to April 2020 that compared SGLT2 inhibitors with placebo or active comparator and reported any renal outcomes in Asian patients with T2DM. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals (CIs). Results We included 14 studies, totaling 3792 patients, in the analysis. In the short term, SGLT2 inhibitors significantly slowed estimated glomerular filtration rate (eGFR) decline (MD: 0.80; 95% CI: 0.66 to 0.94; p p p p = 0.11). However, dapagliflozin does appear to reduce albuminuria (p = 0.005). Lastly, SGLT2 inhibitors increased the incidence of adverse events (AEs) related to renal function (OR: 1.90; 95% CI: 1.24 to 2.91; p = 0.003), but did not increase the incidence of renal impairment (OR: 0.85; 95% CI: 0.40 to 1.81; p = 0.68). Conclusion The use of SGLT2 inhibitors in Asian patients with T2DM can help delay the decline of eGFR and reduce Scr and UA. Although SGLT2 inhibitors have no overall advantage in reducing albuminuria, dapagliflozin does appear to reduce albuminuria, and while they may increase the occurrence of AEs related to renal function, they do not increase the incidence of renal impairment.

Spinal cord injury (SCI) is one kind of severe trauma for central nervous system. Myelin debris clearance and axon regeneration are essential for nerve regeneration after SCI. Metformin, a glucose-lowering drug, has been demonstrated to promote the locomotor functional recovery after SCI. In this study, we investigated the role and molecular mechanism of metformin on myelin preservation in a rat SCI model. SCI was induced in rats by compression at T9 level using a vascular clip. We showed that administration of metformin (50 mg·kg(−1)·d(−1), ip) for 28 days significantly improved locomotor function in SCI rats. Metformin also ameliorated SCI-induced neuronal apoptosis and promoted axon regeneration in the spinal cord. Using co-immunofluorescence of IBa-1 and MBP, and luxol fasting blue (LFB) staining, we demonstrated that metformin promoted the transformation of M1 to M2 phenotype polarization of microglial cells, then greatly facilitated myelin debris clearance and protected the myelin in SCI rats. Furthermore, metformin ameliorated SCI-induced blockade of autophagic flux in the spinal cord, and enhanced the fusion of autophagosome and lysosome by inhibiting the AMPK-mTOR signaling pathway. Moreover, metformin significantly attenuated inflammatory responses in the spinal cord. In LPS-treated BV2 cells, pretreatment with metformin (2 mM) significantly enhanced autophagy level, suppressed inflammation and cell apoptosis. The protective effects were blocked in the presence of an autophagy inhibitor 3-methyladenine (3-MA, 5 mM), suggesting that the effect of metformin on autophagy in microglial cells is essential for the myelin preservation during nerve recovery. This study reveals a novel therapeutic effect of metformin in SCI recovery by regulating the activation of microglial cells and enhancing its autophagy level.

BACKGROUND Compression therapy is a common method for treating breast cancer-related lymphedema. However, no specific evidence exists to guide practitioners on the morbidity of lymphedema, limb volume, and range of motion. OBJECTIVE The aims of this study were to compare the effects of compression therapy and routine nursing during the treatment of breast cancer-related lymphedema and to provide a basis for better clinical decision-making. METHODS The PubMed, Cochrane Library, EMBASE, Web of Science, CBM, CNKI, Wanfang, and VIP databases were searched through January 21, 2021. Meta-analysis and description of the outcomes were performed by using the RevMan 5.3 software. RESULTS A total of 17 studies were included. A meta-analysis of 13 studies was conducted. The experimental group had a lower morbidity of lymphedema, the difference was significant, and there was no heterogeneity (P < .05; odds ratio, 0.35, I2 = 31%). There was no significant difference between the experimental group and control group in limb volume, and there was significant heterogeneity (P = .44, mean difference = 4.51, I2 = 85%). Regarding range of motion, the standardized mean difference of shoulder adduction, shoulder lift, shoulder abduction, and shoulder extension were 1.37, 0.69, 0.56, and 0.87, respectively, and the differences were significant; there was heterogeneity (P < .05, I2 = 92%). CONCLUSIONS Compression therapy can reduce the morbidity of lymphedema and improve limb movement, but the effect on limb volume needs to be further explored. IMPLICATION FOR PRACTICE In terms of therapeutic effectiveness and limb function, the results provide evidence that physicians can reduce the morbidity of lymphedema, reduce the degree of limb, and increase limb mobility by applying compression therapy.

Backgrounds. The prevalence of diabetes has increased with the increase of obesity, and finding indicators to predict diabetes risk has become an urgent need. The purpose of this study is to compare the correlation between four anthropometric indices and the prevalence of diabetes. Methods. A total of 4052 participants aged 40 years and above were selected in Dehui City, Jilin Province, using a multistage stratified whole group sampling method. Face-to-face interviews and physical examinations were conducted. Multivariate logistic analysis was used. The values of BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were divided into quartiles (Q1: study participants ≥ 40 years of age, especially in females.

Drug‐mediated or medical condition‐mediated disruption of hERG function accounts for the main cause of acquired long‐QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG‐HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG) was measured by patch‐clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell‐based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after‐depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long‐term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

BACKGROUND: Airway stenting is frequently used in the palliative treatment of patients with advanced tumor-induced airway stenosis and fistulas. However, there is paucity of studies regarding the use of airway stents in restoring patency. The aim of the study was to assess the efficacy and safety of hybrid silicon Y stents and covered self-expanding metal stents (SEMS) and in reestablishing patency in airway stenoses and fistulas. METHODS: This retrospective study included 31 patients between January 2016 to December 2019 with inoperable complex malignant airway stenoses and fistulas, managed with Silicone Y stents, and covered SEMS. The clinical details, clinical outcomes and complications up to 6 months were extracted from medical records. The improvement of performance was assessed based on modified British Medical Research Council (mMRC) dyspnea scores (t=6.892, P

AIM: To investigate the change of ocular surface and corneal nerve and their correlation in patients suffering from type 2 diabetes mellitus under different degrees of retinopathy. METHODS: Totally 129 type 2 diabetes mellitus patients (257 eyes) were included. They were divided into three groups: no diabetic retinopathy (NDR) group (33 cases, 66 eyes), non-proliferative diabetic retinopathy (NPDR) group (32 cases, 64 eyes), and proliferative diabetic retinopathy (PDR) group (34 cases, 67 eyes). Healthy normal individuals were enrolled as controls (30 cases, 60 eyes). Ocular Surface Disease Index (OSDI) questionnaire was completed by all subjects, and dry eye analyzer was applied to examine tear meniscus height (TMH), first tear break-up time (FTBUT), average tear break-up time (ATBUT), tear film lipid layer thickness classification, and meibomian gland loss (MGL) score. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) were examined by in vivo confocal microscopy (IVCM). The differences and correlation among these parameters were analyzed. RESULTS: Total OSDI score, TMH, FTBUT, ATBUT, tear film lipid layer thickness, MGL score, CNFD, CNBD, CNFL, and CNFT were statistically different among the four groups (P

Background Small extracellular vesicles (sEVs) are nanosized vesicles involved in cell-to-cell communication. sEVs have been widely studied for clinical applications such as early detection of diseases and as therapeutics. Various methods for sEVs isolation are been using, but different methods may result in different qualities of sEVs and impact downstream analysis and applications. Here, we compared current isolation methods and performed a comparative analysis of sEVs from supernatant of cultured pancreatic cancer cells. Methods Ultracentrifugation, ultrafiltration and co-precipitation as concentration methods were firstly evaluated for yield, size, morphology and protein level of pellets. Then, isolate sEVs obtained by four different purification methods: size exclusion chromatography, density gradient ultracentrifugation, ultracentrifugation, and immunoaffinity capturing, were analysed and compared. Results For the concentration process, ultracentrifugation method obtained high quality and high concentration of pellets. For the purification process, immunoaffinity capturing method obtained the purest sEVs with less contaminants, while density gradient ultracentrifugation-based method obtained sEVs with the smallest size. Proteomic analysis revealed distinct protein contents of purified sEVs from different methods. Conclusions For isolating sEVs derived from supernatant of cultured pancreatic cancer cell line, ultracentrifugation-based method is recommended for concentration of sEVs, density gradient ultracentrifugation-based method may be applied for obtaining purified sEVs with controlled size, immunoaffinity capturing may be suitable for studies requiring sEVs with high purity but may loss subtypes of sEVs without specific protein marker.

Patients with liver disease are susceptible to infection with Vibrio vulnificus (V. vulnificus), but the specific reasons remain elusive. Through RNA-seq, we found that when mice with alcoholic liver disease (ALD) were infected with V. vulnificus by gavage, compared with the Pair group, the small intestinal genes affecting intestinal permeability were upregulated; and the number of differentially expressed genes related to immune functions (e.g., such as cell chemotaxis, leukocyte differentiation, and neutrophil degranulation) decreased in the liver, spleen, and blood. Further analysis showed that the number of white blood cells decreased in the Pair group, whereas those in the ALD mice did not change significantly. Interestingly, the blood bacterial load in the ALD mice was about 100 times higher than that of the Pair group. After the ALD mice were infected with V. vulnificus, the concentrations of T cell proliferation-promoting cytokines (IL-2, IL-23) decreased. Therefore, unlike the Pair group, ALD mice had weaker immune responses, lower T cell proliferation-promoting cytokines, and higher bacterial loads post-infection, possibly increasing their susceptibility to V. vulnificus infection. These new findings we presented here may help to advance the current understanding of the reasons why patients with liver disease are susceptible to V. vulnificus infection and provides potential targets for further investigation in the context of treatment options for V. vulnificus sepsis in liver disease patient.

Background: To investigate the correlation between hypertriglyceridemic waist circumference (HTWC) phenotype and gestational diabetes mellitus (GDM).Methods: A total of 1083 patients with gestational age ≤8 weeks were divided into four groups: normal triglyceride and waist circumference group (group A, n=575), simple abdominal obesity group (group B, n=317), simple high triglyceride group (group C, n=125), and HTWC group (group D, n=66). General information and serum biochemical indicators were measured and recorded. Analysis of variance (ANOVA) and logistic regression analysis were used to evaluate the relationship between HTWC with GDM.Results: The prevalence of GDM in the HTWC group was significantly greater than in the other three groups. After adjustment by multivariate logistic regression analysis, the proportion of GDM in the HTWC group was 1.753 times higher than in group A.Conclusion: These findings suggest that there is a significant correlation between HTWC phenotype and GDM, indicating that the HTWC phenotype could be applied as a simple marker for identifying GDM risk factors.

Esophageal squamous cell carcinoma (ESCC) causes aggressive and lethal malignancies with extremely poor prognoses, and accounts for about 90% of cases of esophageal cancer. Neuropilin and tolloid-like 2 (NETO2) protein coding genes have been associated with various human cancers. Nevertheless, little information is reported about the phenotypic expression and its clinical significance in ESCC progression. Here, our study found that NETO2 expression in ESCC patients was associated with tumor clinical stage and lymph node metastasis status. Gain-of-function and loss-of-function analyses showed that NETO2 stimulated ESCC cell proliferation while suppressing apoptosis in vitro and enhanced tumor growth in vivo. Moreover, knockdown of NETO2 significantly inhibited migration and invasion in combination with regulation of epithelial-mesenchymal transition (EMT) related markers. Mechanistically, overexpression of NETO2 increased the phosphorylation of ERK, PI3k/AKT, and Nuclear factor erythroid-2-related factor 2(Nrf2), whereas silencing NETO2 decreased the phosphorylation of these targets. Our data suggest that Nrf2 was a critical downstream event responsible for triggering the PI3K/AKT and ERK signaling pathways and plays a crucial role in NETO2-mediated tumorigenesis. Taken together, NETO2 acts as an oncogene and might serve as a novel therapeutic target or prognostic biomarker in ESCC patients.

BACKGROUND Acquired prosopagnosia is a rare condition characterized by the loss of familiarity with previously known faces and the inability to recognize new ones. It usually occurs after the onset of brain lesions such as in a stroke. The initial identification of prosopagnosia generally relies on a patient’s self-report, which can be challenging if it lacks an associated chief complaint. There were few cases of prosopagnosia presenting purely as eye symptoms in the previous literature confirmed by functional magnetic resonance imaging (MRI). CASE SUMMARY We present a case of delayed diagnosis of prosopagnosia after a right hemisphere stroke in an elderly man whose chief complaint was persistent and progressive "blurred vision" without facial recognition impairment. Ophthalmic tests revealed a homonymous left upper quadrantanopia, with normal visual acuity. He was found by accident to barely recognize familiar faces. The patient showed severe deficit in face recognition and perception tests, and mild memory loss in neuropsychological assessments. Further functional MRI revealed the visual recognition deficits were face-specific. After behavioral intervention, the patient started to rely on other cues to compensate for poor facial recognition. His prosopagnosia showed no obvious improvement eight months after the stroke, which had negative impact on his social network. CONCLUSION Our case demonstrates that the presentation of prosopagnosia can be atypical, and visual difficulties might be a clinical manifestation solely of prosopagnosia, which emphasizes the importance of routinely considering face recognition impairment among elderly patients with brain lesions.

Background Epidemiological studies have shown that genetic factors are among the causes of schizophrenia. Galanin receptor 1 is an inhibitory receptor of galanin that is widely distributed in the central nervous system. This study mainly explored the relationship between polymorphisms of the 5' region of the GALR1 gene and schizophrenia in the northern Chinese Han population. Methods A 1545 bp fragment of the 5' regulatory region of the GALR1 gene was amplified and sequenced in 289 schizophrenia patients and 347 healthy controls. Results Among the haplotypes composed of the 16 detected SNPs, the haplotype H3 was identified as conferring a risk of schizophrenia (p=0.011, OR=1.430, 95% CI=1.084-1.886). In addition, the haplotypes H4 and H7 were both protective against schizophrenia (p=0.024, OR=0.526, 95% CI=0.298-0.927; p=0.037, OR=0.197, 95% CI=0.044-0.885, respectively). In the subgroup analysis by sex, it was found that seven SNP alleles (rs72978691, rs11662010, rs11151014, rs11151015, rs13306374, rs5373, rs13306375) conferred a risk of schizophrenia in females (p

Glutathione peroxidases (GPxs) belong to a family of enzymes that is important in organisms; these enzymes promote hydrogen peroxide metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers’ attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer.

To evaluate the effect of peri-prostatic adipose tissue (PPAT) measurements using preoperative MRI on the prediction of prostate cancer (PCa) aggressiveness in men undergoing radical prostatectomy (RP). We performed a retrospective study on 179 consecutive patients receiving RP from June 2016 to October 2018. Clinical characteristics were collected. PPAT measurements including peri-prostatic fat area (PPFA) and peri-prostatic fat area to prostate area (PA) ratio (PPFA/PA) were calculated by MRI. Multivariable logistic regression analysis was performed to identify independent predictors of PCa lymph node metastasis (LNM). The predictive performance was estimated through ROC curves. Nomograms were created based on the predictors. Pathologic Gleason score positively correlated with digital rectal examination (DRE), PSA, PPFA/PA, P504S, and Ki-67 (all P

Migraine is a recurrent throbbing or pulsing headache with moderate to severe pain intensity. The pain is often one side of the head with nausea and weakness symptoms. Around 12 percent of Americans, 9 percent of Asians experiences migraine and the prevalence is highest among South Koreans (22.3%). The outcome of chronic migraine treatment can be quite disheartening, causing patients to feel out of options who have tried multiple treatments with no results. Poor efficacy, tolerability and safety of migraine preventive therapy in clinical practice lead to poor compliance and failure of therapy. The mean change in number or frequency of headache is considered as the outcome measure of migraine prevention therapy. Upon comparing all migraine prevention therapy, the Fremanezumab, Eptinezumab, Galcanezumab and Erenumab were considered as the front runner in controlling the severity and frequency of migraine. Among these drugs, Erenumab was most effective in controlling the frequency of migraine episodes as it produces more than 50 percent reduction in the mean number of monthly migraine days (MMD) over week 9-week 12. In addition to drug therapy, adequate rest, balanced diet, yoga and meditation will help patients to get rid of migraine severity. A multi-dimensional approach is essential for better control over migraine symptoms.

Heparin-induced thrombocytopenia and thrombosis is a severe immune-mediated adverse drug effect caused by the IgG antibodies to platelet factor4/heparin complexes. Activated platelets, vascular endothelium, and monocytes generate the life-threatening thrombocytopenia and thrombosis. In this review, we will update the reader on recent findings on the pathogenesis and clinical management of heparin-induced thrombocytopenia and thrombosis. Firstly, PF4/heparin complexes make IgM mediate complement activation by classical pathway. Secondly, Marginal zoneB cells play a crucial role in producing anti-PF4/heparin complex IgG antibody. Thirdly, two activation signals of platelets (protease-activated receptor 1/Fc gamma IIA receptor) were confirmed. Based on these findings, we present a potential laboratory test of HITT (receptor glycoprotein Ⅳ) and two possible treatments by using receptor inhibitors (vorapaxar/atopaxar) and IgG-degrading enzyme (streptococcus pyogenes/glutamyl endopeptidase V8/matrix metalloproteinases).

Background Abnormal RGS4 gene expression may cause neurotransmitter disorders, resulting in schizophrenia. The association between RGS4 and the risk of schizophrenia is controversial, and there has been little research on the SNPs in the promoter region of RGS4. Purpose The present study was performed to detect the association between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia. Materials and Methods In this study, the 1757-bp fragment (-1119-+600, TSS+1) of RGS4 was amplified and sequenced in 198 schizophrenia patients and 264 healthy controls of the northern Chinese Han population. Allele, genotype and haplotype frequencies were analyzed by chi-square test. Results Four SNPs were detected in the region. LD analysis determined that rs7515900 was linked to rs10917671 (D' = 1, r2 = 1). Therefore, the data for rs10917671 were eliminated from further analysis. Genotype TT of rs12041948 (P = 0.009, OR = 1.829, and 95% CI = 0.038-0.766) was significantly different between the two groups in the northern Chinese Han population. In males, genotype GG of rs6678136 (P = 0.009, OR = 2.292, and 95% CI = 1.256-4.18) and CC of rs7515900 (P = 0.003, OR = 2.523, and 95% CI = 1.332-4.778) were significantly different. Conclusion The results of this study suggested that genotype TT of rs12041948 in the pooled male and female samples and GG of rs6678136 and CC of rs7515900 in the male samples could be risk factors for schizophrenia. The present study is the first to detect an association between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia in the northern Chinese Han population. Functional studies are required to confirm these findings.

Background Erectile dysfunction (ED) is a well-known complication of diabetes, affecting up to 75% of diabetic men. Although the etiology of diabetic ED is multifactorial, endothelial dysfunction is considered to be a pillar of its pathophysiology. Endothelial dysfunction is caused by the harmful effects of high glucose levels and increased oxidative stress on the endothelial cells that comprise the vascular endothelium. The aim of this study was to identify the proteomic changes caused by high glucose-induced oxidative stress and explore the role of heme oxygenase 1 (HMOX1) in it. Methods The cellular proteomic response to hypoxanthine-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) was analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were analyzed through Network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Further validation assays was performed to validate the role of HMOX1. Results The results showed that 66 and 76 DEPs were markedly upregulated and downregulated, respectively, for HUVECs oxidative stress. Among these proteins, we verified eight dysregulated genes by quantitative reverse transcription PCR, including nucleolin (NCL), X-ray repair cross-complementing protein 6 (XRCC6), ubiquinol-cytochrome C reductase binding protein (UQCRB), non-POU domain containing octamer binding (NONO), heme oxygenase 1 (HMOX1), nucleobindin 1 (NUCB1), DEK, and chromatin target of prmt1 (CHTOP). Further, using overexpression and genetic knockdown approaches, we found that HMOX1 was critical for the oxidative stress response in HUVECs. Conclusions We found that HMOX1 was closely related to the oxidative stress response induced by hypoxanthine. To the best of our knowledge, this study is the first overview of the responses of HUVECs to oxidative stress. The findings will contribute to analyses of the detailed molecular mechanisms involved in the pathogenesis of endothelial dysfunction and related molecular mechanisms in ED patients.

Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1κ that targets sialyl-di-Lewisa–containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non–small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P = 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa–expressing solid tumors, as an antibody–drug conjugate or as an alternative cancer immunotherapy modality.

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-β, β-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

Polysaccharide from Grifola frondosa is an excellent metal-ion chelating agent owing to its distinctive structure and outstanding functional activities. Our previous research has successfully synthesized novel organic chromium derived from the chelation ofG. frondosapolysaccharide-chromium (III) [GFP-Cr(III)]. The purpose of present research was to reveal the hypoglycemic and hypolipidemic mechanism of GFP-Cr(III), and its relationship with the modulation of intestinal microflora. Successful fabrication of GFP-Cr(III) was verified by thermogravimetric analysis (TGA), powder X-ray diffraction (XRD) and 1H NMR spectrum.The hypoglycemic and hypolipidemic effects were examined using type 2 diabetic mice induced by a high-fat diet (HFD) and streptozocin (STZ). Results indicated that GFP-Cr(III) intervention improved abnormal serum biochemical indicators (triglyceride (TG), cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and glucose), inhibited lipid accumulation and steatosis in the liver. Metagenomic analysis revealed that GFP-Cr(III) treatment produced obvious changes on the intestinal microflora in T2DM mice. Thecorrelationnetwork analysis further revealed that the serum and hepatic lipid profiles were positively correlated with Streptococcus and Enterococcus, but negatively correlated with Enterorhabdus, Ruminococcaceae-UCG-011, Coriobacteriaceae and Micrococcaceae. Meanwhile, oral administration with GFP-Cr(III) regulated the mRNA expression related to glucose and lipid metabolism. These results of present study suggest that GFP-Cr(III) could be used as potential functional food ingredients for the amelioration of hyperglycemia and hyperlipidemia.

Lactobacillus plantarum FZU3013, a probiotic previously isolated from the traditional brewing process of Hongqu rice wine, may have the beneficial effect of improving the disorders of lipid metabolism. This study aimed to investigate the role of L. plantarum FZU3013 in improving non-alcoholic fatty liver (NAFL) associated with hyperlipidemia in mice fed a high-fat diet. The results indicated that L. plantarum FZU3013 intervention significantly reduced the HFD-induced body weight gain and the abnormal levels of serum total triglycerides (TG), total cholesterol (TC) and low-density lipoprotein (LDL-C), and inhibited the excessive accumulation of liver lipids. In addition, L. plantarum FZU3013 also promoted the excretion of bile acids through feces. Metagenomic and multivariate statistical analysis revealed that L. plantarum FZU3013 made significant structural changes in the intestinal microbiome of the mice fed with HFD, in particular by modulating the relative abundance of some function related microbial phylotypes. Furthermore, ultra-performance liquid chromatography with quadruple-time of flight mass spectrometry (UPLC-QTOF/MS)-based liver metabolomics demonstrated that L. plantarum FZU3013 had a significant regulatory effect on the composition of liver metabolites in hyperlipidemic mice, especially on the levels of some important biomarkers involved in the pathways of glycerophospholipid metabolism, fatty acid degradation, fatty acid elongation, glycerolipid metabolism, primary bile acid biosynthesis, arachidonic acid metabolism, etc. Moreover, L. plantarum FZU3013 regulated the mRNA expression levels of the genes responsible for liver lipid and cholesterol metabolism. L. plantarum FZU3013 intervention increased the hepatic mRNA levels of cholesterol 7α-hydroxylase (CYP7A1) and the bile salt export pump (BSEP), suggesting enhanced bile acid synthesis and excretion from the liver. These findings present new evidence supporting that L. plantarum FZU3013 has the potential to improve lipid metabolism disorders through modulating specific intestinal microbial phylotypes and regulating hepatic lipid metabolism related genes, therefore it could be used as a potential functional food for the prevention of NAFL and hyperlipidemia.

Reports linking prenatal testosterone exposure to autistic traits and to a masculinized face structure have motivated research investigating whether autism is associated with facial masculinization. This association has been reported with greater consistency for females than for males, in studies comparing groups with high and low levels of autistic traits. In the present study, we conducted two experiments to examine facial masculinity/femininity in 151 neurotypical adults selected for either low, mid-range, or high levels of autistic traits. In the first experiment, their three-dimensional facial photographs were subjectively rated by 41 raters for masculinity/femininity and were objectively analysed. In the second experiment, we generated 6-face composite images, which were rated by another 36 raters. Across both experiments, findings were consistent for ratings of photographs and composite images. For females, a linear relationship was observed where femininity ratings decreased as a function of higher levels of autistic traits. For males, we found a U-shaped function where males with mid-range levels of traits were rated lowest on masculinity. Objective facial analyses revealed that higher levels of autistic traits were associated with less feminine facial structures in females and less masculine structures in males. These results suggest sex-specific relationships between autistic traits and facial masculinity/femininity.

Polysaccharide from Ganoderma lucidum is one of the best metal-ion chelating agents because of its structural characteristics and excellent functional activities. In this study, we synthesized and characterized a novel G. lucidum polysaccharide‑chromium (III) [GLP-Cr(III)] complex. Response surface methodology (RSM) was used to optimize the reaction conditions for the maximum chelation rate of GLP-Cr(III) complex. The optimal reaction conditions obtained from RSM were as follows: concentration of CrCl3 5.71 mg/mL, pH 6.36, temperature 66.4 °C and time 2.0 h, respectively. The pH was the most significant factor, followed by reaction temperature and CrCl3 concentration. Under the optimal conditions, the experimental chelation rate was 94.17 ± 1.0% for GLP-Cr(III) complex, which agreed closely with the predicted value (94.60%). Fourier transform infrared (FT-IR) spectroscopy revealed that the primary sites of chromium (III)-binding in G. lucidum polysaccharide were O H and C O groups, which induce the morphology change from flat sheet to rough surface. Meanwhile, according to the result of X-ray diffraction (XRD), the crystal degree of GLP was disappeared after chelation with Cr(III). The presence of a “blind zone” in the 1H NMR spectrum obviously indicated the binding of Cr(III) to GLP. Additionally, the effects of GLP-Cr(III) complex on hyperglycemia and hyperlipidemia in high fructose and fat diet-induced pre-diabetic mice were also investigated. Results showed that the serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting blood glucose levels and glucose tolerance in mice supplemented with GLP-Cr(III) complex (50 mg/kg day) were significantly lower than the model group (P

Objective: This article aims to present a brief profile of the advances in prevention and treatment of myocardial injury in cancer therapy based on relevant literature or reports. Data sources: The data cited in this review were obtained from articles indexed in PubMed and China National Knowledge Internet (CNKI) up to June 2019. Study selection: Articles were selected with the following keywords "Anti-cancer therapy," "Myocardial injury," "Breast cancer," "Echocardiography," and "Chemotherapy." Results: Due to the rapid development of novel cancer therapeutic approaches, the life expectancy of tumor patients has been prolonged continuously. Meanwhile, a large number of studies have found that among patients benefiting from precise management, some medications have exerted direct or indirect side effects on the cardiovascular system, leading to the occurrence of myocardial injury. Because there are many common risk factors between breast cancer and cardiovascular disease, and there is a special anatomical position between breast and heart, the cardiology related to breast cancer patients is relatively unique in onco-cardiology. Conclusions: Heart function monitoring is critical during anti-cancer therapy so that we can early identify cardiac abnormalities and actively adopt measures to prevent myocardial injury. Key words: Myocardial injury; Anti-cancer therapy; Tumor

Importance Diabetic kidney disease is among the most important causes of end-stage kidney disease worldwide. Risk factors for diabetic kidney disease remain incompletely defined. Recent studies document a high frequency of acute kidney injury (AKI) during diabetic ketoacidosis (DKA) in children, raising the question of whether these AKI episodes might contribute to future risk of diabetic kidney disease. Objective To determine whether episodes of AKI occurring during DKA in children are associated with increased risk of development of microalbuminuria. Design, setting, and participants This retrospective review of medical records included children with type 1 diabetes with 1 or more urine albumin levels measured during routine diabetes care from 2 university-affiliated urban tertiary children's hospitals in the United States from January 2006 to December 2019. Age at diagnosis of diabetes, hemoglobin A1c levels, episodes of DKA, pH and creatinine levels during DKA, and urine albumin and creatinine measurements were analyzed. Cox proportional hazards regression models were used to identify variables affecting the hazard rate for microalbuminuria development. Analyses began January 2021 and ended May 2021. Exposures Episodes of DKA and episodes of AKI occurring during DKA. Main outcomes and measures AKI occurrence and AKI stage were determined from serum creatinine measurements during DKA using Kidney Disease: Improving Global Outcomes criteria. Microalbuminuria was defined as urine albumin-to-creatinine ratio of 30 mg/g or more or excretion of 30 mg or more of albumin in 24 hours. Results Of 2345 children, the mean (SD) age at diagnosis was 9.4 (4.4) years. One or more episodes of DKA occurred in 963 children (41%), and AKI occurred during DKA in 560 episodes (47%). In multivariable models adjusting for the associations of age at diagnosis and mean hemoglobin A1c level since diagnosis, each episode of AKI during DKA was associated with a hazard ratio of 1.56 (95% CI, 1.3-1.87) for development of microalbuminuria. Four or more episodes increased the hazard rate by more than 5-fold. DKA episodes without AKI did not significantly increase the hazard rate for microalbuminuria development after adjusting for other covariates. Conclusions and relevance These data demonstrate that episodes of AKI occurring during DKA in children with type 1 diabetes are significantly associated with risk of developing microalbuminuria. Greater efforts are necessary to reduce the frequency of DKA.

Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Lea/c/x, sdi-Lea, sLea, sLex, sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained significant interest as targets for PDAC imaging. To evaluate their PDAC molecular imaging potential, biomarker expression was determined using immunohistochemistry on PDAC, (surrounding) chronic pancreatitis (CP), healthy pancreatic, duodenum, positive (LN+) and negative lymph node (LN−) tissues, and quantified using a semi-automated digital image analysis workflow. Positive expression on PDAC tissues was found on 83% for Lea/c/x, 94% for sdi-Lea, 98% for sLea, 90% for sLex, 88% for sTn, 96% for MUC1 and 67% for MUC5AC, where all were not affected by the application of neoadjuvant therapy. Compared to PDAC, all biomarkers were significantly lower expressed on CP, healthy pancreatic and duodenal tissues, except for sTn and MUC1, which showed a strong expression on duodenum (sTn tumor:duodenum ratio: 0.6, p &lt, 0.0001) and healthy pancreatic tissues (MUC1 tumor:pancreas ratio: 1.0, p &gt, 0.9999), respectively. All biomarkers are suitable targets for correct identification of LN+, as well as the distinction of LN+ from LN− tissues. To conclude, this study paves the way for the development and evaluation of Lea/c/x-, sdi-Lea-, sLea-, sLex- and MUC5AC-specific tracers for molecular imaging of PDAC imaging and their subsequent introduction into the clinic.

Pyroptosis is a novel programmed cell death process that promotes the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18) by activating inflammasomes and gasdermin D (GSDMD), leading to cell swelling and rupture. Pyroptosis is involved in the regulation of the occurrence and development of cardiovascular and cerebrovascular diseases, tumors, and nerve injury. Diabetes is a metabolic disorder characterized by long-term hyperglycemia, insulin resistance, and chronic inflammation. The people have paid more and more attention to the relationship between pyroptosis, diabetes, and its complications, especially its important regulatory significance in diabetic neurological diseases, such as diabetic encephalopathy (DE) and diabetic peripheral neuropathy (DPN). This article will give an in-depth overview of the relationship between pyroptosis, diabetes, and its related neuropathy, and discuss the regulatory pathway and significance of pyroptosis in diabetes-associated neuropathy.

BACKGROUND Primary intramedullary melanocytoma is an exceedingly rare type of primary melanocytic tumor in the central nervous system. Unfortunately, primary intramedullary melanocytoma lacks specificity in clinical symptoms and imaging features and there is currently no standard strategy for diagnosis or treatment. CASE SUMMARY A 52-year-old male patient suffered from weakness and numbness involving the bilateral lower limbs for 18 mo, and defecation and erectile dysfunction for 6 mo. Furthermore, these symptoms started to worsen for the last 3 mo. Preoperative magnetic resonance imaging (MRI) revealed an intramedullary tumor located at the T9-T10 level. In subsequently surgery, the maximal safe resection extent approached to 98%. The lesion was confirmed to be melanocytoma by pathological examination. In addition, the possibility of original melanocytoma outside the spinal cord was excluded after the examination of the whole body. Therefore, a diagnosis of primary intramedullary melanocytoma was established. The patient refused to accept radiotherapy or Gamma Knife, but MRI examination on July 28, 2020 showed no sign of development. In addition, on April 10, 2021, the recent review showed that the disorder of defecation and lower limbs improved further but erectile dysfunction benefited a little from the surgery. CONCLUSION After diagnosing intramedullary melanocytoma by postoperative pathology, the inspection of the whole body contributed to excluding the possibility of metastasis from other regions and further suggested a diagnosis of primary intramedullary melanocytoma. Complete resection, adjuvant radiation, and regular review are critical. In addition, maximal safe resection also benefits prognosis while the tumor is difficult to be resected totally.

Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process.Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue.Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N.Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway.

BACKGROUND Recently, thymectomy using minimally invasive approaches has been increasing with the development of robotic video-assisted thoracoscopic surgery (R-VATS). Although multimodal approach is effective for robot assisted thymectomy, it is necessary to determine the approach (left, right or subxiphoid) associated with the least complications. METHODS An electronic retrieval from PubMed, Embase, Web of Science, GreyNet International and The Cochrane Library. The single-arm meta-analysis was performed to compare the rate of complications of right- and left-side approaches by R-VATS. RESULTS A total of 21 studies including 930 patients were identified. The pooled incidence of total complications was 12.2% (confidence interval: 10.0%-14.8%) for all studies. The overall complication rate was 17.3% for the right-side compared with 7.4% for the left side (P

Background Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. Methods NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. Results Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). Conclusions Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.

Lung cancer is the most common type of cancer with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of lung cancer cases. In the past two decades, immunotherapy has become a more promising treatment method than traditional treatments (surgery, radiotherapy and chemotherapy). Immunotherapy has been shown to improve the survival rate of patients and to have a superior effect when controlling lung cancer than traditional therapy. However, only a small number of patients can benefit from immunotherapy, and not all patients who qualify experience long-term benefits. In the clinic, the objective response rate of programmed cell death protein 1 treatment without the prior screening of patients is only 15–20%. Immunotherapy is associated with both opportunities and challenges for patients with NSCLC. The current challenges of immunotherapy include the lack of accurate biomarkers, inevitable resistance and insufficient understanding of immune checkpoints. In previous years, several methods for overcoming the challenges posed by immunotherapy have been proposed, but combination therapy is the most suitable choice. A large number of studies have shown that the combination of drugs can significantly improve their efficacy, compared with monotherapy, and that some therapeutic combinations have been approved by the Food and Drug Administration for the treatment of NSCLC. Traditional Chinese medicine (TCM) is a traditional medical practice in China that can play an important role in immunotherapy. Most agents used in TCM originate from plants, and have the advantages of low toxicity and multiple targets. In addition, TCM includes a unique class of drugs that can improve autoimmunity. Therefore, TCM may be a promising treatment method for all types of cancer.

Ferroptosis is a recently discovered special type of regulated cell death that is strongly associated with both homeostasis maintenance and cancer development. Previous studies have indicated that a number of small-molecular agents inducing ferroptosis have great potential in the treatment of different types of cancer, including breast, pancreatic, prostate and head and neck cancer. However, the role of ferroptosis in nasopharyngeal carcinoma (NPC) has remained to be fully determined. To the best of our knowledge, no review of the currently available studies on this subject has been published to date. The metabolism and expression of specific genes that regulate ferroptosis may represent a promising radiosensitization target in cancer treatment. The aim of the present review was to describe the cross-link between ferroptosis and NPC and to discuss the potential value of regulators and the possible mechanism underlying the role of ferroptosis in the radiosensitization of NPC, in the hope that linking the mechanism of ferroptosis with the development of NPC will accelerate the development of novel ferroptosis-based targets and radiotherapy strategies in NPC.

Background: There is a continuous decline in the prevalence of schistosomiasis and the number of Schistosoma japonicum infections in humans and livestock in China. However, there are a large number of factors that have not been resolved and which may contribute to future transmission of schistosomiasis. These include a range of sources for S. japonicum infection, difficulty in management of S. japonicum sources of infection, frequent emergence and re-emergence of Oncomelania hupensis snail habitats, and the problematic elimination of snail habitats. These factors challenge progress towards the elimination of schistosomiasis in China.Methods: Based on multi-stage continuous downscaling of sentinel monitoring, county-based schistosomiasis surveillance data were captured from the national schistosomiasis surveillance sites of China from 2005 to 2019. The data included S. japonicum infections in humans, livestock, and O. hupensis. The spatio-temporal trends for schistosomiasis were detected using a Joinpoint regression model, with a standard deviational ellipse (SDE) tool, which determined the central tendency and dispersion in spatial distribution of schistosomiasis. Further, spatio-temporal clusters of S. japonicum infections in humans, livestock, and O. hupensis were evaluated by Poisson model. Results: The prevalence of S. japonicum human infections was reduced from 2.06% to zero based on the national schistosomiasis surveillance sites of China during the period from 2005 to 2019, with a reduction from 9.42% to zero for the prevalence of S. japonicum infections in livestock, and from 0.26% to zero for the prevalence of S. japonicum infections in O. hupensis. The decline in prevalence of S. japonicum infections in humans, livestock, and O. hupensis was statistically significant from 2005 to 2019 (P < 0.01). There was an exception to the decline in S. japonicum infections in livestock during the period from 2008 to 2012. Using an SDE tool, schistosomiasis-affected regions were reduced yearly from 2005 to 2014 in the endemic provinces of Hunan, Hubei, Jiangxi, and Anhui, as well as in the Poyang and Dongting Lake regions. Poisson model revealed 11 clusters of S. japonicum human infections, six clusters of S. japonicum infections in livestock, and nine clusters of S. japonicum infections in O. hupensis. The clusters of human infection were found to be highly consistent with clusters of S. japonicum infections in livestock and O. hupensis. These clusters were in the five provinces of Hunan, Hubei, Jiangxi, Anhui, and Jiangsu, as well as along the middle and lower reaches of the Yangtze River. Humans, livestock, and O. hupensis infections with S. japonicum were mainly concentrated in the north of the Hunan Province, south of the Hubei Province, north of the Jiangxi Province, and southwestern portion of Anhui Province. In the two mountainous provinces of Sichuan and Yunnan; human, livestock, and O. hupensis infections with S. japonicum were mainly concentrated in the northwestern portion of the Yunnan Province, the Daliangshan area in the south of Sichuan Province, and the hilly regions in the middle of Sichuan Province. Conclusions: This study demonstrate a significant spatio-temporal heterogeneity of schistosomiasis in China. A remarkable decline in endemic schistosomiasis was observed between 2005 and 2019. However, there continues to be a long-term risk of schistosomiasis transmission in local areas, with high-risk areas primarily located in the Poyang Lake and Dongting Lake regions, with frequent acute S. japonicum infections. Using a One Health approach, further reinforcement of an integrated schistosomiasis control strategy, with an emphasis on the sources of S. japonicum infection, is required to facilitate the elimination of schistosomiasis in China by 2030.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy’s potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine’s ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

Background: The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting in renal tubulointerstitial disease. These pathophysiological responses are collectively described as diabetic tubulopathy (DT). Thus, therapeutic strategies targeting DT hold significant promise for early DKD treatment. Shenkang injection (SKI) has been widely used to treat renal tubulointerstitial fibrosis in patients with chronic kidney disease in China. However, it is still unknown whether SKI can alleviate DT. We designed a series of experiments to investigate the beneficial effects of SKI in DT and the mechanisms that are responsible for its effect on epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress-induced apoptosis in DT.Methods: The modified DKD rat models were induced by uni-nephrectomy, streptozotocin intraperitoneal injection, and a high-fat diet. Following the induction of renal injury, these animals received either SKI, rosiglitazone (ROS), or vehicle, for 42 days. For in vitro research, we exposed NRK-52E cells to high glucose (HG) and 4-phenylbutyric acid (4-PBA) with or without SKI or ROS. Changes in parameters related to renal tubular injury and EMT were analyzed in vivo. Changes in the proportion of apoptotic renal tubular cells and ER stress, and the signaling pathways involved in these changes, were analyzed both in vivo and in vitro.Results: SKI and ROS improved the general condition, the renal morphological appearance and the key biochemical parameters, and attenuated renal injury and EMT in the rat model of DKD. In addition, SKI and ROS alleviated apoptosis, inhibited ER stress, and suppressed PERK-eIF2α-ATF4-CHOP signaling pathway activation both in vivo and in vitro. Notably, our data showed that the regulatory in vitro effects of SKI on PERK-eIF2α-ATF4-CHOP signaling were similar to those of 4-PBA, a specific inhibitor of ER stress.Conclusion: This study confirmed that SKI can alleviate DT in a similar manner as ROS, and SKI achieves this effect by inhibiting EMT and ER stress-induced apoptosis. Our findings thereby provide novel information relating to the clinical value of SKI in the treatment of DT.

Background Immunotherapy has shown promising efficacy in patients with nasopharyngeal carcinoma (NPC). Lymphocyte activating 3 gene (LAG-3) represents a significant immune target, however, its relationship with NPC remains unclear. This study aimed to evaluate LAG-3 expression in NPC and its association with CD3+ tumor-infiltrating lymphocytes (TILs), Granzyme B (GZMB), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) expression. Methods A total of 182 patients with NPC from Sun Yat-sen University Cancer Center, China, were included in this retrospective study. LAG-3 expression in 15 NPC cell lines and LAG-3, CD3+ TILs, GZMB, PD-L1 and PD-1 in clinical samples were estimated using immunohistochemistry. The Chi-square test was used to estimate the association between LAG-3, other biomarkers, and clinical characteristics. Survival analysis was performed using the Kaplan–Meier method and the Cox regression model. Results LAG-3 was negatively expressed in all of the 15 NPC cell lines, whereas, 147 patients with NPC (80.8%) exhibited high LAG-3 expression on TILs from tumor tissues. Male patients and those who were EBV-positive presented higher LAG-3 expression. Correlation analyses showed that LAG-3 expression was related to PD-1 expression on TILs, as well as, PD-L1 expression on tumor cells (TCs) and TILs. Both the univariate and multivariate Cox models indicated that pathological type III (P = 0.036), higher LAG-3 on TILs (P P = 0.027), and higher PD-1 on TILs (P P = 0.002). Conclusion Higher LAG-3 and PD-1 on TILs, and higher PD-L1 expression on TCs, and pathological type III were identified as independent risk factors for poorer DFS in NPC patients. Our data demonstrate that LAG-3 is a promising inhibitory receptor that may play an important role in anti-NPC therapy.

To explore a new method of in vitro culture and purification of rat corpus cavernosum endothelial cells (CCECs). Male Sprague-Dawley rats' penile tissue were digested with elastase or collagenase combined with mechanical extrusion to isolate and culture the CCECs. The fixed-point digestion method was used to purify the primary cells. High-purity CCECs were successfully isolated. Following the digestion of the primary CCECs by elastase or collagenase coupled with mechanical extrusion, the cells were paving stone- and cobblestone-shaped over 10 days. The cell purity yielded in the second generation (P2) CCECs after using the fixed-point digestion method was significantly high. Compared with primary CCECs extracted by elastase digestion combined with the mechanical extrusion method, CCECs cultured by collagenase digestion yielded higher purity and a more stable morphology after fixed-point digestion and purification. Immunofluorescence staining of the third generation CCECs and the expression results of endothelial cell-associated marker antibodies CD31 and VWF were positive, and flow cytometry showed the purity of CCECs was 96.9%. Enzymatic digestion combined with mechanical extrusion and fixed-point digestion is a simple, economical method for in vitro culture and purification of CCECs, which is conducive to studying the pathophysiological mechanisms of endothelial dysfunction and erectile dysfunction.

Purpose: To investigate the clinical manifestations of orbital involvement in a large cohort of Chinese patients with IgG4-related disease (IgG4-RD). Methods: A total of 573 patients with IgG4-related disease were included. We described and compared the demographic, clinical, laboratory and histopathologic findings from 314 patients with IgG4-related ophthalmic disease (IgG4-ROD) and 259 with extra-ophthalmic IgG4-RD.Results: Male predominance was found significant in extra-ophthalmic IgG4-RD only. Patients with IgG4-ROD showed younger age at diagnosis and longer duration from onset till diagnosis. In patients with extra-ophthalmic IgG4-RD, the most commonly involved extra-ophthalmic organ was pancreas; while in IgG4-ROD patients, salivary gland was most frequently affected. Multivariate analysis exhibited IgG4-ROD was associated with allergy history, higher serum IgG4/IgG ratio, multiple organs involvement and sialoadenitis. Orbital images were reviewed in 173 (55.1%) IgG4-ROD patients. Fifty-one (29.5%) patients had multiple lesions. Lacrimal gland involvement was detected in 151 (87.3%) patients, followed by extraocular muscles (40, 23.1%), other orbital soft tissue (40, 23.1%) and trigeminal nerve (8, 4.6%). Biopsy was performed from various organs in 390 cases. A dense lymphoplasmacytic infiltration and fibrosis were the main feature in orbital specimens. Storiform fibrosis and obliterative phlebitis were absent in lacrimal gland.Conclusions: Lacrimal gland involvement was the most common orbital manifestation of IgG4-ROD. Patients with IgG4-ROD showed different characteristic in demographic, clinical, laboratory findings compared to patients with extra-ophthalmic IgG4-RD. These features might indicate potential differences in the pathogenesis of these two subgroups of IgG4-RD.

Induced pluripotent, stem cell (iPSC)-derived models of airway tissue have successfully modeled the primary defect in regulated chloride conductance caused by the major Cystic Fibrosis causing mutation, F508del. However, it remains unclear if iPSC-derived airway cultures can be used in high-throughput therapy development for F508del and rarer mutations. There is an urgent need for airway tissue models that reflect the variability of patient-specific responses and are scalable for therapy development. In the current work, we describe a robust, high-throughput fluorescence assay of mutant CFTR function in iPSCs differentiated to immature airway epithelium. This assay measures reproducible functional responses to modulators targeting either the major CF mutant F508del or the nonsense mutant: W1282X-CFTR. We show that the ranking of patient-specific responses to interventions in this stem-cell based model recapitulates the ranking observed in primary nasal epithelial cultures obtained from the same individuals. In summary, these proof-of-concept studies show that this novel platform has the potential to support therapy development and precision medicine for Cystic Fibrosis patients. One Sentence Summary We describe a fluorescence-based platform that enables high-throughput Cystic Fibrosis therapy testing using iPSCs differentiated to immature lung.