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BackgroundTongue cancer, as one of the most malignant oral cancers, is highly invasive and has a high risk of recurrence. At present, tongue cancer is not obvious and easy to miss the opportunity for early diagnosis when in the advanced stage. It is important to find markers that can predict the occurrence and progression of tongue cancer.MethodsBioinformatics analysis plays an important role in the acquisition of marker genes. GEO and TCGA data are very important public databases. In addition to expression data, the TCGA database also contains corresponding clinical data. In this study, we screened three GEO data sets that met the standard, which included GSE13601, GSE34105, and GSE34106. These data sets were combined using the SVA package to prepare the data for differential expression analysis, and then the limma package was used to set the standard to p ResultsA total of 170 differentially expressed genes (DEGs) were identified. In addition, the DEseq package was used for differential expression analysis using the same criteria for samples in the TCGA database. It ended up with 1,589 DEGs (644 upregulated, 945 downregulated). By merging these two sets of DEGs, 5 common upregulated DEGs (CCL20, SCG5, SPP1, KRT75, and FOLR3) and 15 common downregulated DEGs were obtained.ConclusionsFurther functional analysis of the DEGs showed that CCL20, SCG5, and SPP1 are closely related to prognosis and may be a therapeutic target of TSCC.

Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8−/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P

Xi-Yu Yao,1,* Yan Zhou,2,* Shun-Jin Chen,1 Yu Wu,1 Cong Bian,1 Hongbin Chen,1 Hui Liu1 1Department of Head and Neck Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, People’s Republic of China; 2Department of Epidemiology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui LiuDepartment of Head and Neck Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, People’s Republic of ChinaTel +86 138 0506 9511Email liuhuifj@sina.comPurpose: To investigate whether there is a pattern of recovery of parathyroid function after thyroid cancer surgery.Patients and Methods: The study included 183 patients with papillary thyroid cancer (PTC) who underwent “total thyroidectomy (TT)” plus “unilateral central lymph node dissection (UCLND)” or “bilateral central lymph node dissection (BCLND)”. The intact parathyroid hormone (iPTH) and serum calcium (sCa) were analyzed several times within 1 month after surgery to explore the recovery pattern of parathyroid gland function. Then, these 183 cases were divided into group A (97 cases) with UCLND and group B (86 cases) with BCLND to analyze whether the impairment and recovery of parathyroid function were different between the two subgroups.Results: Postoperative hypoparathyroidism was seen in 115 out of 183 cases. iPTH values decreased significantly on postoperative day (POD) 1 compared with preoperative values, dropped to the lowest point on POD 3, showed an increasing trend on POD 5 and 14, and increased to 85.0% of preoperative values at POD30, whereas changes in sCa differ from changes in iPTH, which showed the lowest sCa value on POD1, and rebounded on the POD3 with the intervention of calcium supplementation, and continued to rise on the POD5 and POD14, and the sCa value reached 96.6% of the preoperative level at POD30. Subgroup analysis showed that temporary hypoparathyroidism was more pronounced in group B than in group A. SCa and iPTH levels in both subgroups showed the same trend of first decrease and then increase.Conclusion: The recovery of hypocalcemia and hypo-iPTHemia in the first month after thyroid cancer surgery shows a trend of decreasing and then increasing, and knowing the recovery of parathyroid function at different time points is of great value to surgeons and patients alike.Keywords: hypoparathyroidism, hypocalcaemia, parathyroid hormone, thyroid carcinoma, thyroidectomy, lymph node dissection

BackgroundType D personality and depression are the independent psychological risk factors for adverse outcomes in cardiovascular patients. The aim of this study was to examine the combined effect of Type D personality and depression on clinical outcomes in patients suffering from acute myocardial infarction (AMI).MethodsThis prospective cohort study included 3568 patients diagnosed with AMI between February 2017 and September 2018. Type D personality and depression were assessed at baseline, while the major adverse cardiac event (MACE) rate (cardiac death, recurrent non-fatal myocardial infarction, revascularization, and stroke) and in-stent restenosis (ISR) rate were analyzed after a 2-year follow-up period.ResultsA total of 437 patients developed MACEs and 185 had ISR during the follow-up period. The Type D (+) depression (+) and Type D (+) depression (−) groups had a higher risk of MACE [95% confidence interval (CI) 1.74–6.07] (95% CI 1.25–2.96) and ISR (95% CI 3.09–8.28) (95% CI 1.85–6.22). Analysis of Type D and depression as continuous variables indicated that the main effect of Type D, depression and their combined effect were significantly associated with MACE and ISR. Moreover, Type D (+) depression (+) and Type D (+) depression (−) emerged as significant risk factors for MACE and ISR in males, while only Type D (+) depression (+) was associated with MACE and ISR in female patients.ConclusionsThese findings suggest that patients complicated with depression and Type D personality are at a higher risk of adverse cardiovascular outcomes. Individual assessments of Type D personality and depression, and comprehensive interventions are required.

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

In the normal lung tissues, hsa_circ_0030998 get a balance level. Our study verified that the downregulated hsa_circ_0030998 can inhibit proliferation, migration, invasion and Taxol resistance by sponging miR‐558 in lung cancer. Therefore, the hsa_circ_0030998/miR‐558 axis might be a possible diagnostic and therapeutic target in lung cancer patients., Circular RNAs (circRNAs) are single‐stranded RNAs which form a covalently closed continuous loop. Although originally shown to be non‐protein‐coding, some circRNAs can give rise to micropeptides. circRNAs have also been shown to play essential regulatory roles in a variety of developmental and disease processes. In a previous study, hsa_circ_0030998 was identified as a circRNA downregulated in lung cancer, but its potential implications and mechanisms in lung cancer were not addressed. Here, we showed that overexpressing circ_0030998 decreased proliferation, migration, and invasion of lung cancer cells, while also dampening resistance to Taxol, a classical antitumor drug. Depleting circ_0030998 reversed these phenotypic effects. A high circ_0030998 expression was correlated with a high survival rate in lung cancer patients. Additionally, we found circ_0030998 could downregulate miR‐558 expression, serving as a microRNA sponge. In conclusion, our data support that hsa_circ_0030998 can slow down the progression of lung cancer by targeting miR‐558 and suppress malignant phenotypes such as proliferation, migration, and invasion progression of lung cancer cells. Therefore, we highlight that circ_0030998 could be a novel tumor suppressor of lung cancer.

Background The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. Methods Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. Results The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42–0.66, p Conclusion NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

Background Chemotherapy-induced premature menopause leads to some consequences, including infertility. We initiated this randomized phase III trial to determine whether a cyclophosphamide-free adjuvant chemotherapy regimen would increase the likelihood of menses resumption and improve survival outcomes. Methods Young women with operable estrogen receptor-positive HER2-negative breast cancer after definitive surgery were randomly assigned to receive adjuvant epirubicin and cyclophosphamidefollowed by weekly paclitaxel (EC-wP) or epirubicin and paclitaxel followed by weekly paclitaxel (EP-wP). All patients received at least 5-year adjuvant endocrine therapy after chemotherapy. Two coprimary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year disease-free survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT01026116). All statistical tests were 2-sided. Results Between January 2011 and December 2016, 521 patients (median age = 34 years; interquartile range = 31-38 years) were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. The rate of menstrual resumption at 12 months after chemotherapy was 48.3% in EC-wP (95% confidence interval [CI] = 42.2% to 54.3%) and 63.1% in EP-wP (95% CI = 57.2% to 68.9%), with an absolute difference of 14.8% (95% CI = 6.37% to 23.2%, P Conclusions The cyclophosphamide-free chemotherapy regimen might be associated with a higher probability of menses resumption.

Recent evidence suggests that melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), a neuronal class regulating non-image forming (NIF) vision and generally thought to be injury resistant, are dysfunctional in certain neurodegenerative diseases. Although disrupted NIF visual functions have been reported in patients and animals with diabetes, it remains controversial whether ipRGCs exhibit remodeling during diabetes and if so, whether such remodeling is variable among ipRGC subtypes. Here, we demonstrate that survival, soma-dendritic profiles, and melanopsin-based functional activity of M1 ipRGCs were unaltered in streptozotocin-induced 3-month diabetic mice. Such resistance remained at 6 months after streptozotocin administration. In contrast, M2/M3 ipRGCs underwent significant remodeling in diabetic mice, manifested by enlarged somata and increased dendritic branching complexity. Consistent with the unaltered melanopsin levels, the sensitivity of melanopsin-based activity was unchanged in surviving M2 cells, but their response gain displayed a compensatory enhancement. Meanwhile, the pupillary light reflex, a NIF visual function controlled by M2 cells, was found to be impaired in diabetic animals. The resistance of M1 cells might be attributed to the adjacency of their dendrites to capillaries, which makes them less disturbed by the impaired retinal blood supply at the early stage of diabetes.

Aortic dissection (AD) is a life-threatening clinical emergency requiring rapid diagnosis and effective intervention to improve patient survival and prognosis. Computed tomography angiography (CTA) can be used to diagnose AD accurately and quickly, making it the first choice for diagnosing AD in an emergency. This article reviews the application of CTA in the diagnosis and treatment of AD.

Lead (Pb) is an environmental contaminant that primarily affects the central nervous system, particularly the developing brain. Recently, increasing evidence indicates the important roles of histone deacetylases (HDACs) in Pb-induced neurotoxicity. However, the precise molecular mechanisms involving HDAC4 remains unknown. The purpose of this study was to investigate the role of HDAC4 in Pb-induced neurotoxicity both in vivo and in vitro. In vitro study, PC12 cells were exposed to Pb (10 μM) for 24 h, then the mRNA and protein levels of HDAC4 were analyzed. In vivo study, pregnant rats and their female offspring were treated with lead (50 ppm) until postnatal day 30. Then the pups were sacrificed and the mRNA and protein levels of HDAC4 in the hippocampus were analyzed. The results showed that HDAC4 was significantly increased in both PC12 cells and rat hippocampus upon Pb exposure. Blockade of HDAC4 with either LMK-235 (an inhibitor of HDAC4) or shHDAC4 (HDAC4-knocking down plasmid) ameliorated the Pb-induced neurite outgrowth deficits. Interestingly, HDAC4 was aberrantly accumulated in the nucleus upon Pb exposure. By contrast, blocking the HDAC4 shuffling from the cytosol to the nucleus with ΔNLS2-HDAC4 (the cytosol-localized HDAC4 mutant) was able to rescue the neuronal impairment. In addition, Pb increased PP1 (protein phosphatase 1) expression which in turn influenced the subcellular localization of HDAC4 by dephosphorylation of specific serine/threonine residues. What's more, blockade of PP1 with PP1-knocking down construct (shPP1) ameliorated Pb-induced neurite outgrowth deficits. Taken together, nuclear accumulation of HDAC4 by PP1-mediated dephosphorylation involved in Pb-induced neurotoxicity. This study might provide a promising molecular target for medical intervention with environmental cues.

An 8-year-old, castrated male, Jack Russell Terrier was presented with clinical signs of uveitis and glaucoma in the right eye (oculus dexter (OD)) for 2–3 months. Ophthalmic examination revealed OD episcleral congestion, corneal vascularization, aqueous flare, iris bombe, and vision loss. OD glaucoma and uveitis were under control by medical treatment. After 8 months, the dog had acute uveitis in the left eye (oculus sinister (OS)). General physical examination, blood examinations, radiography, and urinalysis were unremarkable. No improvement was observed after for 1 month of uveitis treatment, and more examinations were strongly suggested. Abdominal ultrasonography revealed several hypoechoic masses or cysts on both kidneys. Computed tomography (CT) showed diffuse nonenhancing hypodense patches in both kidneys. Renal tumor was highly suspected, but biopsy was declined by the owner. Ten days after CT examination, the dog suddenly developed anorexia, weakness, uremia, hyperkalemia, and polycythemia. The dog was euthanatized because of the worsening clinical condition, poor prognosis, and financial constraints, and both kidneys were biopsied for histopathology. Immunohistochemically, the neoplastic cells were positive for B-cell marker (CD20) and negative for T-cell marker (CD3). Bilateral renal B-cell origin lymphoma was diagnosed by histologic and immunophenotyping examinations. In conclusion, bilateral renal lymphoma may be diagnosed with no systemic signs except bilateral uveitis. Renal function impairment was acutely developed with severe clinical signs at the end stage of the disease. Early, aggressive, complete examinations, and treatments are strongly recommended.

Cadmium (Cd) is an occupational and environmental heavy metal pollutant derived from many sources that is linked to endothelial homeostasis. The endothelium is an important site of Cd deposition, while increasing evidence has revealed there is a close relationship between endothelial dysfunction and abnormal lipid metabolism. However, the effects of the alterations in lipid metabolism on endothelial cells (ECs) after Cd exposure still remain unclear. In our study, human microvascular endothelial cells (HMEC-1) were exposed to 40-μM Cd for 6, 12, or 24 h or 10-, 20-, or 40-μM Cd for 24 h, respectively. The Cd exposure accelerated the decomposition of triglyceride (TG) and resulted in the accumulation of free fatty acids (FFAs). These changes stimulated cytotoxicity, impaired fatty acid oxidation (FAO), induced reactive oxygen species (ROS) generation, altered the mitochondrial membrane potential (MMP), and decreased the ATP content, which eventually led to endothelial dysfunction and cell death. In summary, exposure to cadmium caused endothelial dysfunction by disrupting lipid metabolism in HMEC-1. These changes were mainly due to FFA accumulation and FAO inhibition, which further induced ROS generation and mitochondrial dysfunction. Moreover, our results provide novel insight into understanding the alterations of lipid metabolism induced by Cd exposure in ECs.

In this study, we used bioinformatics tools to analyze transcriptome data from cholangiocarcinoma (CCA) patients in multiple datasets (Sun Yat-sen University, TCGA and GSE32225 cohorts) to identify mechanisms that regulate tumor infiltration by immune cells and survival outcomes. We identified 96 differentially expressed genes (DEGs), including 13 upregulated and 83 downregulated genes, in CCA tissues as regulatory T cells were significantly higher and the proportions of activated natural killer cells and monocytes were significantly lower in CCA tissues than the precancerous tissues. The survival outcomes of CCA patients were associated with the TP53 gene mutation status, levels of Oncostatin M (OSM) expression, and the proportions of tumor-infiltrating immune cell types, including dendritic cells, monocytes, and T follicular helper cells. Functional enrichment analysis of the DEGs in the high OSM-expressing CCA tissues showed that pathways related to tumor progression and immune response were significantly upregulated. Our study demonstrates that OSM expression and TP53 mutation status regulate the tumor infiltration by immune cells and survival outcomes in CCA. OSM is thus a potential prognostic biomarker and therapeutic target in cholangiocarcinoma.

OBJECTIVE Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies. METHODS An imiquimod-induced model of SLE was tested in GSDMD-/- mice (n = 30), with wild-type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane-induced lung injury in GSDMD-/- mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice. RESULTS Unexpectedly, GSDMD-/- mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane-induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti-double-stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo. CONCLUSION GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.

The study was aimed to analyse the effects of miR-128 on the proliferation and apoptosis of lung cancer cells of non-small cell by regulating RECK. The expression of miR-128 in non-small cell lung cancer (NSCLC) and its paracancerours tissues was analyzed by sequencing. miR-128 expression level in NSCLC and its paracancerours tissues was detected by qPCR. We over expressed miR-128 by mimics in A549 NSCLC cell line. Establish blank and negative control group. miR-128 and RECK expression level in each group was detected by qPCR. Use MTT assay to test the proliferation ability of each group. The apoptosis level and the level of ROS in each group were tested by hoechst 33258. The expression level of apoptosis-related protein and p38 NF- B signal pathway-related protein in each group was tested by Western blot. The results of sequencing and qPCR showed that compared with the blank control group, the expression level of miR-128 mRNA was significantly higher in the adjacent tissues than in the adjacent tissues (P < 0 05). The expression levels of miR128 mRNA and RECK mRNA in the overexpression group were significantly increased (P

Objective Relatively little is known about the natural history of atherosclerotic common carotid artery occlusion and optimal treatment of these patients is still unclear. The aim of this retrospective study was to evaluate the immediate- and long-term outcomes of axillary to carotid bypass with polytetrafluoroethylene graft for symptomatic patients with chronic common carotid artery occlusion. Methods From March 2001 to December 2017, 58 symptomatic patients (41 men; mean age 64.7 years) with chronic common carotid artery occlusion underwent axillary to carotid bypass at one academic hospital. The clinical data of this patient cohort were retrospectively analyzed. The cumulative graft patency, overall survival, freedom from symptoms, and freedom from ipsilateral stroke were calculated with Kaplan-Meier method. Results Thirty-three patients presented with transient ischemic attack and 25 patients presented with minor stroke. At 30 days after bypass, the overall perioperative complication rate was 3.4% (2/58). Mild injuries of brachial plexus occurred in one (1.7%) patient and myocardial infarction occurred in one (1.7%) patient. No perioperative stroke or death occurred. The median follow-up was 51 months (range, 12-203) for this series. The cumulative graft patency rates at 1, 3, 5, and 10 years were 100%, 100%, 94%, and 83%, respectively. The cumulative freedom from symptoms rates at 1, 3, 5, and 10 years were 100%, 100%, 94%, and 75%, respectively. The cumulative freedom from ipsilateral stroke rates at 1, 3, 5, and 10 years were 100%, 100%, 94%, and 82%, respectively. The overall survival rates at 1, 3, 5, and 10 years were 98%, 89%, 81%, and 67%, respectively. Conclusions Axillary to carotid bypass with polytetrafluoroethylene graft is safe and durable for symptomatic patients with chronic common carotid artery occlusion. The results of this study should be confirmed with a larger, randomized controlled trial in future.

Arthropod vectors serve as native reservoirs and transmitters of hundreds of arboviruses. In arthropod vectors, symbiotic microorganisms residing in the gut lumen and/or hemocoelic tissues maintain complicated relationships with their host and influence multiple aspects of vector physiology. Recently, accumulating evidence has established an important role for symbiotic microorganisms in vector-virus interactions which could potentially be used to control viral transmission. Herein, we review recent progress on symbiotic microbe-arbovirus interactions and summarize the molecular mechanisms by which commensal microbes act on hosts and arboviruses. Understanding the sophisticated interactions among arthropod vectors, microbiota, and arboviruses may offer new strategies for the prevention of arboviral diseases in the future.

To evaluate the clinical efficacy and safety of Congrong Shujing Granules (苁蓉舒 痉颗粒, CSGs) in treating patients with Parkinson’s disease (PD) and Chinese medicine (CM) syndrome of Shen (Kidney) essence deficiency, and to investigate the potential mechanism involving efficacy through a transcriptome sequencing approach. Eligible PD patients with syndrome of Shen essence defificiency were randomly assigned to a treatment group or a control group by a random number table, and were treated with CSGs combined with Western medicine (WM), or placebo combined with WM, respectively. Both courses of treatment lasted for 12 weeks. The Unifified Parkinson’s Disease Rating Scale (UPDRS) score, the PD Question-39 (PDQ-39) score, CM Syndrome Scale score, and drug usage of all patients were evaluated before and after treatment. Safety was evaluated by clinical laboratory tests and electrocardiographs. Blood samples from 6 patients in each group were collected before and after the trial and used for transcriptomic analysis by gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Differentially expressed genes were validated using reverse transcription-polymerase chain reaction. A total of 86 PD patients were selected from the Third Affifiliated People’s Hospital of Fujian University of Traditional Chinese Medicine between January 2017 and December 2017. Finally, 72 patients completed the trial, including 35 in the treatment group and 37 in the control group. When compared with the control group after treatment, patients in the treatment group showed signifificant decreases in UPDRS sub-II score, PDQ-39 score, CM syndrome score, and Levodopa equivalent dose (P 0.05). A possible mechanism of clinical effificacy was proposed that involved regulating cell metabolism-related processes and ribosome-related pathways. Treatment with CSGs had shown to affect relevant gene loci for PD, including AIDA, ANKRD36BP2, BCL2A1, BCL2L11, FTH1P2, GCH1, HPRT1, NFE2L2, RMRP, RPS7, TGFBR1, WIPF2, and COX7B. CSGs combined with WM can be used to treat PD patients with CM syndrome of Shen essence defificiency with a good safety. The possible mechanism of action and relevant gene loci were proposed. (Registration No. ChiCTR-IOR-16008394)

Background This study aimed to investigate the effect of matrix metalloproteinase-9 (MMP-9) copy number variations (CNVs) on hepatocellular carcinoma (HCC) poor prognosis and recurrence. Methods A total of 35 patients were collected between January 2016 and December 2018. The copy number and expression level of MMP-9 were measured in 35 HCC tumor tissues and 35 paired adjacent non-tumor tissues using digital polymerase chain reaction (dPCR) and quantitative reverse transcription polymerase chain reaction (RT-qPCR), respectively. Results Our results showed that MMP-9 expression was significantly upregulated in HCC tumor tissues compared to adjacent non-tumor tissues (5.521±9.545 versus 1.000±0.000, P=0.0047). Interestingly, MMP-9 CNVs only existed in tumor tissues (15/35 versus 0/35, P=0.002). A breakdown analysis by the occurrence of CNVs in tumor tissues had shown that there were significant differences between CNVs group and non-CNVs group in the expression levels of tissue alpha-fetoprotein (AFP) (P=0.015), tumor size (P

Background: This study aimed to investigate the association of circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH) expression with disease risk, clinical characteristics, progression-free survival (PFS) and overall survival (OS) of multiple myeloma (MM), and to explore the influence of circ-ITCH overexpression on MM cell activities n vitro . Methods: Bone marrow samples from 92 MM patients and 30 healthy controls were collected, and circ- ITCH expression was detected by quantitative polymerase chain reaction. PFS and OS in MM patients were calculated. Circ-ITCH in human MM cell lines and normal bone marrow mononuclear cells (BMMCs) were detected. Circ-ITCH overexpression and control overexpression plasmids were transfected to U226 cell line, and cell proliferation as well as apoptosis were assessed. Results: Circ-ITCH expression was under-expressed in MM patients compared to healthy controls. And receiver operating characteristic curve displayed that circ-ITCH could distinguish MM patients from healthy controls [area under curve: 0.809 (95% CI: 0.722–0.895)]. Additionally, circ-ITCH high expression was associated with decreased International Staging System (ISS) stage in MM patients. Kaplan-Meier curves and Cox’s regression analysis displayed that circ-ITCH expression was positively correlated with PFS and OS. In vitro , circ-ITCH expression was lower in MM cell lines (including RPMI8226, U226 and NCI-H929) compared to normal BMMCs. In U226 cells, cell proliferation was decreased but apoptosis was elevated by circ-ITCH overexpression. Conclusions: Circ-ITCH might serve as a potential biomarker and treatment target for MM.

Background: To explore the prediction value of PI-RADS v2 in high-grade prostate cancer and establish a prediction model combined with related variables of prostate cancer. Material and Methods: A total of 316 patients with newly discovered prostate cancer at Zhongnan Hospital of Wuhan University and Renmin Hospital of Wuhan University from December 2017 to August 2019 were enrolled in this study. The clinic information as age, tPSA, fPSA, prostate volume, Gleason score and PI-RADS v2 score have been collected. Univariate analysis was performed based on every variable to investigate the risk factors of high-grade prostate cancer. ROC curves were generated for the risk factors to distinguish the cut-off points. Logistic regression analyses were used to investigate the independent risk factors of high-grade prostate cancer. Nomogram prediction model was generated based on multivariate logistic regression analysis. The calibration curve, ROC curve, leave-one-out cross validation and independent external validation were performed to evaluate the discriminative ability, accuracy and stability of the nomogram prediction model. Results: Of 316 patients, a total of 187 patients were diagnosed as high-grade prostate cancer. Univariate analysis showed tPSA, fPSA, prostate volume, PSAD and PI-RADS v2 score were significantly different between the high- and low-grade prostate cancer patients. Univariate and multivariate logistic regression analyses showed only tPSA, prostate volume and PI-RADS v2 score were the independent risk factors of high-grade prostate cancer. The nomogram could predict the probability of high-grade prostate cancer, with a sensitivity of 79.4% and a specificity of 77.6%. The calibration curve displayed good agreement of the predicted probability with the actual observed probability. AUC of the ROC curve was 0.840 (0.797-0.884). Leave-one-out cross validation indicated the nomogram prediction model could classify 81.4% cases accurately. External data validation was performed with a sensitivity of 80.6% and a specificity of 77.3%, the Kappa value was 0.5755. Conclusions: PI-RADS v2 score had the value in predicting high-grade prostate cancer and the nomogram prediction model may help early diagnose the high risk prostate cancer.

Background Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular morbidity and mortality worldwide. Pyroptosis is a form of inflammatory cell death that plays a major role in the development and progression of cardiac injury in AMI. However, the underlying mechanisms for the activation of pyroptosis during AMI are not fully elucidated. Methods and Results Here we show that RBP4 (retinol‐binding protein 4), a previous identified proinflammatory adipokine, was increased both in the myocardium of left anterior descending artery ligation‐induced AMI mouse model and in ischemia‐hypoxia‒induced cardiomyocyte injury model. The upregulated RBP4 may contribute to the activation of cardiomyocyte pyroptosis in AMI because overexpression of RBP4 activated NLRP3 (nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3) inflammasome, promoted the precursor cleavage of Caspase‐1, and subsequently induced GSDMD (gasdermin‐D)‐dependent pyroptosis. In contrast, knockdown of RBP4 alleviated ischemia‐hypoxia‒induced activation of NLRP3 inflammasome signaling and pyroptosis in cardiomyocytes. Mechanistically, coimmunoprecipitation assay showed that RBP4 interacted directly with NLRP3 in cardiomyocyte, while genetic knockdown or pharmacological inhibition of NLRP3 attenuated RBP4‐induced pyroptosis in cardiomyocytes. Finally, knockdown of RBP4 in heart decreased infarct size and protected against AMI‐induced pyroptosis and cardiac dysfunction in mice. Conclusions Taken together, these findings reveal RBP4 as a novel modulator promoting cardiomyocyte pyroptosis via interaction with NLRP3 in AMI. Therefore, targeting cardiac RBP4 might represent a viable strategy for the prevention of cardiac injury in patients with AMI.

The presence of microvascular invasion (MVI) is a critical determinant of early hepatocellular carcinoma (HCC) recurrence and prognosis. We developed a nomogram model integrating clinical laboratory examinations and radiological imaging results from our clinical database to predict microvascular invasion presence at preoperation in HCC patients. 242 patients with pathologically confirmed HCC at the Ningbo Medical Centre Lihuili Hospital from September 2015 to January 2021 were included in this study. Baseline clinical laboratory examinations and radiological imaging results were collected from our clinical database. LASSO regression analysis model was used to construct data dimensionality reduction and elements selection. Multivariate logistic regression analysis was performed to identify the independent risk factors associated with MVI and finally a nomogram for predicting MVI presence of HCC was established. Nomogram performance was assessed via internal validation and calibration curve statistics. Decision curve analysis (DCA) was conducted to determine the clinical usefulness of the nomogram model by quantifying the net benefits along with the increase in threshold probabilities. Survival analysis indicated that the probability of overall survival (OS) and recurrence-free survival (RFS) were significantly different between patients with MVI and without MVI (P 0.05). Histopathologically identified MVI was found in 117 of 242 patients (48.3%). The preoperative factors associated with MVI were large tumor diameter (OR = 1.271, 95%CI: 1.137-1.420, P 0.001), AFP level greater than 20 ng/mL (20-400 vs. ≤ 20, OR = 2.025, 95%CI: 1.056-3.885, P = 0.034; 400 vs. ≤ 20, OR = 3.281, 95%CI: 1.661-6.480, P = 0.001), total bilirubin level greater than 23 umol/l (OR = 2.247, 95%CI: 1.037-4.868, P = 0.040). Incorporating tumor diameter, AFP and TB, the nomogram achieved a better concordance index of 0.725 (95%CI: 0.661-0.788) in predicting MVI presence. Nomogram analysis showed that the total factor score ranged from 0 to 160, and the corresponding risk rate ranged from 0.20 to 0.90. The DCA showed that if the threshold probability was 5%, using the nomogram to diagnose MVI could acquire much more benefit. And the net benefit of the nomogram model was higher than single variable within 0.3-0.8 of threshold probability. In summary, the presence of MVI is an independent prognostic risk factor for RFS. The nomogram detailed here can preoperatively predict MVI presence in HCC patients. Using the nomogram model may constitute a usefully clinical tool to guide a rational and personalized subsequent therapeutic choice.

Structural MRI (sMRI) has been widely used to examine the cerebral changes that occur in Parkinson's disease (PD). However, previous studies have aimed for brain changes at the group level rather than at the individual level. Additionally, previous studies have been inconsistent regarding the changes they identified. It is difficult to identify which brain regions are the true biomarkers of PD. To overcome these two issues, we employed four different feature selection methods [ReliefF, graph-theory, recursive feature elimination (RFE), and stability selection] to obtain a minimal set of relevant features and nonredundant features from gray matter (GM) and white matter (WM). Then, a support vector machine (SVM) was utilized to learn decision models from selected features. Based on machine learning technique, this study has not only extended group level statistical analysis with identifying group difference to individual level with predicting patients with PD from healthy controls (HCs), but also identified most informative brain regions with feature selection methods. Furthermore, we conducted horizontal and vertical analyses to investigate the stability of the identified brain regions. On the one hand, we compared the brain changes found by different feature selection methods and considered these brain regions found by feature selection methods commonly as the potential biomarkers related to PD. On the other hand, we compared these brain changes with previous findings reported by conventional statistical analysis to evaluate their stability. Our experiments have demonstrated that the proposed machine learning techniques achieve satisfactory and robust classification performance. The highest classification performance was 92.24% (specificity), 92.42% (sensitivity), 89.58% (accuracy), and 89.77% (AUC) for GM and 71.93% (specificity), 74.87% (sensitivity), 71.18% (accuracy), and 71.82% (AUC) for WM. Moreover, most brain regions identified by machine learning were consistent with previous findings, which means that these brain regions are related to the pathological brain changes characteristic of PD and can be regarded as potential biomarkers of PD. Besides, we also found the brain abnormality of superior frontal gyrus (dorsolateral, SFGdor) and lingual gyrus (LING), which have been confirmed in other studies of PD. This further demonstrates that machine learning models are beneficial for clinicians as a decision support system in diagnosing PD.

Background As one of the most common cause of cancer death in the world, lung cancer causes approximate 1.6 million deaths annually. Among, NSCLC accounts approximately 85% of patients in whole lung cancer patients. As one of miRNAs, miR-126 closely involves in pathogenesis of several types of cancers including colorectal, prostate, bladder and gastric cancer, and so on. Thus, the present study aims to investigate effects of miR126 on pathogenesis of NSCLC. In the study, two lung cancer cell lines including A549 and H1650 were used. Results It was found that expression of miR126 was decreased in PBMC of NSCLC patients compared to healthy control. Expression of miR126 was decreased in cancer tissue compared to paracancerous tissues in NSCLC patients. MiR-126 KD remarkably increased expression of apoptosis genes including caspase3 and capsae9, and decreased cell viability in lung cancer cells including A549 and H1650 cells. Interesting, In Silico analysis indicated that miR-126 could target PI3K signaling pathway, which was confirmed by WB assay. KD of PI3KR2 compromised promotion of miR-126 on cell apoptosis. Similarly, it was found that KD of mTOR compromised promotion of miR-126 on cell apoptosis. Conclusions Thus, the present study confirmed that miR-126 plays an important role in apoptosis of lung cells via mTOR signaling pathway. miR-126 might be a potential therapeutic target for developing novel drugs against NSCLC.

Posterior recurrent laryngeal nerve (RLN) lymph node dissection remains controversial in the operation of thyroid cancer, especially in cases of papillary thyroid microcarcinoma (PTMC). The present study aimed to evaluate the risk factors for posterior RLN lymph node metastasis in patients with PTMC. Two hundred and thirty-nine patients pathologically diagnosed with PTMC after surgery between June 2016 and June 2017 were included. Risk factors including age, sex, tumor diameter, multiple tumor focus, membrane invasion and lateral cervical lymph node metastasis condition, were analyzed, and their corresponding OR values were calculated. The results indicated that posterior RLN lymph node metastasis was pathologically identified in 27/239 patients. Membrane invasion (p = 0.024), VIa lymph node metastasis (p < 0.01), and lateral cervical lymph node metastasis (p < 0.01) were considered to be risk factors for posterior RLN lymph node metastasis. It is concluded that membrane invasion, VIa lymph node metastasis, and lateral cervical lymph node metastasis significantly increased the incidence of posterior RLN lymph node metastasis. Complete dissection of the posterior RLN lymph node was essential for patients with these risk factors.

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively.ObjectiveThis study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC.MethodsA literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis.ResultsRadiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients.ConclusionRadiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC.

Background Fragility fracture is associated with bone mineral density (BMD), and most databases used in related researches are instrument-matched. Little is known about the relationship between BMD and fragility fracture risk of native Chinese, especially using local databases as reference databases. Objective To investigate relationship between BMD and risk of fragility fracture in native China. Methods 3,324 cases, including 2,423 women (67.7 ± 8.9 years) and 901 men (68.4 ± 11.6 years) having radiological fragility fractures and 3,324 age- and gender-matched controls participated in the study. We measured BMD at posteroanterior spine and hip using dual-energy X-ray absorptiometry (DXA), calculated BMD measurement parameters based on our own BMD reference database. Results BMDs and mean T-scores were lower in case group (with clinical fragility) than in control group (without clinical fragility). In patients with fragility fractures, prevalence of lumbar osteoporosis, low bone mass, and normal BMD were 78.9 %, 19.3 %, and 1.8 %, respectively, in women, and 49.5, 44.8 %, and 5.7 %, respectively, in men. In hip, these prevalence rates were 67.2 %, 28.4 %, and 4.4 % in females, and 43.2 %, 45.9 %, and 10.9 % in males, respectively, showing differences between females and males. Multivariate Cox regression analysis showed that after adjusting age, height, weight, and body mass index, fracture hazard ratio (HR) increased by 2.7–2.8 times (95 % CI 2.5–3.1) and 3.6–4.1 times (95 %CI 3.0–5.1) for women and men respectively with decreasing BMD parameters. In both sexes, risk of fragility fracture increased approximately 1.6–1.7 times (95 % CI 1.5–1.8) for every 1 T-score reduction in BMD. Conclusions Risk of clinical fragility fracture increases with decreasing BMD measurement parameters and anthropometric indicators in native China, and fracture HR varies from gender and site.

BackgroundPrenatal alcohol exposure (PAE) has been linked to atypical brain development and a wide range of cognitive and behavioral impairments, including poor reading performance in childhood and adolescence. However, little is known about how structural and/or functional teratogenesis in the brain mediate reading impairment in fetal alcohol spectrum disorders (FASD) and whether neural correlates of reading and phonological processing differ between FASD subtypes with different clinical presentations in facial morphology.MethodsThe current study utilized functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize functional and structural mechanisms mediating reading deficits in 26 syndromal adolescents with PAE-related facial dysmorphology (i.e., fetal alcohol syndrome (FAS) or partial FAS (PFAS)) and 30 heavily exposed (HE) without this dysmorphology, in comparison with 19 typically developing controls. Importantly, the levels of PAE and reading ability were comparable between the FAS/PFAS and HE groups in the current study.ResultsCompared to the nonsyndromal HE and control groups, the syndromal adolescents showed greater activation in the right precentral gyrus during an fMRI phonological processing task and rightward lateralization in an important reading-related tract (inferior longitudinal fasciculus, ILF), suggesting an atypical reliance on the right hemisphere during reading. By contrast, in the HE group, better reading skills were associated with increased neural activation in the left angular gyrus (LAG) and higher fractional anisotropy in the white matter organization of the left ILF. However, the brain function-behavior relation was weaker in the HE than among the controls, suggesting less efficient function of the typical reading neural network that may contribute to the observed reading impairments.ConclusionsOur findings provide the first evidence for the distinctive functional and structural mechanisms underlying atypical reading and phonological processing in PAE adolescents with and without FAS facial dysmorphology.HighlightsPrenatal alcohol exposure is associated with altered neural reading networksFASD subtypes exhibit distinctive neural correlates of phonological processingGreater right-hemispheric reliance was observed in FASD with facial dysmorphologyNon-syndromal FASD showed deficits in the typical left-hemispheric reading network

Importance Asymmetric retinitis pigmentosa (RP) is a rare presentation of a normally symmetric condition. Histopathologic evidence should be examined to see if this asymmetry extends to the tissue and cellular levels. Objective To determine whether additional information can be obtained about asymmetric RP from studying clinical imaging and pathology correlates, including pathology samples from autopsied eyes. Design, Setting, and Participants In this case report, clinical and postmortem histopathological characteristics were compared in 2 eyes of a patient in her 50s with asymmetric RP. Individuals with rare mendelian diseases, such as RP, were studied using data from the curated National Eye Institute Eye Pathology collection. Main Outcome and Measures Results of clinical evaluation, multimodal retinal imaging, histopathology, and molecular genetic testing in a case of nonsyndromic asymmetric RP using resources from the ocular pathology collection. Results Eyes from a deceased patient in her 50s with nonsyndromic asymmetric RP found within the ocular pathology collection were studied. The patient was diagnosed with RP as an adolescent and presented in her 50s to the eye clinic with advanced RP, with the left eye affected much more severely than the right. The patient’s phenotype was studied using in vivo imaging and postmortem histopathology to identify interocular differences in tissue degeneration. Extraction of blood-derived DNA and formalin-fixed paraffin-embedded DNA from autopsied eyes analyzed using next-generation sequencing did not yield a definitive molecular diagnosis nor significant tissue differences. Conclusions and Relevance This study demonstrates newly reported histopathological and molecular correlates in asymmetric RP. This report also highlights the relevance of studying previously seen patients and reevaluating their conditions using resources within the ocular pathology collection to gain further insight on their disease.

Purpose To analyze the reliability and validity of the Brief international classification of functioning, disability and health (ICF) core set for chronic obstructive pulmonary disease (COPD). Patients and Methods A cross-sectional study was conducted in four tertiary hospitals in Tianjin, China. A total of 100 patients with COPD were selected to evaluate functioning and disability involving body functions, body structures, activities and participation as well as environmental factors of the Brief ICF core set for COPD. Internal consistency was calculated by Cronbach’s α. Content validity was examined using the content validity index (CVI), scale-level CVI/universal agreement, and scale-level CVI/average agreement (S-CVI/Ave). In addition, construct validity and convergent validity were also examined. Results The Brief ICF core set for COPD had a high internal consistency, 0.873 for the total scale, with values of 0.750, 0.640, and 0.843 for body functions, body structures, and activity and participation, respectively. The content validity was calculated by the CVI, scale-level CVI/universal agreement, and S-CVI/Ave at values of 0.80–1, 0.929, and 0.986, respectively. Meanwhile, the ICF core set for COPD had good convergent validity, correlating with the mMRC dyspnea score (r=0.690, P, Video Abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/EP14t95RULY

The presence of microvascular invasion (MVI) is a critical determinant of early hepatocellular carcinoma (HCC) recurrence and prognosis. We developed a nomogram model integrating clinical laboratory examinations and radiological imaging results from our clinical database to predict microvascular invasion presence at preoperation in HCC patients. 242 patients with pathologically confirmed HCC at the Ningbo Medical Centre Lihuili Hospital from September 2015 to January 2021 were included in this study. Baseline clinical laboratory examinations and radiological imaging results were collected from our clinical database. LASSO regression analysis model was used to construct data dimensionality reduction and elements selection. Multivariate logistic regression analysis was performed to identify the independent risk factors associated with MVI and finally a nomogram for predicting MVI presence of HCC was established. Nomogram performance was assessed via internal validation and calibration curve statistics. Decision curve analysis (DCA) was conducted to determine the clinical usefulness of the nomogram model by quantifying the net benefits along with the increase in threshold probabilities. Survival analysis indicated that the probability of overall survival (OS) and recurrence-free survival (RFS) were significantly different between patients with MVI and without MVI (P OR = 1.271, 95%CI: 1.137–1.420, P OR = 2.025, 95%CI: 1.056–3.885, P = 0.034; > 400 vs. ≤ 20, OR = 3.281, 95%CI: 1.661–6.480, P = 0.001), total bilirubin level greater than 23 umol/l (OR = 2.247, 95%CI: 1.037–4.868, P = 0.040). Incorporating tumor diameter, AFP and TB, the nomogram achieved a better concordance index of 0.725 (95%CI: 0.661–0.788) in predicting MVI presence. Nomogram analysis showed that the total factor score ranged from 0 to 160, and the corresponding risk rate ranged from 0.20 to 0.90. The DCA showed that if the threshold probability was > 5%, using the nomogram to diagnose MVI could acquire much more benefit. And the net benefit of the nomogram model was higher than single variable within 0.3–0.8 of threshold probability. In summary, the presence of MVI is an independent prognostic risk factor for RFS. The nomogram detailed here can preoperatively predict MVI presence in HCC patients. Using the nomogram model may constitute a usefully clinical tool to guide a rational and personalized subsequent therapeutic choice.

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

Cancer stem cells (CSCs) are considered as the origin and driving cells of cancer, and play a key role in the progress of cancer. Studies have shown that capsaicin exerted inhibitory effect on prostate cancer cells, however, the effects of capsaicin on prostate CSCs remain undefined. In the present study, we showed that capsaicin could downregulate prostate CSCs markers and inhibit the growth of PC-3 and DU145 prostate cancer stem cells. Further, we found capsaicin suppressed the expression of Wnt-2, p-GSK3β and β-catenin, along with downregulation of Wnt/β-catenin pathway target genes c-myc and cyclinD1. Using LiCl, a activator of Wnt/β-catenin pathway, we found activation of Wnt/β-catenin pathway could ameliorate the downregulation of prostate CSCs markers and the growth inhibition induced by capsaicin in prostate cancer stem cells. Those data suggested that the inhibition effect of capsaicin on prostate cancer stem cells and the anti-cancer effect of capsaicin on prostate cancer stem cell may be mediated by Wnt/β-catenin pathway. Findings from this study reveals for the first time the potential role and mechanisms of capsaicin on prostate cancer stem cells.

Background Cervical cancer is a major public health concern in China. We report the end‐of‐study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04‐human papillomavirus (HPV)‐16/18 vaccine in Chinese women aged 18‐25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. Methods Healthy 18‐25‐year‐old women (N = 6051) were randomized (1:1) to receive three doses of AS04‐HPV‐16/18 vaccine or Al(OH)3 (control) at Months 0‐1‐6. Vaccine efficacy against HPV‐16/18 infection and cervical intraepithelial neoplasia (CIN), cross‐protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according‐to‐protocol efficacy (ATP‐E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC‐E; vaccine N = 2987; control N = 2985) and TVC‐naïve (vaccine N = 1660; control N = 1587). Results In initially HPV‐16/18 seronegative/DNA‐negative women, vaccine efficacy against HPV‐16/18‐associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP‐E, 88.7% (95% CI: 18.5, 99.7) in the TVC‐E, and 100% (95% CI: 17.9, 100) in the TVC‐naïve. Cross‐protective efficacy against incident infection with HPV‐31, HPV‐33 and HPV‐45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP‐E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti‐HPV‐16/18 antibodies; anti‐HPV‐16 and anti‐HPV‐18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. Conclusions This is the first large‐scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV‐16/18‐associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. Trial registration NCT00779766., Cervical cancer is one of the most aggressive forms of cancer that women can suffer from. The presence of human papillomavirus (HPV) is responsible for almost all cases of cervical cancer. For these reasons, the world health organization recommends that HPV vaccines should be included in national vaccination programs. From the first licensure of the first HPV vaccine in 2006 to the development of new HPV vaccines, the latter have been studied in clinical trials and demonstrated to decrease in the number of cervical cancers while remaining acceptably safe. Many developed countries have included HPV vaccination in their program. These countries reported a decrease of cervical cancer cases. Many countries from the less developed regions are still yet to introduce HPV vaccination. The novelty: In 2016, the Chinese authorities approved licensure of the first HPV vaccine for use in China to help prevent cervical cancer and based their decision on clinical trials conducted in China. We present here the final results of the key clinical trial of this HPV vaccine that involved around 6000 Chinese women over 6 years. The impact: Chinese women represent almost 10% of the worldwide population at risk of cervical cancer. Latest estimations from 2016 indicate that 111 000 new cervical cancer cases are reported every year in China. This number could be reduced with the HPV vaccination.

Subclinical hypothyroidism (SCH) plays a crucial role in the development and progression of coronary heart disease (CAD). Retinol-binding protein 4 (RBP4) is an adipokine correlated with cardiovascular diseases. Recent studies found that RBP4 levels are increased in patients with SCH. However, the relationship of RBP4 with CAD in SCH patients remains unclear. A total of 199 SCH patients (148 with CAD and 51 without CAD) and 102 healthy controls were enrolled in this study. Serum RBP4 was increased in SCH patients than controls. Moreover, serum RBP4 was higher in SCH patients with CAD. Although there was no significant difference of metabolic parameters between SCH patients with and without CAD, serum RBP4 was positively correlated with body mass index, total cholesterol, and low-density lipoprotein cholesterol, as well as thyroid stimulating hormone. Multivariable logistic regression analyses revealed elevated RBP4 was correlated with increased risk for CAD in SCH patients. Serum RBP4 levels were also increased as the number of stenosed vessels increased. Furthermore, increased RBP4 was positively correlated with the severity of CAD quantified by the Gensini score. Our findings demonstrate that serum RBP4 is associated with the presence and severity of CAD in patients with SCH.

Objective: To report the incidence and risk factors of urosepsis after ureteroscopic lithotripsy (URSL). Patients and Methods: We retrospectively reviewed 1,421 patients who underwent URSL for ureteral calculi between July 2015 and June 2018 at our department to identify factors predicting postoperative urosepsis. Demographic characteristics, clinical data, operative information, and complications were compared, and risk factors of postoperative urosepsis were identified and analyzed. Results: Of the 1,421 patients treated with URSL using holmium: yttrium-aluminum-garnet laser, 12 (0.8%) developed a urosepsis after operation. The positive preoperative multidrug resistance (MDR) urine culture and operative duration were statistically different between those who did and did not develop a urosepsis (4.61 vs. 25%, p = 0.017; 70 vs. 62 min, p < 0.001). However, patient age, sex, body mass index, diabetes mellitus, history of urolithiasis, positive preoperative urine cultures, stone size and location, degree of hydronephrosis, and prior stent placement were similar in 2 groups. Multivariate analysis revealed that positive preoperative MDR urine culture and long operation duration significantly increased the risk of postoperative urosepsis (OR 5.090, 95% CI 1.312–19.751, p = 0.019; OR 1.034, 95% CI 1.004–1.063; p = 0.024). Matched-pair analysis demonstrated that positive preoperative MDR urine culture and operation duration were significantly associated with postoperative urosepsis (OR 15.77, 95% CI 1.033–240.7, p = 0.047; OR 1.087, 95% CI 1.011–1.169, p = 0.025). Conclusions: Patients with positive preoperative MDR urine culture or long operation duration had a higher risk of developing urosepsis after URSL. When treating patients who present with positive preoperative MDR urine culture or long operation duration, urologists should be vigilant and aware of the potential risk of urosepsis.

Cancer monitoring of Shanghai showed a rapid increase in the incidence of colorectal cancer. Colorectal cancer risk assessment allows for rapid screening of high-risk populations. The colorectal cancer screening of elderly residents is ongoing since 2013 in Shanghai. This initiative screened 85,525 people from 11 communities of the Qingpu District. Screening included a questionnaire-based risk assessment and two Fecal Occult Blood Tests (FOBTs). We conducted a retrospective case study of patients with positive screening results that underwent fibro-colonoscopy examinations to investigate their histories of schistosoma infection, smoking, alcohol consumption, and dietary habits. A total of 85,525 people were screened in this study. Colorectal cancer was resulted in a prevalence of 59.84/100,000. And the prevalence of schistosoma infection was 400/100,000. Among patients with schistosoma infection, the positive rate of FOBT was 67.01%, in contrast to an overall positive rate of FOBT among all subjects of 17.00% [(Pearson ⎥2=672.42, P 2 = 980.62, P

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin.

Background Bladder cancer (BC) is the 5th most common cancer in the USA. Non-muscle invasive bladder cancer represents about 70% of all cases and has generally a favorable outcome. However, recurrence rates as high as 60 to 70% and progression rates of 10 to 20% necessitate intensive surveillance with cystoscopy. The invasiveness and high cost of cystoscopy poses significant burden on BC patients as well as on the healthcare system. In this study we test the feasibility of a simple, sensitive, and non-invasive detection of BC using Bladder CARE test in urine samples. Results Urine from 136 healthy and 77 BC subjects was collected using the at-home Bladder CARE Urine Collection Kit and analyzed with Bladder CARE test. The test measures the methylation level of three BC-specific biomarkers and two internal controls using methylation-sensitive restriction enzymes coupled with qPCR. Bladder CARE showed an overall sensitivity of 93.5%, a specificity of 92.6%, and a PPV and NPV of 87.8% and 96.2%, respectively. Bladder CARE has an LOD as low as 0.046%, which equates to detecting 1 cancer cell for every 2,200 cells analyzed. We also provided evidence that bisulfite-free methods to assess DNA methylation, like Bladder CARE, are advantageous compared to conventional methods that rely on bisulfite conversion of the DNA. Conclusion Highly sensitive detection of BC in urine samples is possible using Bladder CARE. The low LOD of the test and the measurement of epigenetic biomarkers make Bladder CARE a good candidate for the early detection of BC and possibly for the routine screening and surveillance of BC patients. Bladder CARE and the at-home urine sample collection system have the potential to (1) reduce unnecessary invasive testing for BC (2) reduce the burden of surveillance on patients and on the healthcare system, (3) improve the detection of early stage BC, and (4) allow physicians to streamline the monitoring of patients.

BACKGROUND: Controversy remains regarding the predictive and prognostic value of serum human epidermal growth factor receptor 2 (HER2) in breast cancer. The purpose of this retrospective study was to determine the clinical utility and efficacy of serum HER2 (sHER2) in predicting treatment response and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy and trastuzumab treatment. METHODS: A total of 309 HER2-positive breast cancer patients diagnosed at Fudan University Shanghai Cancer Center from July 2015 to January 2019 were analyzed. Baseline sHER2 levels were obtained for all patients and sHER2 levels were collected after 2 cycles of treatment in 208 patients. A sHER2 level ≥15 ng/mL was regarded as “high expression” and sHER2

Purpose: To identify the independent risk factors for transarterial embolization (TACE) refractoriness and to develop a novel TACE refractoriness score and nomogram for predicting TACE refractoriness in patients with hepatocellular carcinoma (HCC).Methods: Between March 2006 and March 2016, HCC patients who underwent TACE monotherapy as initial treatment at two hospitals formed the study cohort and validation cohort. The criteria of TACE refractoriness followed the Japan Society of Hepatology 2014 version of TACE refractoriness. In the study cohort, the independent risk factors for TACE refractoriness were identified, and TACE refractoriness score and nomogram were then developed. The accuracy of the systems was validated externally in the validation cohort.Results: In total, 113 patients from hospital A formed the study cohort and 122 patients from hospital B formed the validation cohort. In the study cohort, 82.3% of the patients (n = 93) developed TACE refractoriness with a median overall survival (OS) of 540 days (95% CI, 400.8–679.1), and the remaining 20 patients in the TACE-non-refractory group had a median OS of 1,257 days (95% CI, 338.8–2,175.2) (p = 0.019). The median time for developing TACE refractoriness was 207 days (95% CI, 134.8–279.2), and a median number of two TACE procedures were performed after refractoriness developed. The independent risk factors for TACE refractoriness were the number of tumors and bilobular invasion of HCC. TACE refractoriness scores 3.5 points indicated a higher incidence (p < 0.001). In the validation cohort, 77.9% of the patients (n = 95) developed TACE refractoriness with a median OS of 568 days (95% CI, 416.3–719.7), and a median OS of 1,324 days was observed in the TACE-non-refractory group (n = 27; 95% CI, 183.5–2,464.5).Conclusions: TACE refractoriness impairs the OS of HCC patients. The number of tumors and bilobular invasion status were independent risk factors for TACE refractoriness. The TACE refractoriness score can be an effective tool and easy approach to predict the risk of TACE refractoriness status.

The evaluation and management of papillary thyroid microcarcinoma (PTMC) have always been challenging and controversial. Our retrospective study aimed to investigate the metastatic trend and risk factors of cN0 papillary thyroid microcarcinoma patients and provide advice for surgical strategies. The clinicopathological features of 556 cN0 PTMC patients undergoing thyroidectomy combined with central compartment dissection (CCD) were compared by the χ2 test and risk factors were identified by binary logistic regression analysis. Numbers of dissected lymph nodes (DLN) and metastatic lymph nodes (MLN) were analyzed using the Mann-Whitney U test to compare metastatic trends between different lobes. Male gender, tumor maximum diameter (TMD) larger than 5 mm, multifocality, and capsular/extracapsular invasion were metastatic risk factors of central compartment metastasis (CCM) (p0.05). The number of DLN in the right level VI was larger than in the left (p0.05), while the number of MLN was similar (p0.05). The chance of CCM was higher when the number of DLN was larger than 5 (p0.05). After identified metastatic trends and risk factors, we recommend surgery for patients deciding on aggressive treatment, especially for cases where a combination of risk factors is present. And to ensure no residual metastatic lymph nodes and reduce secondary surgery rates, adequate lymphadenectomy on the diseased side would be a better choice considering the standard of care.

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is concentrated predominantly in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with let7 microRNA.

BackgroundMalocclusion is a common oral disorder. Childhood is a critical period for the development of malocclusion. This protocol will explore the clinical efficacy and safety of bracketless invisible orthosis (BIO) in the treatment of children with malocclusion.MethodsThis study will search MEDLINE, PUBMED, Cochrane Library, Web of Science, WANGFANG, VIP, CNKI, and CBM from inception to the present. We will not apply any limitations to the language and publication status. All potential randomized controlled trials (RCTs) on the efficacy of BIO for the treatment of children with malocclusion will be considered for inclusion. Two authors will independently carry out study identification, data extraction, and study quality assessment in each study. Any disagreement will be resolved through discussion with a third author. When a number of included studies are sufficient, we will conduct meta-analysis, as well as subgroup analysis and sensitivity analysis. The certainty of evidence will be appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Outcome of interest will be presented in summary of findings tables, and statistical analysis will be performed utilizing RevMan 5.4 software. DiscussionThis systematic study will summarize all available studies to investigate the clinical efficacy of BIO in treating children with malocclusion. Findings of this study will highlight efficacy and safety of BIO for the treatment of children with malocclusion for both clinical practice and future strategies. Study registrationOSF (https://osf.io/avpmx).

Background De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

© 2020 John Wiley & Sons Ltd Recent efforts have focused on screening methods to identify children at risk for dyslexia as early as preschool/kindergarten. Unfortunately, while low sensitivity leads to under-identification of at-risk children, low specificity can lead to over-identification, resulting in inaccurate allocation of limited educational resources. The present study focused on children identified as at-risk in kindergarten who do not subsequently develop poor reading skills to specify factors associated with better reading outcomes among at-risk children. Early screening was conducted in kindergarten and a subset of children was tracked longitudinally until second grade. Potential protective factors were evaluated at cognitive-linguistic, environmental, and neural levels. Relative to at-risk kindergarteners with subsequent poor reading, those with typical reading outcomes were characterized by significantly higher socioeconomic status (SES), speech production accuracy, and structural organization of the posterior right-hemispheric superior longitudinal fasciculus (SLF). A positive association between structural organization of the right SLF and subsequent decoding skills was found to be specific to at-risk children and not observed among typical controls. Among at-risk children, several kindergarten-age factors were found to significantly contribute to the prediction of subsequent decoding skills: white matter organization in the posterior right SLF, age, gender, SES, and phonological awareness. These findings suggest that putative compensatory mechanisms are already present by the start of kindergarten. The right SLF, in conjunction with the cognitive-linguistic and socioeconomic factors identified, may play an important role in facilitating reading development among at-risk children. This study has important implications for approaches to early screening, and assessment strategies for at-risk children., Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant R01HD067312), National Institutes of Health National Research Service Award (Grant F31-DC015919-01)