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Microcystin-leucine-arginine (MC-LR) is positively linked with multiple cancers in humans. However, the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies. No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies. The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers. MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls. The adjusted odds ratio (OR) for prostate cancer risk by serum MC-LR was 1.75 (95%CI: 1.21-2.52) in the whole subjects, and a positive correlation between MC-LR and advanced tumor stage was observed. Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival. Human, animal, and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α (ERα) and promotes epithelial-mesenchymal transition (EMT) in prostate cancer. Moreover, MC-LR-induced decreased E-cadherin levels, increased vimentin levels, and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERα knockdown. MC-LR-induced xenograft tumor growth and lung metastasis in BALB/c nude mice can be effectively alleviated with ERα knockdown. Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα, promoting migration and invasion of prostate cancer cells. Our findings highlight the role of MC-LR in prostate cancer, providing new perspectives to understand MC-LR-induced prostatic toxicity.

Background: Colon cancer is a gastrointestinal malignancy with high incidence and poor prognosis. Objective: Saikosaponin B4 (SSB4) is a monomeric component of the Traditional Chinese medicine (TCM), Bupleurum. The current study investigates the therapeutic effect and mechanisms of SSB4 in colon cancer. Methods: The proliferation of two colon cancer cell lines, SW480 and SW620, were assessed using CCK8 and expression of regulatory molecules, including Bax, Caspase3, Caspase9, Cleaved Caspase3, Cleaved Caspase9 and Bcl2 by flow cytometry and Western blotting. Results: Survival rates, assessed by CCK8, of SW480 and SW620 cells decreased significantly when the SSB4 concentration was in the range 12.5–50 μg/ml. Flow cytometry measurements indicated apoptosis rates of 55.07% ± 1.63% for SW480 cells and 33.07% ± 1.28% for SW620 cells treated with 25 μg/ml SSB4. Western blotting revealed upregulation of the proapoptotic proteins, Bax, Caspase3, Caspase9, Cleaved Caspase3 and Cleaved Caspase9, and downregulation of the anti-apoptotic protein, Bcl2, in the presence of SSB4. Network pharmacology and molecular docking predicted that the PI3K/Akt/mTOR pathway might be the main regulatory target for the antitumor effect of SSB4. Further Western blotting experiments showed that SSB4 downregulated (p < 0.01) expression of PI3K, Akt, mTOR and the phosphorylated proteins, P-PI3K, P-Akt and P-MTOR. Expression of PI3K, Akt and mTOR mRNA was found to be downregulated by SSB4 (P < 0.01) as the result of RT-PCR measurements. Conclusion: SSB4 is a potent anti-colon cancer agent. Its effects are likely to be mediated by suppression of the PI3K/AKT/mTOR pathway.

To assess the efficacy of Sanyrene liquid dressing (Urgo Medical) in preventing radiation dermatitis (RD) among patients with cancer after radiotherapy.The authors searched the China National Knowledge Infrastructure, SinoMed, WanFang Data, PubMed, Web of Science, EMBASE, and the Cochrane Library databases for articles published from inception to January 2021.The preliminary search identified 146 studies. After removing duplicates, applying exclusion criteria, and screening titles and abstracts, 19 studies met the inclusion criteria.A standardized form was constructed to extract data from eligible studies. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies.The authors identified a total of 19 studies involving 1,508 patients that assessed the effectiveness of Sanyrene liquid dressing in preventing RD in patients with cancer after radiotherapy. The findings suggested that Sanyrene decreases the total incidence of RD (odds ratio [OR], 5.00; 95% CI, 2.77-9.03; P.00001), as well as the incidence of RD grade 2 (OR, 0.55; 95% CI, 0.36-0.85; P = .007), grade 3 (OR, 0.22; 95% CI, 0.09-0.57; P = .002), and grade 4 (OR, 0.32; 95% CI, 0.13-0.78; P = .01). In addition, in comparison with controls, Sanyrene liquid dressing improves the cure rate (OR, 8.18; 95% CI, 4.03-16.60; P.00001) and delays the occurrence of RD (mean difference, 3.69; 95% CI, 3.03-4.36; P.00001).Sanyrene liquid dressing can decrease both the total incidence of RD and the incidence of RD above grade 2. It also improves the cure rate and delays the occurrence of RD. Thus, Sanyrene may be a superior option for preventing RD after radiotherapy. However, the findings were assessed as moderate- to low-quality evidence and more high-quality trials are needed to support this result.

The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically 'cold' pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.

BBIBP-CorV exerts efficient protection against SARS-CoV-2 infection. However, waning vaccine-induced humoral immune responses after two-dose vaccination have significantly undermined durable immuno-protection. In this study, we have demonstrated that although anti-spike (S) antibody responses in BBIBP-CorV vaccinees exhibited three serotypes after 6 months, including de novo sero-negative, sero-positive, and sero-decay features, S-specific interferon-γ release as well as Th1 cytokine production in CD4+ and CD8+ T cells were comparable, especially in vaccinees without detectable neutralizing antibodies. Notably, regardless of dramatic increases in humoral immunity after booster vaccination, T cell responses targeting S protein from either wild type or Omicron remained stable before and after booster vaccination in all three serotype vaccinees. No severe cases were observed even in the sero-decay group during the Omicron epidemic in Shanghai. Our results thus illustrate that unlike fluctuating humoral responses, viral-specific T cell responses are extremely stable after booster vaccination. Sustained T cell responses might be dedicated to the rapid restoration of antibody responses after booster vaccination.

The COVID-19 pandemic‒related BMI gain and obesity prevalence changes in children have not been clearly elucidated, especially in China. This study aims to assess the impact of pandemic-related BMI and obesity prevalence change in Chinese children aged 8-12 years.On the basis of the Health Promotion Program for Children and Adolescents in Suzhou of China, a total of 72,175 children aged 8-12 years with complete data during 2017-2020 were included. Yearly BMI z-score changes and age- and sex-adjusted BMI changes before (2017-2019) and during (2019-2020) the pandemic were calculated. Multivariate mixed linear models were used to examine the possible difference in annual BMI change rate before and during the pandemic among subgroups.The obesity prevalence slightly increased from 12.29% (2017) to 13.28% (2019) but substantially increased to 15.29% in 2020. The mean yearly change in BMI z-score before and during the pandemic were 0.039 (95% CI=0.037, 0.042) and 0.131 (95% CI=0.125, 0.138), respectively, yielding a difference of 0.092 (95% CI=0.087, 0.096). Similarly, changes and age- and sex-adjusted BMI increased by 0.191 (95% CI=0.179, 0.202) during the pandemic compared with those of previous years. Meanwhile, the increase in BMI changes in 2019-2020 compared with that before the pandemic was more obvious in boys than in girls and in underweight or normal-weight children than in their overweight and obese counterparts.BMI gain increased among Chinese children aged 8-12 years during the pandemic. There is an urgent need to formulate effective public health policies to reduce the risk of pandemic-related childhood obesity.

To investigate the characteristics of the ocular surface microbiome in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the associations between the microbial dysbiosis and chronic ocular graft-versus-host disease (oGVHD).Prospective cohort study.Ocular surface samples from 48 healthy subjects and 76 patients after allo-HSCT, including 50 patients with chronic oGVHD and 26 patients without oGVHD, were collected. Species-level composition of the ocular surface microbiome was surveyed via metagenomic shotgun sequencing. OGVHD was diagnosed and graded according to the International Chronic Ocular GVHD Consensus Group criteria.The α-diversity of the microbiota was significantly decreased in patients after allo-HSCT. Nevertheless, we detected more types of viral species in the allo-HSCT group than the healthy group, especially anelloviruses. The mismatch of donor-recipient sex was only negatively associated with the α-diversity in male but not female recipients. Moreover, the microbiome of patients with oGVHD was distinct from patients without oGVHD. Gordonia bronchialis and Pseudomonas parafulva were enriched in patients with oGVHD and positively associated with International Chronic Ocular GVHD score.This study suggests that the ocular surface microbiome after allo-HSCT is characterized by a loss of diversity. Furthermore, the microbial dysbiosis at the ocular surface is associated with the status and severity of chronic oGVHD. These results lay the groundwork for future investigations of the potential microbial mechanism for oGVHD.

Alzheimer's disease (AD), a neurodegenerative disease with insidious onset and progressive progression, is the main type of dementia. Currently, there is no specific cure for the disease. At the same time, a series of drug developments based on the classic theory, the Aβ cascade hypothesis, have not completed phase III clinical trials, challenging the hypothesis. Polysaccharides obtained from natural products can be used in the treatment of AD, which has attracted academic attention due to its advantages of multi-target, multi-channel, no or modest side effects. The TCM syndrome type of AD is mainly "qi and blood deficiency, kidney essence deficiency", and the medicine is mainly used to replenish qi and blood, kidney and bone marrow. Thus, there has been extensive and in-depth research on polysaccharides obtained from tonic Chinese herbal medicine in China. Based on this background, this paper evaluated the effects and mechanisms of natural polysaccharides on AD by combing and screening English and related literature in recent 5 years and summarized the extraction process and structure-activity relationship of polysaccharides.

Background: Immune-related long noncoding RNAs (lncRNAs) play an important role in the development of cancer. This study aimed to identify immune-related lncRNAs in thyroid cancer (THCA) and develop a prognostic model for THCA. Method: We downloaded immune-related gene sets from the Gene Set Enrichment Analysis (GSEA) website and obtained THCA gene expression and clinical data from The Cancer Genome Atlas (TCGA) database. Immune-related lncRNAs were then obtained by performing correlation analysis on the expression of lncRNAs and immune-related genes. A prognostic model for THCA immune-related lncRNAs was developed through univariate Cox regression and multiple Cox regression analyses. We confirmed the results in clinical samples using quantitative real-time PCR. Results: A total of 26 immune-related lncRNAs in THCA were obtained. Then we constructed a prognosis model composed of seven lncRNAs (LINC01614, AC017074.1, LINC01184, LINC00667, ACVR2B-AS1, AC090673.1, and LINC00900). Our model can be used as an independent prognostic factor. Principal component analysis displayed that the lncRNAs in the model can distinguish between high and low-risk groups. Clinical correlation analysis showed that the expression levels of AC090673.1 (P Conclusion: We identified and experimentally validated seven immune-related lncRNAs that can serve as potential biomarkers for THCA prognosis.

Previous studies on oral submucous fibrosis (OSF) mostly focused on the activation of fibroblasts and collagen metabolism, while little involved in the epithelium. As we have reported the role of differentiated embryo-chondrocyte expressed gene 1 (DEC1) in oral cancer and other precancerous lesions, this research aimed to explore its role in the OSF epithelium.Expression of DEC1 and other proteins were investigated in tissue array constructed with 33 OSF and 14 normal oral mucosa (NOM) tissues. Human oral keratinocytes treated with arecoline and/or hypoxia were used to simulate OSF epithelium and detected for morphological and protein alterations. Inhibition of DEC1 was used to explore its mediating role. Finally, animal models of OSF constructed by locally arecoline injecting in buccal mucosa were used to verify our findings.DEC1 overexpression could be detected in the epithelium of OSF compared with that in NOM followed by phosphorylated FAK and Akt, and DEC1 showed a significant positive correlation with them. Cytology experiment revealed that OSF-like treatment could upregulate DEC1 expression followed by phosphorylated FAK, Akt, but inhibit E-cadherin, while knockdown of DEC1 could suppress the effects. In addition, OSF mice revealed higher expression of DEC1 in the epithelium of buccal mucosa, along with synchronized alterations of phosphorylated FAK and Akt.In the epithelium of OSF, overexpression of DEC1 induced activation of FAK/Akt signal axis, caused mesenchymal transition in epithelial cells, and may promote malignant transformation of OSF. Targeting DEC1 in OSF could be promising a new target for the diagnosis and treatment of this process.

Atherosclerosis, a chronic inflammatory disease, is a leading cause of death worldwide. Vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs) and macrophages play extremely vital roles in the formation of atherosclerotic plaques and subsequent atherosclerosis. Necroptosis, a caspase-independent programmed cell necrosis, occurs in advanced atherosclerotic plaques and has been implicated in VEC, VSMC and macrophage function. Although necroptosis may have considered as a defensive line against intracellular infection, it can induce a pro-inflammatory state, which will accelerate the disease process. Accordingly, necroptosis plays an important pathophysiologic role. In this review, we explore the role of necroptosis in VECs, VSMCs and macrophages in atherosclerotic plaques and their connection to atherosclerosis.

Spinal cord injury patients are prone to develop deep tissue injury because of long-term mechanical load. However, there is a lack of statistical research on the influence of tissue characteristics on the internal mechanical state of soft tissue. This study aimed to investigate the influence of tissue characteristics on the internal mechanical state of buttock in spinal cord injury patients. A three-dimensional reference buttock model was established and a visualization program was generated to modify the parameter values. Through changing the muscle atrophy, body mass index and the radius of curvature of the ischial tuberosity, 96 different model variants were simulated and validated in this study. With body mass index increasing from 16 to 40, the principal shear stress was 10.4 times principal compressive stress, the maximum shear strain and the max cluster volume increased by 1.2 (P 0.001) and 8.8 times (P 0.001), respectively. The interaction between BMI and muscle atrophy was significant when BMI was greater than or equal to 22.5 kg/m

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. This study aimed to uncover the underlying molecular features for different types of IPF. IPF microarray datasets were retrieved from GEO databases. Weighted gene co-expression analysis (WGCNA) was used and identified subgroup-specific WGCNA modules. Infiltration-level immune cells in different subgroups of microenvironments were analyzed with CIBERSORT algorithms. The result is we classified 173 IPF cases into two subgroups based on gene expression profiles, which were retrieved from the GEO databases. The SGRQ score and age were significantly higher in C2 than in C1. Using WGCNA, five subgroup-specific modules were identified. M4 was mainly enriched by MAPK signaling, which was mainly expressed in C2; M1, M2, and M3 were mainly enriched by metabolic pathways and Chemokine signaling, and the pathway of M5 was phagosome inflammation; M1, M2, M3, and M5 were mainly expressed in C1. Utilizing the CIBERSORT, we showed that the number of M1 macrophage cells, CD8 T cells, regulatory T cells (Tregs), and Plasma cells was significantly different between C1 and C2. We found the molecular subgroups of IPF revealed that cases from different subgroups may have their unique patterns and provide novel information to understand the mechanisms of IPF itself.

Voluntary contribution has become the only source of donor lungs in China since 2015. To elaborate the outcomes of patients awaiting lung transplantation (LTx) after the implementation of donation after brain death, we performed a retrospective study that encompassed 205 patients with end-stage lung disease who registered for LTx at Shanghai Pulmonary Hospital from January 1, 2015 to January 1, 2021. A total of 180 patients were enrolled in the study. The median waiting time was 1.25 months. Interstitial lung disease (ILD) (103/180, 57.2%) and chronic obstructive pulmonary disease (COPD) (56/180, 31.1%) were the most common diseases in our study population. The mean pulmonary artery pressure (mPAP) of patients in the died-waiting group was higher than that of the survivors (53.29±21.71 mmHg vs. 42.11±18.58 mmHg, P=0.002). The mortality of patients with ILD (34/103, 33.00%) was nearly twice that of patients with COPD (10/56, 17.86%) while awaiting LTx (P=0.041). In the died-waiting group, patients with ILD had a shorter median waiting time than patients with COPD after being listed (0.865 months vs. 4.720 months, P=0.030). ILD as primary disease and mPAP35 mmHg were two significant independent risk factors for waitlist mortality, with hazard ratios (HR) of 3.483 (95% CI 1.311-9.111; P=0.011) and 3.500 (95% CI 1.435-8.536; P=0.006). Hence, LTx is more urgently needed in patients with ILD and pulmonary hypertension.

Abstract: Protein tyrosine phosphatase receptor-type Q (PTPRQ), a member of the type III tyrosine phosphatase receptor (R3 PTPR) family, is composed of three domains, including 18 extracellular fibronectin type III (FN3) repeats, a transmembrane helix, and a cytoplasmic phosphotyrosine phosphatase (PTP) domain. PTPRQ was initially identified as a transcript upregulated in glomerular mesangial cells in a rat model of glomerulonephritis. Subsequently, studies found that PTPRQ has phosphotyrosine phosphatase and phosphatidylinositol phosphatase activities and can regulate cell proliferation, apoptosis, differentiation, and survival. Further in vivo studies showed that PTPRQ is necessary for the maturation of cochlear hair bundles and is considered a potential gene for deafness. In the recent two decades, 21 mutations in PTPRQ have been linked to autosomal recessive hearing loss (DFNB84) and autosomal dominant hearing loss (DFNA73). Recent mutations, deletions, and amplifications of PTPRQ have been observed in many types of cancers, which indicate that PTPRQ might play an essential role in the development of many cancers. In this review, we briefly describe PTPRQ structure and enzyme activity and focus on the correlation between PTPRQ and human disease. A profound understanding of PTPRQ could be helpful in the identification of new therapeutic targets to treat associated diseases.

Chlamydia psittaci can infect a wide range of avian species, occasionally causing psittacosis (also known as parrot fever) in humans. Most human psittacosis cases are associated with close contact with pet birds or poultry. In December, 2020, an outbreak of severe community-acquired pneumonia of unknown aetiology was reported in a hospital in Shandong province, China, and some of the patients' close contacts had respiratory symptoms. Our aims were to determine the causative agent of this epidemic and whether there had been human-to-human transmission.For this epidemiological and aetiological investigation study, we enrolled patients who had community-acquired pneumonia confirmed by chest CT at two local hospitals in Shandong Province in China. We collected sputum, bronchoalveolar lavage fluid, and nasopharyngeal swab samples from participants and detected pathogens by surveying for 22 target respiratory microbes using a commercial assay, followed by metagenomic next-generation sequencing, specific nested PCR, and qPCR tests. We excluded individuals who were C psittaci-negative on both tests. We recruited close contacts of the C psittaci-positive patients, and tested nasopharyngeal swabs from the close contacts and samples from ducks from the processing plant where these patients worked. We then integrated the epidemiological, clinical, and laboratory data to reveal the potential chain of transmission of C psittaci that characterised this outbreak.Between Dec 4 and 29, 2020, we used metagenomic next-generation sequencing and different PCR-based approaches to test 12 inpatients with community-acquired pneumonia, of whom six (50%) were workers at a duck-meat processing plant and two (17%) were unemployed people, who were positive for C psittaci and enrolled in this study. We contacted 61 close contacts of the six patients who worked at the duck-meat processing plant, of whom 61 (100%) were enrolled and tested, and we determined that the community-acquired pneumonia outbreak was caused by C psittaci. Within the outbreak cluster, 17 (77%) of 22 participants had confirmed C psittaci infections and five (23%) of 22 participants were asymptomatic C psittaci carriers. The outbreak had begun with avian-to-human transmission, and was followed by secondary and tertiary human-to-human transmission, which included transmission by several asymptomatic carriers and by health-care workers. In addition, some of the participants with confirmed C psittaci infection had no identified source of infection, which suggested cryptic bacterial transmission.Our study data might represent the first documented report of human-to-human transmission of C psittaci in China. Therefore, C psittaci has the potential to evolve human-to-human transmission via various routes, should be considered an elevated biosecurity and emergent risk, and be included as part of the routine diagnosis globally, especially for high-risk populations.Academic Promotion Programme of Shandong First Medical University, National Science and Technology Major Project, ARC Australian Laureate Fellowship.

Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73-22.48) for TOMM40GG, 1.47 (0.89-2.42) for PVRL2AA, and 12.87 (3.97-41.73) for having both risk alleles (P

Background: Sustained Hif1α (hypoxic-inducible factor-1 alpha) accumulation plays a central role in osteogenic transdifferentiation and subsequent calcification. Capsaicin, the potent agonist of TRPV1 (transient receptor potential vanilloid type 1), was found to mitigate hypoxic-related injury and reverse phenotypic switch of vascular smooth muscle cells. However, its role in arterial calcification and the underlying mechanisms remain unexplored. Methods: We used data from Multi-Ethnic Study of Atherosclerosis to examine the association of coronary artery calcification and chili consumption. Chronic kidney disease mice and high phosphate–induced vascular smooth muscle cells calcification models were established to investigate the anticalcification effect of capsaicin, evaluated by calcium deposition and changes in phenotype markers. Results: Chili consumption was negatively correlated with coronary artery calcification and conferred a smaller progression burden during follow-up. Capsaicin reduced calcium deposition and osteogenic transdifferentiation both in vivo and in vitro. Using siTRPV1 (small interfering RNA and the antagonist of TRPV1), the anticalcification effect of capsaicin was abrogated. Hif1α was increased in phosphate-treated vascular smooth muscle cells and its degradation was accelerated by capsaicin. Retaining Hif1α stability using cobalt chloride (CoCl 2 ) or MG132 abolished the protective effect of capsaicin. We further identified an increased expression of SIRT6 (Sirtuin 6) in response to capsaicin and confirmed the physical interaction between SIRT6 and Hif1α. Acetylated Hif1α was decreased, whereas hydroxylated Hif1α was increased under capsaicin treatment. Using immunohistochemistry analysis, we observed increased SIRT6 and reduced Hif1α in both SIRT6 transgenic and capsaicin-treated chronic kidney disease mice. Conclusions: Capsaicin facilitates deacetylation and degradation of Hif1α by upregulating SIRT6, which inhibits osteogenic transdifferentiation and protects against arterial calcification. These data highlight a promising therapeutic target for the management of arterial calcification.

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.

Objective. Oxidative stress and inflammation play critical roles in the pathogenesis of spinal cord injury (SCI). Regulator of G protein signaling 6 (RGS6) is involved in controlling ROS generation and inflammatory response under different contexts. This study is aimed at investigating its role and underlying mechanism in SCI. Methods. Contusive SCI mouse models were generated, and lentiviral vectors were injected to silence or overexpress RGS6 in the spinal cord. To inhibit AMP-activated protein kinase (AMPK) activity, SCI mice were intraperitoneally injected with compound C (20 mg/kg) every two days. Oxidative and inflammatory markers were detected. Results. Spinal RGS6 expression was elevated upon SCI stimulation. RGS6 knockdown suppressed, while RGS6 overexpression aggravated oxidative stress, inflammation, and SCI in mice. Mechanistically, RGS6 elevation during SCI deactivated AMPK pathway, thereby exacerbating oxidative stress and inflammation in SCI mice. Conclusion. RGS6 is required for the initiation and progression of SCI, and knocking down RGS6 may provide promising therapeutic strategies for SCI patients.

Studies have demonstrated that glycerol can act as an optical clearing agent (OCA) to increase the light penetration through the skin and laser deposition to the target chromophore, thus potentially increasing the efficacy of laser treatment.To evaluate whether a pulsed dye laser (PDL) in combination with an OCA can increase the efficacy in treating port-wine stains (PWSs).Thirteen patients with untreated PWSs underwent 3 treatment sessions at 6-week intervals. Each PWS was divided into OCA + PDL sites (PDL treatment after topical use of 0.5 mL hydrous glycerol for 5 minutes), PDL sites, and untreated sites. The chromametric evaluation and visual evaluation (VAS) of the efficacy and the assessment of side effects were conducted 3 months after the final treatment.Visual evaluation was 2.69 versus 2.07 (p = .025) and 3.38 versus 3.07 (p = .04) for OCA + PDL and PDL-only sites after the first and second sessions. After the third session, the chromameter and VAS indicated no significant difference between the 2 sites. Permanent side effects were not observed.Greater efficacy was observed after the first 2 treatments on the OCA + PDL sites. Although after multiple sessions, the OCA + PDL treatment did not improve efficacy over just PDL alone.

RIP1 and RIP3, cell death mediators, form fibrous amyloids. How RIP1/RIP3 amyloidal oligomers assemble functional necrosomes and control cell death is largely unknown. Here we use super-resolution microscopy to directly visualize cellular necrosomes as mosaics of RIP1 and RIP3 oligomers. The small (initial) mosaic complexes are round, and the large mosaics are in a rod shape. RIP3 oligomers with sizes of tetramer or above are the domains in mosaics that allow MLKL, recruited by phosphorylated RIP3, to oligomerize for necroptosis. Unexpectedly, RIP1 autophosphorylation not only controls the ordered oligomerization of RIP1 but also is required for RIP1-initiated RIP3 homo-oligomerization in correct organization, which is indispensable for the formation of functional rod-shaped mosaics. Similarly, apoptosis initiated by enzymatically defective RIP3 requires the formation of rod-shaped mosaics of RIP3 and RIP1 oligomers. The revealing of nanoscale architecture of necrosomes here innovates our understanding of the structural and organizational basis of this signalling hub in cell death.

Based on the complex pathological environment of perioperative stroke, the development of targeted therapeutic strategies is important to control the development of perioperative stroke.Recently, great progress has been made in nanotechnology, and nanodrug delivery systems have been developed for the treatment of ischemic stroke.In this review, the pathological processes and mechanisms of ischemic stroke during perioperative stroke onset were systematically sorted. As a potential treatment strategy for perioperative stroke, the review also summarizes the multifunctional nanodelivery systems based on ischemic stroke, thus providing insight into the nanotherapeutic strategies for perioperative stroke.

Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPase of the Rab family, is a key regulator of endosome dynamics and thus cell migration. However, how its activity is regulated still remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA, namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poor prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single-cell migration by repressing β1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248-1347 nt and suppresses β1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.

Yingzhe Cheng,1 Yuanjing Li,2 Xiaoyan Liang,3,4 Pin Wang,3 Wenxin Fa,1 Cuicui Liu,1,3,4 Yongxiang Wang,1,3,4 Keke Liu,5 Nan Wang,3,4 Yifeng Du1,3,4 1Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2Aging Research Center and Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Stockholm University, Stockholm, Sweden; 3Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 4Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong, People’s Republic of China; 5Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yifeng Du, Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of China, Tel/Fax +86-531-68776354, Email duyifeng@email.sdu.edu.cnPurpose: To investigate the associations of genotypes of NDUFAF6 rs6982393 and APOE and their combined genotypes with the risk of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) in Chinese rural elderly.Methods: This cross-sectional population-based study included 5096 older adults (age ≥ 60 years, 57.1% female). Genotypes of NDUFAF6 rs6982393 and APOE were detected using the multiple-polymerase chain reaction amplification. We diagnosed AD following the criteria of Diagnostic and Statistical Manual of Mental Disorders, the fourth edition and diagnosed MCI following the Petersen’s criteria MCI. Data were analyzed using the logistic regression model.Results: The overall prevalence of AD and MCI was 3.57% (95% confidence interval [CI]: 0.040, 0.053) and 22.65% (95% CI: 0.223, 0.247), separately. The TT versus CC/CT genotype of NDUFAF6 rs6982393 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 1.61 (1.02, 2.54) in the total sample, 3.36 (1.48, 7.60) in those aged 60– 69, and 1.24 (0.71, 2.17) in those aged 70 years and above. The interaction between genotype of NDUFAF6 rs6982393 with age groups (60– 69 versus ≥ 70 years) was significant on the risk of AD. The presence of APOE &epsiv;4 was not significantly associated with the risk of AD. Carrying both NDUFAF6 TT and APOE &epsiv;4 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 2.69 (1.10, 2.56). In addition, there was no significant association between the above genotypes and MCI.Conclusion: In Chinese rural elderly, the TT versus CT/CC genotype of NDUFAF6 rs6982393 was associated with an increased likelihood of AD; such an association only existed among young-old adults. Carrying both NDUFAF6 rs6982393-TT and APOE &epsiv;4 was related to a higher risk of AD. This finding highlights the importance of considering age and combined genotype in studying the genetic profiles of AD.Keywords: NDUFAF6 rs6982393, APOE, dementia, population-based study

The importance of structural variants (SVs) for human phenotypes and diseases is now recognized. Although a variety of SV detection platforms and strategies that vary in sensitivity and specificity have been developed, few benchmarking procedures are available to confidently assess their performances in biological and clinical research. To facilitate the validation and application of these SV detection approaches, we established an Asian reference material by characterizing the genome of an Epstein-Barr virus (EBV)-immortalized B lymphocyte line along with identified benchmark regions and high-confidence SV calls. We established a high-confidence SV callset with 8938 SVs by integrating four alignment-based SV callers, including 109× Pacific Biosciences (PacBio) continuous long reads (CLRs), 22× PacBio circular consensus sequencing (CCS) reads, 104× Oxford Nanopore Technologies (ONT) long reads, and 114× Bionano optical mapping platform, and one de novo assembly-based SV caller using CCS reads. A total of 544 randomly selected SVs were validated by PCR amplification and Sanger sequencing, demonstrating the robustness of our SV calls. Combining trio-binning-based haplotype assemblies, we established an SV benchmark for identifying false negatives and false positives by constructing the continuous high-confidence regions (CHCRs), which covered 1.46 gigabase pairs (Gb) and 6882 SVs supported by at least one diploid haplotype assembly. Establishing high-confidence SV calls for a benchmark sample that has been characterized by multiple technologies provides a valuable resource for investigating SVs in human biology, disease, and clinical research.

Progestin resistance is a critical factor that prevents patients with endometrial cancer (EC) from receiving conservative therapy. However, the etiology remains elusive. Cancer stem cells (CSCs) may be a contributing factor to progestin resistance in EC. These cells share similar stemness properties with embryonic stem cells that have a multipotent but differential naïve phenotype. Embryonic stem cells are programed to self-renew, to differentiate and to show plasticity toward a normal cellular phenotype in their defined microenvironment. However, whether this microenvironment may promote CSC differentiation toward a better responsive phenotype and reverse progestin resistance has not yet been clarified. In the current study, we found that progestin resistance of endometrial CSCs can be improved or reversed by using in vitro fertilization (IVF)-generated embryonic sac-derived fluid containing the embryonic microenvironment. Furthermore, suppression or reversal of progestin resistance was mediated by placental alkaline phosphatase (ALPP), a factor secreted into the embryonic microenvironment by IVF-generated blastocysts. ALPP significantly reversed progestin resistance by facilitating endometrial CSC differentiation through downregulating the stemness genes NANOG, OCT4 and SOX2. We further showed that the downregulation of NANOG, OCT4 and SOX2 by ALPP was carried out by TET1/2-mediated epigenetic modulation of the promoter regions of these genes. Such changes at the molecular level initiated endometrial CSC differentiation and promoted a better responsive endometrial cancer phenotype. In fact, their response to progestin treatment was similar to that of well-differentiated endometrioid carcinoma cells without CSCs. ALPP could be a novel target in the process to overcome progestin resistance, and such findings may provide a new approach for the conservative treatment of endometrial cancer.

To investigate the relationship between epidermal growth factor receptor (EGFR) expression and clinicopathological characteristics in sebaceous carcinoma (SbC) of the eyelid.Clinical records and microscopic slides of 102 cases of SbC in the eyelid were reviewed. An immunohistochemical antibody for EGFR was employed. Differentiation, pagetoid spread, and mitosis were evaluated.Of the 102 patients, 46 (45.1%) cases were male and 56 (54.9%) cases were female (male:female, 1:1.2). The mean age of the patients was 57.32 ± 13.23 years (range, 26-85 years). Fifty-two (51%) cases occurred in the right eye and 50 (49%) cases in the left eye. The stage T1 and stage T2 cases were 71 (69.6%) and 31 (30.4%), respectively. There were 69 (67.6%) cases with pagetoid spread and 33 (32.4%) cases without pagetoid spread. There were 15 (14.7%) well-differentiated cases, 33 (32.4%) moderately differentiated cases, and 54 (52.9%) poorly differentiated cases. There was 1 (1%) case of 0 to 1/ high power field (HPF) mitosis, 46 (45.1%) cases of 2 to 5/HPF mitoses, and 55 (53.9%) cases of5/HPF mitoses, respectively. The EGFR positivity of SbCs was 97.1% (99 cases) with 2% (2 cases) weak expression, 46.1% (47 cases) moderate expression, and 49% (50 cases) strong expression. While EGFR was weakly positive only in a few conjunctival epithelial cells and basal cells of the sebaceous glands. The EGFR expression of SbCs was related to the clinic T category statistically ( P = 0.048) but not related to age, gender, differentiation, nuclear mitosis, and pagetoid spread of these tumors statistically ( P0.05). And the differentiation of these SbCs was related to the mitosis of these tumors statistically ( P0.001).The EGFR expression of SbCs was related to the tumor stage statistically, which implied that EGFR might be used as a prognostic marker of SbCs. EGFR is expressed in most SbC cases, which implied that it might act in the tumorigenesis mechanisms of SbC and could be a therapeutic target in the treatment of SbC for some metastatic cases.

Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS)

Background Public drinking water can be an important source exposure to lead, which can affect children’s cognitive development and academic performance. Few studies have looked at the impact of lead exposures from community water supplies or their impact on school achievements. We examined the association between annual community water lead levels (WLLs) and children’s academic performances at the school district level. Methods We matched the 90th percentile WLLs with the grade 3–8 standardized test scores from the Stanford Education Data Archive on Geographic School Districts by geographic location and year. We used multivariate linear regression and adjusted for urbanicity, race, socioeconomic characteristics, school district, grade, and year. We also explored potential effect measure modifications and lag effects. Results After adjusting for potential confounders, a 5 μg/L increase in 90th percentile WLLs in a GSD was associated with a 0.00684 [0.00021, 0.01348] standard deviation decrease in the average math test score in the same year. No association was found for English Language Arts. Conclusions We found an association between the annual fluctuation of WLLs and math test scores in Massachusetts school districts, after adjusting for confounding by urbanicity, race, socioeconomic factors, school district, grade, and year. The implications of a detectable effect of WLLs on academic performance even at the modest levels evident in MA are significant and timely. Persistent efforts should be made to further reduce lead in drinking water.

A single treatment strategy to produce a significant effect on cancer treatment is difficult due to the complex variability of the tumor environment. Herein, considering over-expressed glutathione (GSH) in the tumor environment can reduce Mn

Many biomarkers for early diagnosis of cancer and other diseases are difficult to detect because they often exist in body fluids in very low concentrations and are masked by high-abundance proteins such as albumin and immunoglobulins. At the same time, water pollution is one of the most serious environmental problems, but the existing adsorption materials have many shortcomings such as slow kinetics, small adsorption capacity and low adsorption efficiency. Nanotraps, mixed with gases or liquids, can capture and concentrate target substances, such as biomolecules, metal ions and oxoanions. Using nanotraps is a versatile sample pre-processing approach and it can improve the sensitivity of downstream analysis techniques. Herein, the preparations and applications of different types of nanotraps are mainly introduced. What's more, the shortcomings of using nanotraps in practical applications are also discussed. Using nanotraps is a promising sample pre-processing technology, which is of great significance for biomarkers discovery, diseases diagnosis, sewage purification and valuable ions recovery. STATEMENT OF SIGNIFICANCE: This review collates and summarizes the preparations and applications of different types of nanotraps, and discusses the shortcomings of using nanotraps in practical applications. Nanotraps, mixed with gases or liquids, can capture and concentrate target materials, such as biomolecules, metal ions and oxoanions. Using nanotraps is a versatile sample pre-processing approach and it can improve the sensitivity of downstream analysis techniques. During the COVID-19 pandemic, hydrogel nanotraps were successfully utilized for RT-PCR analysis with the FDA Emergency Used Authorization for COVID-19. Using nanotraps is a promising sample pre-processing technology, which is of great significance for biomarkers discovery, diseases diagnosis, sewage purification and valuable ions recovery.

Background & Aims The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial, and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells. Here, we explored whether the IEC intrinsic Ahr could modulate the development of alcohol-related liver disease (ALD) via the gut–liver axis. Methods Mice with IEC specific Ahr deficiency (AhrΔIEC) were generated and fed with a control or ethanol diet. Alterations of intestinal microbiota and metabolites were investigated by 16S ribosomal RNA sequencing, metagenomics, and untargeted metabolomics. AHR agonists were used to evaluate the therapeutic potentials of intestinal Ahr activation for ALD treatment. Results AhrΔIEC mice showed more severe liver injury after ethanol feeding than control mice. Ahr deficiency in IECs altered the intestinal metabolite composition, creating an environment that promoted the overgrowth of Helicobacter hepaticus and Helicobacter ganmani in the gut, enhancing their translocation to mesenteric lymph nodes and liver. Among the altered metabolites, isobutyric acid was increased in the cecum of ethanol-fed AhrΔIEC mice relative to control mice. Furthermore, both H.hepaticus and isobutyric acid administration aggravated ethanol-induced liver injury in vivo and in vitro. Supplementation with AHR agonists, 6-formylindolo[3,2-b]carbazole and indole-3-carbinol, protected mice from ALD development by specifically activating intestinal Ahr without affecting liver Ahr function. Alcoholic patients showed lower intestinal AHR expression and higher H.hepaticus levels compared with healthy individuals. Conclusions Our results indicate that targeted restoration of IEC intrinsic Ahr function may present as a novel approach for ALD treatment., Graphical abstract