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The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. Significance: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC. In this study, GOLM1 was positively correlated with infiltrating tumor-associated macrophages (TAMs) expressed high levels of programmed death-ligand 1 (PD-L1) and CD8+ T cell suppression in HCC tissues. Both gain- and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression. In the mechanism, GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression. Furthermore, co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages. Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1+ TAMs infiltration and alleviated CD8+ T cell suppression, resulting in tumor growth inhibition in the mouse HCC model. Together, our study unveils a mechanism by which GOLM1 induces CD8+ T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent. Targeting PD-L1+ TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.

The mood disorders have been recognized as common comorbidities of rheumatoid arthritis (RA), however unknown in patients with different RA courses. Therefore, we aimed to investigate the status of mood disorders in early RA and non-early RA patients and further identify the associated factors for mood disorders.Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were assessed in all enrolled RA patients. Besides clinical assessments, power Doppler and greyscale (GS) ultrasound of 28 joints was performed. The frequency of mood disorders was compared between early RA and non-early RA patients. Multivariate regression was used to identify the associated factors for mood disorders.Tow hundred one RA patients were enrolled, with 76 early RA (disease duration ≤ 2 years) and 125 non-early RA (disease duration 2 years). Mood disorders (depression and/or anxiety) were found in 42 (20.9%) patients. Depression was more frequently observed in early RA than non-early RA patients (26.3% vs. 14.4%, P = 0.036). A similar trend for anxiety was also observed in early RA compared to non-early RA patients, although the difference was insignificant (13.2% vs. 5.6%, P = 0.062). Disease duration (OR = 0.991, 95% CI 0.985-0.998, P = 0.009), health assessment questionnaire disability index (HAQ-DI) (OR = 1.045, 95% CI 1.005-1.086, P = 0.029) and GS synovitis score (OR = 1.065, 95% CI 1.017-1.115, P = 0.007) were identified as factors associated with depression. Disease duration (OR = 0.981, 95% CI 0.967-0.995, P = 0.009), HAQ-DI (OR = 1.071, 95% CI 1.013-1.133, P = 0.017) and GS synovitis score (OR = 1.072, 95% CI 1.012-1.136, P = 0.019) were identified to be associated with anxiety.Depression and anxiety were almost doubled in frequency in early RA than in long-standing RA patients. RA patients with short disease duration, high HAQ-DI and GS score were more likely to be in depression and anxiety. Key Points • Mood disorders were more frequent in early RA than non-early RA patients. • More attention to psychological status is needed in RA patients. • RA patients with short disease duration, poor physical function and severe synovitis were more likely to have depression and/or anxiety.

The dietary supplementation of prebiotics is considered a promising strategy for the modulation of gut microbiota. Due to the wide variety of animal models and tremendous inter-individual variability from human investigations, the prebiotic effect of fibers is often difficult to compare between studies. Here, the effects of 11 dietary fibers on human fecal microbiota were studied using an in vitro human fecal fermentation model under well-controlled conditions. All fibers showed positive regulatory effects on short chain fatty acids (SCFAs) and several beneficial bacteria, including Parabacteroides distasonis and Bifidobacterium spp. Cultures supplemented with xylo-oligosaccharide and konjac flour showed the highest SCFAs. According to regulatory effects, fibers were divided into three groups, with 13 indicator OTUs (operational taxonomic units) identified. Fecal microbiota regulated by isomalto-oligosaccharide and chitosan-oligosaccharide were similar to fructo-oligosaccharide and inulin outputs. As a supplement to in vivo studies, our results comprehensively summarized the similarities and distinctiveness of fibers in regulating fecal microbiota structures. KEY POINTS: • Fibers were divided into three groups based on the regulatory effects in microbiota. • Thirteen indicator OTUs were identified using pairwise comparisons. • Fiber similarities and distinctive traits in regulating microbiota effect were identified.

The rapid detection and characterization of carbapenemases in isolates of Enterobacterales are crucial for precise antibiotic administration and infection control. This article reports the findings from a parallel evaluation of the NG-Test Carba 5 (NG Biotech, Guipry, France) and Xpert Carba-R (Cepheid, Sunnyvale, CA) assays in the detection and differentiation of five carbapenemases [imipenem-resistant phenotype (IMP), Klebsiella pneumoniae carbapenemase, New Delhi metallo-β-lactamase (NDM), oxacillin-hydrolyzing β-lactamase (OXA)-48-like, and Verona integron-encoded metallo-β-lactamase] or the genes that encode them. A total of 122 isolates recovered from blood cultures and 106 positive blood culture broth (BCB) specimens, including 134 Klebsiella pneumoniae, 54 Escherichia coli, 27 Enterobacter cloacae, 8 Klebsiella oxytoca, 2 Klebsiella aerogenes, and 3 Citrobacter freundii, were collected from two tertiary hospitals (Xi'an, China). Using PCR sequencing techniques, 89 isolates and 29 BCB specimens were determined to be Enterobacterales harboring carbapenem-resistance genes. In comparison to the PCR sequencing results, the specificities with both the NG-Test Carba 5 and Xpert Carba-R assays were 100%; the sensitivities were 92.1% and 100%, respectively, for recovered isolates and 79.3% and 100% for BCB specimens. The NG-Test Carba 5 missed eight NDM, four OXA-48-like, and one IMP β-lactamases in specimens containing two or three carbapenemase types. In summary, the NG-Test Carba 5 assay may yield false-negative results if isolates or BCB specimens contain two or three carbapenemases.

Intercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

Obesity has caused wide concerns due to its high prevalence in patients with severe coronavirus disease 2019 (COVID-19). Coexistence of diabetes and obesity could cause an even higher risk of severe outcomes due to immunity dysfunction. We conducted a retrospective study in 1,637 adult patients who were admitted into an acute hospital in Wuhan, China. Propensity score–matched logistic regression was used to estimate the risks of severe pneumonia and requiring in-hospital oxygen therapy associated with obesity. After adjustment for age, sex, and comorbidities, obesity was significantly associated with higher odds of severe pneumonia (odds ratio [OR] 1.47 [95% CI 1.15–1.88]; P = 0.002) and oxygen therapy (OR 1.40 [95% CI 1.10–1.79]; P = 0.007). Higher ORs of severe pneumonia due to obesity were observed in men, older adults, and those with diabetes. Among patients with diabetes, overweight increased the odds of requiring in-hospital oxygen therapy by 0.68 times (P = 0.014) and obesity increased the odds by 1.06 times (P = 0.028). A linear dose-response curve between BMI and severe outcomes was observed in all patients, whereas a U-shaped curve was observed in those with diabetes. Our findings provide important evidence to support obesity as an independent risk factor for severe outcomes of COVID-19 infection in the early phase of the ongoing pandemic.

Liver cancer is one of the most important cancers that easily affects many organs in the body. Valproate is a well-known branched fatty acid and is commonly used as an antiepileptic in liver cancer therapy. Similar to many drugs, this chemical drug can induce fulminant liver failure in patients with liver cancer. So, finding new therapeutic agents with fewer side effects is of great attention. This study explains synthesis and characterization of a new effective nanocatalyst ZnO@SiO2–NH2, which can be a suitable candidate for valproate. The prepared nanocatalyst was characterized by FT-IR, TEM, XRD and FE-SEM and formation of the desired nanoparticles with a medium grain size of 70–90 nm is justified. Then, the synthesized nanocatalyst is checked in the multi-component synthesis of some important model drugs involving substituted 2-aminothiophenes, as effective compounds against human liver cancer. The present methodology showed good generality and wide scope, nearly short span of time, good yield, easy workup and environmental friendly conditions for the preparation of the target compounds. At the final part of this study, the in vitro cytotoxicity potential of the prepared nanoparticle is investigated against a well-known human cancer cell line HepG2 via the MTT assay. The experiments reveal that ZnO@SiO2–NH2 nanoparticles have significant cytotoxicity towards the selected cell line. As a result, although ZnO@SiO2–NH2 can be used to treat liver cancer cells, however, this nanoparticle can be utilized to synthesize 2-aminothiophenes, as effective anti-liver cancer drugs like valproate.

Objectives To evaluate the pharmacokinetics, pharmacodynamics, and tolerability of JY09, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, in healthy subjects. Materials and methods Healthy subjects were enrolled into 5 cohorts (0.3, 0.7, 1.5, 3.0, and 6.0 mg JY09) and received subcutaneous JY09 or placebo according to a randomized, double-blind, placebo-controlled, single-center, dose-escalating phase I trial design. Blood samples were collected over a 42-day period, and JY09 in plasma was determined by an electrochemical luminescence method. For the pharmacodynamic evaluation, oral glucose tolerance tests (OGTTs) were conducted predose and on day 5 after the target dose, during which plasma glucose, insulin, C-peptide, and glucagon concentrations were analyzed. Tolerability was assessed using physical examination and queries, vital sign measurements, laboratory analysis, and detection of immunogenicity. Results In healthy Chinese subjects, JY09 exhibited a dose-dependent increase in AUC0-inf and Cmax from 0.7 to 6.0 mg JY09. The half-life of JY09 was ~ 9.3 days, and the peak concentration was reached at ~ 60 - 72 hours. Following the OGTT, an increase in C-peptide concentration was observed after exposure to JY09 at the dose of 6.0 mg compared to the placebo group. JY09 was well tolerated in healthy Chinese subjects following a single dose of up to 6.0 mg. No symptomatic hypoglycemia was reported, and the most commonly observed adverse event was suppressed appetite, and its incidence was dose-dependent. Four subjects (13%) developed anti-JY09 antibodies. Conclusion JY09 has a long half-life of ~ 9.3 days, with an acceptable safety profile.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hypertension is a common comorbidity in hospitalized patients with COVID-19 infection. This study aimed to estimate the risks of adverse events associated with in-hospital blood pressure (BP) control and the effects of angiotensin II receptor blocker (ARB) prescription in COVID-19 patients with concomitant hypertension. In this retrospective cohort study, the anonymized medical records of COVID-19 patients were retrieved from an acute field hospital in Wuhan, China. Clinical data, drug prescriptions, and laboratory investigations were collected for individual patients with diagnosed hypertension on admission. Cox proportional hazards models were used to estimate the risks of adverse outcomes associated with BP control during the hospital stay. Of 803 hypertensive patients, 67 (8.3%) were admitted to the ICU, 30 (3.7%) had respiratory failure, 26 (3.2%) had heart failure, and 35 (4.8%) died. After adjustment for confounders, the significant predictors of heart failure were average systolic blood pressure (SBP) (hazard ratio (HR) per 10 mmHg 1.89, 95% confidence interval (CI): 1.15, 3.13) and pulse pressure (HR per 10 mmHg 2.71, 95% CI: 1.39, 5.29). The standard deviations of SBP and diastolic BP were independently associated with mortality and ICU admission. The risk estimates of poor BP control were comparable between patients receiving ARBs and those not receiving ARBs, with the only exception of a high risk of heart failure in the non-ARB group. Poor BP control was independently associated with higher risks of adverse outcomes of COVID-19. ARB drugs did not increase the risks of adverse events in hypertensive patients.

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

Objective Whether intensive therapy can alleviate subclinical synovitis and reduce flare in rheumatoid arthritis (RA) patients in clinical remission remains unclear. We designed a 1-year open-labelled, randomized controlled clinical trial to elucidate this question. Methods RA patients in clinical remission/low disease activity (defined by DAS28-CRP≤ 3.2), however with subclinical synovitis on ultrasound [power Doppler (PD)≥1 and/or gray scale (GS)≥2] were randomized to receive maintenance or intensive treatment at a ratio of 1:1. The primary outcome was the rate of RA relapse (defined by DAS28-CRP>3.2 and an increase≥0.6). The secondary outcomes were changes of PD and GS scores, and clinical disease activity at each visit from baseline. Results 108 patients with 54 in each group were enrolled. During 1-year follow-up, the relapse rate was significantly higher in maintenance group than in intensive group, regardless of all enrolled patients or those in remission [24.1% (13/54) vs. 9.1% (5/54), p=0.039; 26.2% (11/42) vs. 5.3% (2/38), p=0.026, respectively]. Although GS and PD scores were decreased at 12 months in both groups, the decline was more remarkable in intensive group than in maintenance group. The improvement of clinical disease activity score was only observed in intensive group, not maintenance group. Adverse events were comparable between two groups. Abnormal liver function tests were observed in 24 (22%) patients with 16 from intensive group. Conclusion Intensive therapy can alleviate subclinical synovitis on ultrasound and clinical disease activity, and prevent relapse in RA patients who have achieved clinical remission or low disease activity, with comparable safety profiles to maintenance therapy. Registration number ChiCTR2000029279

The pathogenesis of psoriasis is still not fully understood. Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and is implicated in various inflammatory conditions, but research regarding Drp1 in the skin is scarce. To examine Drp1 expression in psoriasis vulgaris lesional skin and the effect of Drp1 expression on keratinocyte proliferation and inflammatory mediator release in vitro. Skin biopsies were collected, and the expression of Drp1 and TNF-α was investigated in the skin. Serum TNF-α level was also examined. The effect of Drp1 on keratinocyte proliferation and inflammatory mediator release was evaluated in HaCaT cells following Drp1 transfection. The effect of TNF-α on Drp1 expression was also studied in HaCaT cells. Drp1 expression was significantly increased and positively correlated with PASI score and TNF-α expression in skin. In HaCaT cells, Drp1 transfection altered cellular ATP and proliferation, induced G2/M arrest, and affected inflammatory mediator (TNF-α, IL-6 and CXCL8) release. Moreover, TNF-α induced Drp1 expression and recovered cellular ATP content and mediator release. Drp1 is significantly elevated in psoriasis vulgaris skin and positively correlates with disease severity, moreover, in vitro, Drp1 regulates keratinocyte function.

The patient was an 88-year-old woman with a 10-year history of hypertension. She was suspected to have been hit by a car. At the time of the event, she was conscious and able to stand on her own and had no obvious injuries. She was sent home, but she lapsed into unconsciousness and was nonresponsive after 2 hours. She was sent to the hospital, and her heartbeat and breathing stopped. After half an hour of rescue attempts, her heartbeat did not recover, and she was declared dead. During the autopsy, a small subcutaneous hemorrhage was observed below the right knee joint. No obvious internal organ injuries or bone fractures were observed. The deceased also had mild atherosclerosis in the coronary arteries and an old cerebral infarction in the right cerebellum. The tissue histopathological tests showed distinct fat embolism in multiple organs, including the brain, lungs, kidneys, liver, and pancreas. A postmortem blood biochemistry test of the heart blood showed that the levels of low-density lipoprotein, cholesterol, triglycerides, and free fatty acids in the blood were increased, and the level of C-reactive protein was elevated. According to the autopsy results, the direct cause of death was multiorgan fat embolism. This case suggests that aging, hypertension, and hyperlipidemia may be risk factors for nontraumatic fat embolism under stressful conditions.

Significance Melanomas are notorious due to their propensity to form lethal metastases. Currently, no treatments are available to stop the metastatic spread. We observed that in malignant melanomas, a protein called the cyclin-dependent kinase 5 (CDK5) is essential for melanoma metastasis. Using mouse and human melanoma cells, we demonstrated that in this tumor type CDK5 promotes the metastatic spread by directly phosphorylating a mesenchymal-type intermediate filament, vimentin. We found that a genetic shutdown of CDK5 in a mouse model of melanoma abrogated metastasis, while chemical inhibition of CDK5 kinase in mice carrying patient-derived tumors impeded the metastatic spread of tumor cells. Our results indicate that inhibition of CDK5 might represent a therapeutic strategy to block the metastatic dissemination of melanoma cells.

Background Insulin resistance (IR) and lipid peroxidation are accepted as ‘two-hit’ hypothesis of Non-alcoholic fatty liver disease (NAFLD). However, there are few published research on identifying genes which connect lipid and glucose metabolism by gene microarray. Objective To identify target genes related to lipid and glucose metabolism that might be responsible for the pathogenesis of NAFLD. Methods A rat model of NAFLD was established by feeding male rats with high-fat diet and gene expression profiles of liver tissues were determined using Agilent DNA microarray. We then investigated differentially expressed genes (DEGs) and intersection of them by using Gene Ontology (GO) and Pathway Analyses. Target genes were verified by Real-time polymerase chain reaction (RT-PCR). Results Compared with control, 932 genes, including 783 up-regulated and 149 down-regulated, exhibited differences in expression. The up-regulated genes were involved in biosynthesis, cell development, cell differentiation and down-regulated genes contributed to biological metabolic process, adipokine metabolic pathway and insulin signaling pathway. We identified genes involved in insulin signaling pathway, Notch signaling pathway and lipid synthetic process to be closely related to liver fat accumulation and insulin resistance. Among them, IGFBP7, Notch1 and HMGCR were up-regulated (2.85-fold, 3.22-fold, and 2.06-fold, respectively, all P P Conclusions These findings provide innovative information on the whole genome expression profile due to high-fat diet feeding, and bring new insight into the regulating effects of genes on the lipid and glucose metabolism of NAFLD.

COVID-19 vaccines are of great importance in reducing SARS-CoV-2 infection and severe cases. Patients with autoimmune inflammatory rheumatic diseases (AIIRDs) have been strongly recommended to be vaccinated according to the novel guidance because they are more vulnerable to SARS-CoV-2 infection.1 However, patients with AIIRDs were largely excluded from vaccine trials, leading to very limited data on the safety of COVID-19 vaccines. Notably, previous studies mainly focused on mRNA and adenovirus vector vaccines; however, little is known about inactivated COVID-19 vaccines that also have been authorised by WHO and widely used in several most populated countries, for instance, China, Brazil, Turkey and Indonesia.2 A large randomised clinical trial consisting of 40 382 participants has demonstrated two inactivated COVID-19 vaccines significantly reduced the risk of symptomatic COVID-19.3 We conducted a real-world survey to evaluate the safety profiles and disease flare in patients with AIIRDs who received any dose of inactivated COVID-19 vaccines in China. From 1 Aug 2021 to 15 Oct 2021, eligible participants completed a predefined 25-question-based questionnaire by invitation on social media or visiting the outpatient department. There was no restriction on the time interval from vaccination to completing the survey. In total, 1507 adults patients with AIIRDs who received inactivated COVID-19 vaccine participated in this study (flow diagram …

Infantile hepatic hemangioma (IHH) is the most common benign liver tumor in infancy, some life-threatening complications like abdominal compartment syndrome, consumptive hypothyroidism and cardiac failure may occur in these patients. Hypothyroidism should be focused on and managed earlier to prevent intellectual and growth retardation. We described a 4 months old infant complaint of progressive abdominal distention, who was diagnosed with diffuse hepatic hemangiomas by ultrasonography and MRI, treated successfully with propranolol and levothyroxine for consumptive hypothyroidism. At 8 months old levothyroxine was stopped, she grew up with a normal growth trajectory and neurodevelopment at her last follow-up at the age of 13 months. Our study suggests that thyroid function should be evaluated even though negative neonatal screen and propranolol should be first-line agent for diffuse IHH. It is instrumental that simultaneous anti-tumor and thyroid replacement make diffuse IHH patients with consumptive hypothyroidism recovery better.

Background. Hepatocellular carcinoma (HCC) is a malignant tumor with poor prognosis. Immune checkpoint genes are considered novel tumor immunotherapy targets for many cancer types. Erythropoietin (EPO) is a protein secreted mainly in the liver and kidneys; in several cancer types, EPO expression stimulates tumor growth and corelates with patient survival. The study aimed to identify EPO as a prognostic biomarker correlated with immune infiltration in HCC. Methods. We investigated the correlation between EPO expression and HCC patient clinical characteristics using data from The Cancer Genome Atlas. The relationship between EPO expression and HCC patient survival was investigated using Kaplan–Meier analysis. We also used R (v.3.6.3) to analyze the correlation between EPO expression and immune infiltration in HCC. Results. We found that EPO expression was downregulated in HCC. Notably, EPO was upregulated in advanced-stage HCC and had a diagnostic value of 0.83 (p < 0.001) in HCC diagnosis. HCC patients with increased EPO expression had poor prognoses. Furthermore, altered EPO expression was associated with immune cell infiltration and immune checkpoint gene expression in HCC. Conclusions. EPO expression was positively correlated with hepatocellular carcinoma stage, and negatively correlated with patient prognosis, with influening HCC immune cell infiltration and checkpoint gene expression. EPO can be as both a potential prognostic biomarker and a novel potential treatment target for HCC.Our work is not a clinical trial, but preclinical basic study.

Background Chemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) function as important regulators in chemoresistance. This study aimed to explore the regulation of circRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A) in DDP resistance. Methods The expression analysis of circ_PIP5K1A, micoRNA-493-5p (miR-493-5p) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) was conducted through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell sensitivity was determined using 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell proliferation and cell viability were evaluated by colony formation assay and MTT assay, respectively. Cell cycle and apoptosis detection was performed via flow cytometry. Cell motility was examined by transwell migration or invasion assay. Dual-luciferase reporter assay was applied to confirm the target binding. ROCK1 protein level was assayed via Western blot. In vivo assay was carried out using xenograft model in mice. Results Circ_PIP5K1A level was abnormally increased in DDP-resistant NSCLC tissues and cells. Silencing circ_PIP5K1A reduced DDP resistance, proliferation, cell cycle progression and cell motility in DDP-resistant NSCLC cells. Circ_PIP5K1A directly interacted with miR-493-5p in NSCLC cells. The function of circ_PIP5K1A was dependent on the negative regulation of miR-493-5p. MiR-493-5p directly targeted ROCK1 and circ_PIP5K1A regulated the ROCK1 level via acting as a sponge of miR-493-5p. Overexpression of miR-493-5p inhibited chemoresistance and cancer progression by downregulating ROCK1 expression in DDP-resistant NSCLC cells. Circ_PIP5K1A regulated DDP sensitivity in vivo via the miR-493-5p/ROCK1 axis. Conclusion These findings suggested that circ_PIP5K1A upregulated the ROCK1 expression to promote DDP resistance and cancer progression in NSCLC by sponging miR-493-5p.

SCOPE Cereal vinegar sediment (CVS) is precipitation generated during the preservation of vinegar. It has various functions such as anti-inflammatory, anti-tumor, hypoglycemic, and hypolipidemic. This study evaluates the effects of CVS on spontaneous colitis in Il-10-/- mice. METHODS AND RESULTS CVS (1 g kg-1 body weight) is administered to mice for 42 days. CVS alleviated epithelium damage, inhibited myeloperoxidase (MPO) activity and malondialdehyde (MDA) level, decreased gene expression of tumor necrosis factor (Tnf )-a, inducible nitric oxide synthase (Inos), Interleukin(Il-23) in colon tissues is found. CVS also inhibited secretion of IL-2, IL-6, IL-13, Granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GMCSF), Interferon (IFN)-γ, and Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) in serum. While CVS enhanced Regenerating Family Member 3 Gamma (Reg3γ), Mucin (Muc2, Muc3, and Muc4 gene expression, promoted intestinal epithelial cells to secrete Muc-2, and increased the content of acetic acid in intestinal tract of Il-10-/- mice. Additionally, CVS altered the composition of the gut microbiota by promoting the abundance of Akkermansia, Alistipes, and Lactobacillus, while inhibiting Desulfovibrio and Clostridium sensu stricto 1. These changes may be related to the regulation of steroid, fatty acids, and bile acid biosynthesis. CONCLUSION This study demonstrated that CVS ameliorates spontaneous ulcerative colitis in Il-10-/- mice, which suggests CVS supplementation may serve as a protective dietary nutrient against colitis.

Transverse fracture of the skull base is common both in the crushing of temporal regions of the skull and in the case of force acting on one temporal region. However, the mechanism of transverse skull base fracture caused by maxillofacial force has not been fully clarified. To provide an injury identification basis for forensic pathologists and clinicians, this paper combines accident reconstruction and finite element analysis methods to study the injury mechanism of an incomplete transverse fracture of skull base after the injured individual’s mandible was subjected to violence in a traffic accident. The results show that after the injured individual’s mandible was subjected to violence, forces in the direction of the left mandibular fossa and the right mandibular fossa were generated, creating the component forces. The combination of the two forces can produce a crushing effect toward the center of the skull base, as if the left and right temporal regions are being crushed, and the stress is concentrated at the joint of the mandible, the middle cranial fossa and the hypophyseal fossa. When the stress exceeds a certain limit, it will cause a transverse fracture of the skull base.

This study aimed to assess the association of coagulation-related indicators such as plasma fibrinogen (FIB), d-dimer, and fibrin degradation product (FDP) in rheumatoid arthritis (RA) with the disease activity. Data from 105 RA patients and 102 age- and gender-matched healthy controls were collected in the retrospective study. Disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) was used to divide RA patients into low activity group (DAS28-CRP ≤ 2.7) and active group (DAS28-CRP > 2.7). Receiver operating characteristic (ROC) curve was applied to determine area under the curve (AUC). The association between plasma FIB, d-dimer, and FDP and DAS28-CRP was evaluated by spearman correlation. Logistical regression analysis was used to identify the independent variables associated with RA disease activity. RA patients showed higher levels of plasma FIB, d-dimer, and FDP than the controls (P d-dimer, and FDP were also increased in active groups of RA patients than those in inactive groups (P d-dimer was higher than erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF), and that of FDP was higher than RF in RA patients. In addition, the optimal cut-off value of plasma FIB, d-dimer, and FDP for RA diagnosis was 286 mg/dL, 470 μg/L, and 1.45 mg/L, respectively. Spearman analysis showed that plasma FIB, d-dimer, and FDP were positively related with DAS28-CRP (P d-dimer (odds ratio 2.862, 95% confidence interval 1.851–5.426, P d-dimer, and FDP were increased in RA patients and positively correlated with the disease activity of RA. d-dimer may act as a novel inflammatory indice for indicating disease activity in RA patients.

Background Highly expressed STOML2 has been reported in a variety of cancers, yet few have detailed its function and regulatory mechanism. This research aims to reveal regulatory mechanism of STOML2 and to provide evidence for clinical therapeutics, via exploration of its role in colorectal cancer, and identification of its interacting protein. Methods Expression level of STOML2 in normal colon and CRC tissue from biobank in Nanfang Hospital was detected by pathologic methods. The malignant proliferation of CRC induced by STOML2 was validated via gain-of-function and loss-of-function experiments, with novel techniques applied, such as organoid culture, orthotopic model and endoscopy monitoring. Yeast two-hybrid assay screened interacting proteins of STOML2, followed by bioinformatics analysis to predict biological function and signaling pathway of candidate proteins. Target protein with most functional similarity to STOML2 was validated with co-immunoprecipitation, and immunofluorescence were conducted to co-localize STOML2 and PHB. Pathway regulated by STOML2 was detected with immunoblotting, and subsequent experimental therapy was conducted with RAF inhibitor Sorafenib. Results STOML2 was significantly overexpressed in colorectal cancer and its elevation was associated with unfavorable prognosis. Knockdown of STOML2 suppressed proliferation of colorectal cancer, thus attenuated subcutaneous and orthotopic tumor growth, while overexpressed STOML2 promoted proliferation in cell lines and organoids. A list of 13 interacting proteins was screened out by yeast two-hybrid assay. DTYMK and PHB were identified to be most similar to STOML2 according to bioinformatics in terms of biological process and signaling pathways; however, co-immunoprecipitation confirmed interaction between STOML2 and PHB, rather than DTYMK, despite its highest rank in previous analysis. Co-localization between STOML2 and PHB was confirmed in cell lines and tissue level. Furthermore, knockdown of STOML2 downregulated phosphorylation of RAF1, MEK1/2, and ERK1/2 on the MAPK signaling pathway, indicating common pathway activated by STOML2 and PHB in colorectal cancer proliferation. Conclusions This study demonstrated that in colorectal cancer, STOML2 expression is elevated and interacts with PHB through activating MAPK signaling pathway, to promote proliferation both in vitro and in vivo. In addition, combination of screening assay and bioinformatics marks great significance in methodology to explore regulatory mechanism of protein of interest.

Objective To investigate the frequency and determinants of achieving the lupus low disease activity state (LLDAS), and the effect of LLDAS attainment on disease flare and damage accrual in a prospective, single-center cohort of Chinese lupus patients. Methods Baseline and follow-up data from consecutive patients at the Peking University First Hospital were collected from January 2017 to June 2020. Results A total of 185 patients were enrolled, with median (range) disease duration at enrolment of 2.3 (0.8–7.7) years, and median follow-up of 2.2 (1.0–2.9) years. By the end of the study, 139 (75.1%) patients had achieved LLDAS at least once; 82 (44.3%) patients achieved LLDAS for ≥ 50% of observations. Multivariable logistic regression analysis showed that 24-h urinary total protein (UTP; per g) (OR = 0.447, 95%CI [0.207–0.968], p = 0.041), serum creatinine (Scr; per 10 µmol/L) (OR = 0.72, 95%CI [0.52–0.99], p = 0.040), and C3 level (per 100 mg/L) (OR = 1.60, 95%CI [1.18–2.17], p = 0.003) at recruitment had independent negative associations with achieving LLDAS for ≥ 50% of observations. Kaplan–Meier analyses showed a significant reduction in flare rate with increased proportion of time in LLDAS. Attainment of LLDAS in at least 50% of observations was an independent protective factor for damage accrual (OR = 0.19, 95%CI [0.04–0.99], p = 0.049). Conclusions In this prospective Chinese cohort, LLDAS was an attainable goal in clinical practice. Nephritis-related markers (UTP and Scr) and C3 level at recruitment negatively influenced achievement of LLDAS. LLDAS achievement was significantly protective from flare and damage accrual. Key points • Low disease activity status (LLDAS) is an achievable target during SLE treatment in China. Urine protein, serum creatinine, and C3 level at recruitment independently affect LLDAS achievement in this group of Chinese lupus patients. • As a treatment target, LLDAS achievement has a highly protective effect for preventing flare and damage accrual, especially in case of achieving LLDAS for ≥ 50% of observations. • The present results further highlight the practical significance of treat-to-target principle in SLE management (T2T/SLE) and the needs for promoting the application of T2T/SLE in clinical practice as well as exploring the concrete implement strategy.

A full-term female baby born with an Apgar score of 10 exhibited a continual decrease in blood glucose and acid-base imbalance until she died at 40 h postpartum despite emergency rescue efforts. Autopsy showed a highly oedematous brain and a swollen liver. The cells of the myocardium, liver and kidney exhibited extensive microscopic vacuolar degeneration. The cardiac muscle and liver and kidney tissues were positive for Sudan III staining. Tandem mass spectrometry analysis revealed that the deceased was deficient in free carnitine, accompanied by an increase in multiple acylcarnitines. Genetic testing showed the parents of the deceased to be ETFDH mutation carriers, and the deceased carried a complex heterozygous mutation in ETFDH. Therefore, based on the results of autopsy, specific staining, genetic metabolic disease testing and genetic testing, we speculated that glutaric aciduria type IIc was the cause of death.

Dexmedetomidine (DEX) has been demonstrated to inhibit inflammatory response and protect against multiorgan injury in various scenarios. The objectives of the present study were to ascertain whether DEX is able to attenuate acute lung injury (ALI) under heatstroke (HS), and to explore the underlying mechanism.Male C57BL/6 mice were exposed to ambient temperature of 39.5 ± 0.2°C until core temperature reach 43°C. DEX or 0.9% saline was injected i.p. immediately. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lung tissue were harvested.HS induce ALI and pulmonary dysfunction, while DEX treatment could significantly inhibit lung injury and improve respiratory dysfunction under HS. The overall effect was beneficial and improved the 72 h cumulative survival rate of mice with HS. Furthermore, HS significantly elevated the levels of cytokines in BALF, as well as increased the activity of toll-like receptor 4 (TLR4)/MyD88/nuclear factor-κB (NFκB) signaling pathway in lung tissue, while DEX treatment could inhibit such effects. Finally, DEX could upregulate the expression of caveolin 1 downregulated by HS, which may contribute to the inhibition of TLR4/MyD88/NFκB signaling pathway.In conclusion, the present results indicated that DEX may protect against lung inflammatory response and injury under HS via TLR4/MyD88/NFκB signaling pathway, and caveolin-1 may participate in the effects.