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This study aimed to examine the effectiveness of high-intensity interval training (HIIT) on pulmonary function and exercise capacity in individuals with chronic obstructive pulmonary disease (COPD). Ten databases (PubMed, the Cochrane Library, Web of Science, EMBASE, MEDLINE, CINAHL, CNKI, Wanfang, Weipu, and CBM) were searched for relevant articles published from inception to 30 June 2020. Studies were included if they were randomized controlled trials (RCTs) comparing a HIIT group with usual care or other training groups. Quality was assessed using the Physiotherapy Evidence Database (PEDro) scale, and the overall quality of evidence was assessed using the GRADE approach. The primary outcomes were peak VO2 and FEV1% predicted, and the secondary outcomes were FEV1/FVC, peak VE, peak WR, 6MWD, dyspnea, health-related quality of life, and adverse event. Twelve articles (689 patients) were included. HIIT was shown to have a positive effect on exercise capacity (peak WR, 6MWD), pulmonary function (FEV1% pred, peak VE), dyspnea, and quality of life. However, sensitivity analyses for dyspnea were unstable, and the result changed from positive to negative after removing one study (SMD = − 0.13, 95% CI [− 0.44, 0.17], P = 0.40). HIIT could improve pulmonary function, exercise capacity, and quality of life but may not decrease dyspnea in patients with COPD. It can be recommended as a safe and effective exercise modality in rehabilitation programs. Given that the overall results were based on a limited number of studies with significant heterogeneity and some of the results were based on low GRADE rating evidence, more high-quality, larger sample size, multicenter, and long-term follow-up RCTs are needed to confirm the clinical efficacy of HIIT in patients with COPD. CRD42020165897.

PURPOSE There is some uncertainty about the optimal ranges for urinary iodine concentration (UIC) during pregnancy. This study aimed to explore associations between maternal UIC and thyroid function in iodine sufficient and mildly iodine deficient areas. METHODS It was a cross-sectional study in which 1461 healthy pregnant women were enrolled to collect their blood and urine samples during their routine antenatal care in Tianjin and Wuqiang, China. Wuqiang was a mildly iodine-deficient region, while Tianjin was iodine sufficient. UIC, free triiodothyronine (FT3), free thyroid hormone (FT4), thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), serum iodine concentration (SIC) including total serum iodine concentration (tSIC) and non-protein bound serum iodine concentration (nbSIC) were assessed during the routine antenatal care visits. RESULTS The median UIC in pregnant women was 174 (113, 249) μg/L in Tianjin and 111 (63, 167) μg/L in Wuqiang, respectively. Compared with Tianjin, UIC, FT3 and TSH were lower, and FT4, tSIC, nbSIC, rates of TPOAb and TgAb positivity and the thyroid dysfunction rate (TDR) were higher in Wuqiang (P

Background: Photoreceptor death and neurodegeneration is the leading cause of irreversible vision loss. The inflammatory response of microglia plays an important role in the process of neurodegeneration. In this study, we examined the involvement of myosin 1f as a key regulator of immune cell activation via the AKT and MAPK pathways in microglia. Methods: We chose retinal detachment as the model of photoreceptor degeneration. Immunofluorescence and Western Blot was performed to confirm the expression and location of myosin 1f in detached retina. The RD mouse model was induced in WT and myosin 1f-/- mice and confirmed by HE and TUNEL staining. The expression of inflammatory cytokine and downstream pathways was assessed via qPCR and WB.Results: Myosin 1f was upregulated after retinal detachment, and it was specifically expressed in microglia. Deficiency of myosin 1f protected against cell death by inhibiting microglia activation. The elimination of microglia can abolish the protective effect of myosin 1f deficiency. After stimulation by LPS, microglia with myosin 1f deficiency showed downregulation of the MAPK and AKT pathways.Conclusions: Myosin 1f plays a crucial role in microglia-induced neuro-inflammation after retinal injury and photoreceptor degeneration by regulating 2 classic pathways, MAPK and AKT, and thereby decreasing the expression of inflammatory cytokines. Myosin 1f can be inhibited to prevent a decline in visual acuity after photoreceptor degeneration.

AIM: To illustrate the underlying mechanism how prominin-1 (also known as Prom1) mutation contribute to progressive photoreceptor degeneration. METHODS: A CRISPR-mediated Prom1 knockout (Prom1-KO) mice model in the C57BL/6 was generated and the photoreceptor degeneration phenotypes by means of structural and functional tests were demonstrated. Immunohistochemistry and immunoblot analysis were performed to reveal the localization and quantity of related outer segment (OS) proteins. RESULTS: The Prom1-KO mice developed the photoreceptor degeneration phenotype including the decreased outer nuclear layer (ONL) thickness and compromised electroretinogram amplitude. Immunohistochemistry analysis revealed impaired trafficking of photoreceptor OS proteins. Immunoblot data demonstrated decreased photoreceptor OS proteins. CONCLUSION: Prom1 deprivation causes progressive photoreceptor degeneration. Prom1 is essential for maintaining normal trafficking and normal quantity of photoreceptor OS proteins. The new light is shed on the pathogenic mechanism underlying photoreceptor degeneration caused by Prom1 mutation.

Background Previous studies suggested that the prevalence of chronic respiratory disease in patients hospitalised with COVID-19 was lower than its prevalence in the general population. The aim of this study was to assess whether chronic lung disease or use of inhaled corticosteroids (ICS) affects the risk of contracting severe COVID-19. Methods In this population cohort study, records from 1205 general practices in England that contribute to the QResearch database were linked to Public Health England's database of SARS-CoV-2 testing and English hospital admissions, intensive care unit (ICU) admissions, and deaths for COVID-19. All patients aged 20 years and older who were registered with one of the 1205 general practices on Jan 24, 2020, were included in this study. With Cox regression, we examined the risks of COVID-19-related hospitalisation, admission to ICU, and death in relation to respiratory disease and use of ICS, adjusting for demographic and socioeconomic status and comorbidities associated with severe COVID-19. Findings Between Jan 24 and April 30, 2020, 8 256 161 people were included in the cohort and observed, of whom 14 479 (0·2%) were admitted to hospital with COVID-19, 1542 (

Glyburide (Gly) could inhibit NLRP3 inflammasome, as well as could be treated with Type 2 diabetes as a common medication. Despite more and more studies show that Gly could influence cancer risk and tumor growth, it remains unclear about the effect of Gly in lung tumorigenesis. To evaluate whether Gly inhibited lung tumorigenesis and explore the possible mechanisms, a benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS)-induced non-diabetes mice model was established with B(a)p for 4 weeks and once a week (1 mg/mouse), then instilled with LPS for 15 weeks and once every 3 weeks (2.5 μg/mouse) intratracheally. Subsequently, Gly was administered by gavage (10 μl/g body weight) 1 week before B(a)p were given to the mice until the animal model finished (when Gly was first given named Week 0). At the end of the experiment called Week 34, we analyzed the incidence, number and histopathology of lung tumors, and detected the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein. We found that vehicles and tricaprylin+Gly could not cause lung carcinogenesis in the whole process. While the incidence and mean tumor count of mice in B(a)P/LPS+Gly group were decreased compared with B(a)p/LPS group. Moreover, Gly could alleviate inflammatory changes and reduce pathological tumor nest numbers compared with mice administrated with B(a)p/LPS in histopathological examination. The B(a)p/LPS increased the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein significantly than Vehicle, whereas decreased in B(a)P/LPS+Gly (0.96 mg/kg) group compared with B(a)p/LPS group. Results suggested glyburide might inhibit NLRP3 inflammasome to attenuate inflammation-related lung tumorigenesis caused by intratracheal instillation of B(a)p/LPS in non-diabetes mice.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor of the digestive system which has a less than 1% 5-year survival rate. The pathogenesis of PDAC development is incompletely understood. Genetic predisposition, disease history of chronic pancreatitis and diabetes elevate the risk of PDAC while environmental and dietary factors including smoking, alcohol abuse, high fat/protein intake as well as air pollution exacerbate PDAC progression. BCAAs, consisting of leucine, isoleucine and valine are essential amino acids that are obtained from food and play versatile roles in carcinogenesis. Recent studies have demonstrated that BCAA metabolism affects PDAC development but the results are controversial. To explore the possible engagement of BCAA metabolism in PDAC, we took advantage of the GEO and TCGA database and discovered that BCAA uptake is closely related to PDAC development while BCAA catabolism is down-regulated in PDAC tissue. Besides, NOTCH and MYC are differentially involved in BCAA metabolism in tumor and muscle, and enhanced lipid synthesis is independent of BCAA catabolism. Altogether, we highlight BCAA uptake as a promising target for PDAC treatment.

POEMS syndrome is a rare plasma cell dyscrasia with distinct lipid metabolism abnormalities at disease onset. However, the serum lipidomic characteristics in patients with POEMS syndrome were not investigated. The study performed an untargeted lipidome screening by liquid chromatography‐tandem mass spectrometry (LS‐MS/MS) in the pre‐ and post‐treatment serum of 24 patients with POEMS syndrome, together with the serum of 24 paired healthy controls. Patients with POEMS syndrome had a distinct serum lipid composition compared with healthy controls, and a 3‐lipid model had a predictive accuracy of 93.5% in distinguishing patients and healthy controls consisting of fatty acyl 17‐oxo‐20Z‐hexacosenoic acid, phosphatidylcholine(16:0/18:1(9Z)) and sterol lipid 5b‐pregnanediol. Four lipids including 17‐oxo‐20Z‐hexacosenoic acid (r = 0.423, P = .040) were correlated with risk stratification, and 2 lipids including Cer(d18:0/13:0) were inversely related to serum vascular endothelial growth factor level (r=−0.465, P = .022). Eleven lipids were related to disease activity, including arachidonic acid which was inversely related and lysoPC(20:4) which was positively related. The study indicated a distinct lipid characteristic profile of patients with POEMS syndrome different from healthy controls and identified several lipids that may serve as potential diagnostic markers and monitors of therapeutic efficacy, as well as indicating potential metabolism pathways involved in the pathological process.

Endothelial dysfunction plays a central role in the patho­genesis of diabetic vascular complications. 2,3,5,4′-tetra­hydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from the roots of Polygonum multiflorum Thunb, has been shown to have strong antioxidant and antiapoptotic activities. In the present study, we investigated the protective effect of TSG on apoptosis induced by high glucose in human umbilical vein endothelial cells (HUVECs) and the possible mechanisms. Our data demonstrated that TSG significantly reversed the high glucose-induced decrease in cell viability, suppressed high glucose-induced generation of intracellular reactive oxygen species (ROS), the activity of caspase-3, and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, we found that TSG not only increased the expression of Bcl-2, while decreasing Bax expression, but also activated phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) with subsequent nitric oxide production and ultimately reduced high glucose-induced apoptosis. However, the antiapoptotic effects of TSG were abrogated by pretreatment of the cells with PI3K inhibitor (LY294002) or eNOS inhibitor NG-L-nitro-arginine methyl ester, respectively. These results suggest that TSG inhibits high glucose-induced apoptosis in HUVECs through inhibition of ROS production, activation of the PI3K/Akt/eNOS pathway, and upregulation of the Bcl-2/Bax ratio, and thus may demonstrate significant potential for preventing diabetic cardiovascular complications.

Long noncoding RNAs (lncRNAs) play vital roles in development and progression of various cancers. To investigate the relationship between three tag single-nucleotide polymorphisms (SNPs) (rs1325229...

Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) as an adipocytokines is a new hypoglycemic strategy and is inversely related to bone mineral density.Methods: To evaluate the contribution of FGF21 to VC in HD patients, we preliminary sreened 802 HD patients of two large HD centers in China. At last 388 HD patients were entered this cross-sectional study. We detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the three segments of thoracic aorta (TA), including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our 388 HD patients. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro.Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1) and Ln(DTACS+1) respectively in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 combined with age, calcium and intact parathyroid hormone demonstrated a high area under the curve (AUC=0.84) with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition (EndMT).Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.Trial registration Chinese Clinical Trial Registry, identifier: ChiCTR1900028249. Registered 16 December 2019-Retrospectively registered,http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=5981

Objective: To review medical management of inoperable malignant bowel obstruction. Data Sources: A literature review using PubMed and MEDLINE databases searching malignant bowel obstruction, etiology, types, pathophysiology, medical, antisecretory, anti-inflammatory, antiemetic drugs, analgesics, promotion of emptying, prevention of infection, anticholinergics, somatostatin analogs, gastric antisecretory drugs, prokinetic agents, glucocorticoid, opioid analgesics, antibiotics, enema, and adverse effects. Study Selection and Data Extraction: Randomized or observational studies, cohorts, case reports, or reviews written in English between 1983 and November 2020 were evaluated. Data Synthesis: Malignant bowel obstruction (MBO) commonly occurs in patients with advanced or recurrent malignancies and severely affects the quality of life and survival of patients. Its management remains complex and variable. Medical management is the cornerstone of MBO treatment, with the goal of reducing distressing symptoms and optimizing quality of life. Until now, there has been neither a standard clinical approach nor registered medications to treat patients with inoperable MBO. Relevance to Patient Care and Clinical Practice: This review provides information on the etiology, type and pathophysiology, and medical treatment of MBO and related adverse reactions of the drugs commonly used, which can greatly assist clinicians in making clinical decisions when treating MBO. Conclusions: Published research shows that medical management of MBO mainly consists of antisecretory, anti-inflammatory strategies, controlling vomiting and pain, promoting emptying, preventing infection, and combination therapy. Being knowledgeable about the most current treatment options, the related adverse effects, and the evidence supporting different practices is critical for clinicians to provide individualized medical therapy for MBO patients.

Background: POEMS syndrome is a rare plasma cell dyscrasia. Despite the presence of monoclonal protein, POEMS syndrome patients commonly have less than 5% monoclonal plasma cells in the bone marrow. Only one study has reported the genetic and transcriptional features of bone marrow plasma cells, and the underlying role of aberrant plasma cells is not well understood. Herein, in the current study, we aimed to characterize the genetic profile of bone marrow CD138-positive cells from Chinese patients with newly diagnosed POEMS syndrome. Methods: Forty-two patients with newly diagnosed POEMS syndrome based on the International Myeloma Working Group criteria at our institute were included in our study. Twenty milliliters of bone marrow aspirates was obtained and sorted by magnetic microbeads conjugated to monoclonal human anti-CD138 antibodies. The mutational features of these bone marrow plasma cells were analyzed using a two-step strategy. DNA of the bone marrow plasma cells from ten patients was first sequenced by whole exome sequencing to find significantly mutated genes and mutated driver genes, with paired peripheral blood mononuclear cells as a control. Bone marrow plasma cells of an additional thirty-two patients were then analyzed by target region sequencing to validate the mutations. Results: Whole exome sequencing of 10 newly diagnosed patients showed a total of 170 somatic mutations in exonic regions and splicing sites. Three significantly mutated genes-LILRB1 (10%), HEATR9 (20%), and FMNL2 (10%)-and eight mutated known driver genes (MYD88, NFKB2, CHD4, SH2B3, POLE, STAT3, CHD3, CUX1) were identified in five patients. The mutation spectrum of WES revealed C > T/G > A as the most common mutation type, while the mutation signature was not the same as known signatures reported in various cancer types. For significant pathway and gene ontology analysis, 69 genes with possibly pathogenic nonsynonymous mutations were selected. Mutated genes were enriched in pathways including "chromatin organization", "chromatin modifying enzymes", and "apoptosis", and terms such as "cellular anatomical entity", "regulatory region nucleic acid binding" and "centrosome" that are used to describe cellular structure construction. To evaluate the mutation prevalence of genes identified in WES, we performed target region sequencing of 77 candidate genes in 32 other patients. The candidate gene list consisted of significantly mutated genes and known driver genes identified in WES, recurrently mutated genes previously detected in POEMS syndrome, the VEGF gene, and genes of light-chain amyloidosis, multiple myeloma, hematopoietic disease or lymphoid neoplasm in the public databases. As a result, a total of 32 mutated genes were identified in 28 of 32 patients. Genes recurrently mutated in more than three patients included CUX1 (19%), DNAH5 (16%), USH2A (16%), KMT2D (16%), and RYR1 (12%). Driver genes of multiple myeloma (BIRC3, LRP1B, KDM6A, ATM) and eleven genes reported in light-chain amyloidosis were also identified in target region sequencing. Notably, VEGFA mutations were detected in one patient. Conclusions: Heterogeneous genomic profiles of bone marrow plasma cells in POEMS syndrome were revealed in our study. The mutational landscape of POEMS syndrome might share some similarity to that of other plasma cell diseases. Disclosures No relevant conflicts of interest to declare.

Background Disseminated intravascular coagulation (DIC), a severe complication of sepsis, promotes multiple organ dysfunctions and lethality. Bacterial infection is the most common cause of sepsis. We previously show an important role of bacteria-released outer membrane vesicles (OMVs) in bacterial infection-induced DIC. In the light of recent advance that activation of caspase-11 and its enzymatic substrate gasdermin D (GSDMD) is able to trigger coagulation, we postulate that OMVs might induce DIC through the caspase-11-GSDMD pathway. Methods Caspase-11- or GSDMD-deficient mice and their wild-type (WT) controls were injected with purified Escherichia coli-derived OMVs. Blood samples were then collected. The development of DIC was assessed in terms of the occurrence of coagulopathy, the organ injuries and the lethality. Peritoneal macrophages derived from WT, Caspase-11- or GSDMD-deficient mice were stimulated with OMVs. Then the cell surface tissue factor (TF) activity and thrombin generation were assessed. Results Genetic deletion of Caspase-11 or GSDMD or pharmacological inhibition of caspase-11 markedly attenuated OMVs-induced coagulopathy, multiple organ injuries and mortality. Caspase-11- or GSDMD-deficient macrophages exhibited markedly reduced TF activity after OMVs stimulation. Conclusion OMVs induce DIC through the caspase-11-GSDMD pathway. These findings might open a new avenue to prevent or treat bacterial infection-induced DIC.

Aim To investigate the value of pretreatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting lymph node metastasis in patients with endometrial cancer. Methods A retrospective analysis of 145 patients with endometrial cancer who were treated at the Peking University Cancer Hospital and Institute between October 2010 and November 2013 was performed. Preoperative NLR, PLR, serum CA125 and HE4 were assessed. Clinicopathological parameters were evaluated for LN metastasis using logistic regression. Receiver operating characteristic (ROC) curves were plotted and the optimal cut-off values of NLR, PLR, CA125 and HE4 were calculated for predicting lymph node metastasis. Results The levels of NLR, PLR, serum CA125 and HE4 were significantly higher in patients with lymph node metastasis than those without lymph node metastasis. Multivariate analysis showed that only the higher NLR and HE4 were independent predictors for lymph node metastasis (odds ratio, OR = 3.509, P = 0.016; OR = 1.446, P = 0.016). The optimal cut-off values of NLR and HE4 for predicting lymph node metastasis were 2.50 (area under the curve, AUC = 0.809) and 80.4 pmol/L (AUC = 0.713). The sensitivity and specificity were 75.0% and 84.9% for NLR, 86.7% and 73.8% for HE4, respectively. When HE4 was combined with NLR to predict lymph node metastasis, the sensitivity and specificity were significantly improved. Conclusion Preoperative higher NLR and serum HE4 are predictors of lymph node metastasis in endometrial cancer, and the predictive value was superior to that of serum CA125.

Background Keratoacanthoma (KA) is a special kind of tumor, which is regarded as a variant of squamous cell carcinoma (SCC) in some academic disciplines. But differentiating KA from SCC remains a diagnostic challenge. The noninvasive techniques dermoscopy and reflectance confocal microscopy (RCM) can provide new insights for diagnosis. Objective To observe the characteristics of KA under dermoscopy and reflectance confocal microscopy (RCM), in order to gain experience and reference for clinicians to facilitate earlier diagnosis. Methods We collected two cases of KA, which were confirmed by clinical and histopathological examination. The two cases were examined by dermoscopy and RCM, respectively. Then, we collected the microscopic characteristics of KA lesions. Results The dermoscopy features of KA are concentric circles of central crater, keratin mass, keratin scale, and polymorphic vascular pattern. The RCM features are described as refractile crust, atypical honeycomb pattern, dark center cells, large round nucleated cells, dendritic cells, and linear or round vessels traversing dermal papillae in the dermis. Conclusion KA has some specific dermoscopy and RCM features, which can provide a basis for doctors to diagnose and intervene earlier.

Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive procedure, which is widely used in the management of pancreas and biliary tract diseases. It may induce complications, such as pancreatitis, bleeding, and perforation. Splenic injury is an extremely rare but life threatening complication. We reviewed the literature, and found that 23 ERCP associated splenic injuries cases had been reported. We discussed the likely mechanism, clinical features, diagnostic modality, and treatment, also shared our experience on a patient who suffered splenic laceration after ERCP and was successfully treated by splenectomy.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is associated with increased risk for ischemic stroke (IS). Because POEMS syndrome is rare, little is known regarding the underlying mechanism and prognosis for IS in patients in whom it occurs. The medical records of patients with POEMS syndrome were screened between January 2018 and January 2000 at Peking Union Medical College Hospital to identify those with IS. The baseline characteristics, IS features, and patient outcomes were analyzed. Forty-one (8.0%) of 510 POEMS patients were documented to have IS. Patients with IS were older, had a higher percentage of Overall Neuropathy Limitation Scale score >4, and had a higher level of fibrinogen compared with those who did not have IS. Ninety-three percent of IS events occurred before or within 3 months after a diagnosis of POEMS. Of 41 occurrences of IS, 29 (46.3%) were multifocal. Recurrent IS was observed in 13 (31.7%) of 41 patients, but not in patients with successful anti-plasma cell therapy. The 3-year overall survival rate in patients with IS was 71.0% and for those without IS, it was 88.5% (P = .002). We showed that 8.0% of POEMS patients had IS, and most IS events occurred in POEMS patients not being treated effectively. Having IS was a predictor of unfavorable prognosis. Early diagnosis, immediate initiation of treatment for POEMS, and control of POEMS syndrome is key to reducing the occurrence of IS, improving survival, and preventing recurrence of IS.

AIM The use of prophylactic antibiotics has greatly reduced the incidence of surgical site infections after hysterectomy. It is worth discussing which antibiotic is better. The purpose of this study was to investigate the role of the combined utilization of cefazolin and metronidazole for the prevention of surgical site infection in laparoscopic staging surgery of endometrial cancer. METHODS A retrospective analysis was performed on the incidence of surgical site infection in patients with endometrial cancer who underwent laparoscopic surgical staging from January 2000 to June 2019 within 1 month after surgery. Logistic regression model was used for univariate and multivariate analysis. RESULTS A total of 1783 patients were included in this study, of which 641 were treated with cefazoline plus metronidazole (group 1) as a prophylactic antibiotic, while the other 1142 were treated with cefoxitin (group 2). There was no difference in clinical characteristics between the two groups. The rates of surgical site infection in groups 1 and 2 were 3.6% (n = 23) and 5.7% (n = 65), respectively. The most common site of infections was vaginal, with the incidence of 1.7% (n = 11) and 3.3% (n = 38) in groups 1 and 2, respectively. The multivariate analysis disclosed that cefazoline plus metronidazole significantly reduced the incidence of surgical site infections compared with cefoxitin (logistic, odds ratio = 2.213, 95% confidence interval 1.193 to 4.107). CONCLUSION Cefazolin plus metronidazole as prophylactic antibiotics for surgical staging of endometrial cancer can more effectively reduce the incidence of surgical site infections than cefoxitin.

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Background Mesenchymal-epithelial transition (MET) exon14 skipping mutations represent a clinically unique molecular subtype of NSCLC. The prevalence rates of MET exon 14 skipping in lung adenocarcinoma (ADC) range from 0.9% to 4.0% in Asian populations. Since some somatic variants that do not encompass the MET exon 14 splice sites might also induce MET exon 14 skipping, the RNA-based sequencing is speculated as the most accurate method for detecting exon 14 skipping. Patients and Methods A total of 951 NSCLC patients from two hospitals were enrolled in this study. MET exon14 skipping was detected using RNA-based next-generation sequencing (NGS). Also, immunohistochemistry (IHC) was performed in 405 samples simultaneously. Results The overall estimated prevalence of MET exon 14 skipping was approximately 1.8% in ADCs and 1.7% in NSCLCs. The detection rate of MET exon 14 skipping from surgical resection specimen was 2.3% in NSCLCs and 2.0% in ADCs. The MET exon 14 skipping was identified in 6.6% of EGFR/KRAS/ALK/ROS1/RET-negative ADCs. Additionally, PD-L1 was found to be highly expressed in NSCLC patients harboring MET exon 14 skipping (P

Introduction: Hyperuricemia has been associated with increased cardiovascular events in the general population. However, the role of serum uric acid (SUA) level on the severity of coronary artery s...

As the incidence of diabetes and cardiovascular comorbidities continues to rise, driven by increased prevalence of obesity and an aging population, so does the demand for percutaneous coronary intervention (PCI) to restore cardiac blood flow. Renin-angiotensin-aldosterone system (RAAS) inhibitors are commonly prescribed to hypertensive diabetic patients to prevent diabetic nephropathy. However, evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of contrast-induced acute kidney injury (CIAKI) following coronary angiography (CAG) and PCI. We therefore conducted a retrospective, multicenter study applying the propensity score matching method to evaluate the impact of RAAS inhibition on CIAKI in diabetic patients undergoing CAG/PCI. Among 2240 subjects that met the inclusion criteria, 704 patients in the ACEIs/ARBs group were successfully matched to eligible control patients. The incidence of CIAKI (serum creatinine increase ≥0.5 mg/dl or ≥25% from baseline within 72 h post-CAG/PCI) was significantly higher in the ACEIs/ARBs group than in the control group (26.6% vs. 16.2%, P

The serious ambient fine particulate matter (PM2.5) is one of the key risk factors for lung cancer. However, existing studies on the health effects of PM2.5 in China were less considered the regional transport of PM2.5 concentration. In this study, we aim to explore the association between lung cancer and PM2.5 and then forecast the PM2.5-induced lung cancer morbidity and mortality in China. Ridge regression (RR), partial least squares regression (PLSR), model tree-based (MT) regression, regression tree (RT) approach, and the combined forecasting model (CFM) were alternative forecasting models. The result of the Pearson correlation analysis showed that both local and regional scale PM2.5 concentration had a significant association with lung cancer mortality and morbidity and compared with the local lag and regional lag exposure to ambient PM2.5; the regional lag effect (0.172~0.235 for mortality; 0.146~0.249 for morbidity) was not stronger than the local lag PM2.5 exposure (0.249~0.294 for mortality; 0.215~0.301 for morbidity). The overall forecasting lung cancer morbidity and mortality were 47.63, 47.86, 39.38, and 39.76 per 100,000 population. The spatial distributions of lung cancer morbidity and mortality share a similar spatial pattern in 2015 and 2016, with high lung cancer morbidity and mortality areas mainly located in the central to east coast areas in China. The stakeholders would like to implement a cross-regional PM2.5 control strategy for the areas characterized as a high risk of lung cancer.

The role of non-coding RNA, once thought to be dark matter, is increasingly prominent in cancer. Our article explores the effect of non-coding RNA in lung adenocarcinoma and lung squamous cell carcinoma by mining TCGA public database. Download the data by applying the official TCGA software. The data were analyzed by R data analysis packages, ‘edgeR’, ‘gplots’ and ‘survival’. We better illustrate the potential networks of lung cancer genes by constructing ceRNAs, using Cytoscape software. We obtained genes which were differentially expressed in lung adenocarcinoma and lung squamous cell carcinoma analysis. Within these differentially expressed genes, we also conducted a survival analysis to find differentially expressed genes associated with prognosis in both lung adenocarcinoma and lung squamous cell carcinoma. Based on genes differentially expressed of both lung adenocarcinoma and lung squamous cell carcinoma, we constructed a ceRNA network to illustrate the mechanism of lung adenocarcinoma and lung squamous cell carcinoma. Our study analyzed genes which were differentially expressed in lung adenocarcinoma and lung squamous cell carcinoma using the TCGA database. Based on this, the prognosis in both lung squamous cell carcinoma and lung adenocarcinoma was analyzed. We have also constructed a ceRNA network to provide a basis for the study of ceRNA in lung adenocarcinoma and lung squamous cell carcinoma.

Postinflammatory hyperpigmentation (PIH) is a common disfiguring complication following inflammatory dermatoses and cosmetic procedures in dark-skinned individuals. Anti-inflammatory and repairing agents targeting primary inflammation and injury are becoming promising choices for preventing PIH. The aim of this active-controlled, assessor-blinded, intra-individual monocentric study was to evaluate the preventive effect of a wound-dressing biomaterial, mussel adhesive protein (MAP) in the suction blister-induced PIH model. Twenty Chinese patients underwent suction blister epidermal grafting had defined wound areas to receive a topical MAP spray or a potent corticosteroid cream once daily for seven consecutive days after operation. In situ semi-quantitative evaluations of inflammation and pigmentation were achieved by Mexameter, reflectance confocal microscopy and dermoscopy on week 1, week 4, and week 12. Topical application of MAP exerted remarkably inhibitory effect on PIH comparable to fluticasone propionate, manifested as significantly lower melanin index and papillary contrast measured by Mexameter and confocal microscopy on week 12 compared to untreated sites. Although MAP exhibited moderate anti-inflammatory effect weaker than fluticasone propionate, MAP-treated sites healed faster than steroid-treated and untreated sites. The biological activity of MAP was further studied in UVB-irradiated HaCaT cell model, which revealed MAP decreased the expression of UVB-induced α-melanocyte stimulating hormone (α-MSH) and pro-inflammatory cytokines (IL-1α, IL-6, COX-2). It also protected HaCaT cells from UVB-induced cell death and apoptosis. In conclusion, MAP could be a novel postoperational wound dressing preventing PIH associated with skin inflammation and injury.

© 2020 Gao et al. Purpose: This study aimed to predict stage of exercise among Chinese patients with type 2 diabetes by using an extended theory of planned behavior model (TPB) incorporating descriptive norm and self-identity. Patients and Methods: Participants (N=791) were included in a cross-sectional study. Structural equation modeling was used to explain how the extended TPB could predict the stage of exercise. Results: The model accounted for 41% of the variance in stage of exercise and 81.1% of the variance in intention. Intention (β=0.359, P

Purpose: To identify the differential expression of microRNAs (miRs) and the related gene networks and signal pathways in lacrimal glands (LGs) of rabbit autoimmune dacryoadenitis. Methods: Autoimmune dacryoadenitis in rabbits was induced by transferring activated peripheral blood lymphocytes (PBLs). The LGs of normal and model group rabbits were collected for small RNA sequencing. The most differentially expressed miRs were validated by quantitative real time-polymerase chain reaction (qRT-PCR). Further, bioinformatics analysis including target gene prediction, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Results: A total of 15 miRs were differentially expressed in the LGs of rabbit autoimmune dacryoadenitis relative to normal controls. GO and KEGG analysis revealed that most target genes of these dysregulated miRs were implicated in MAPK signaling pathway. Conclusion: Our results showed for the first time the differentially expressed miRs and the related pathways involved in the pathogenesis of rabbit autoimmune dacryoadenitis. These results may contribute to elucidating molecular pathogenesis of Sjögren's syndrome (SS) dry eye.

Rationale: Amyloid β (Aβ) deposition, an essential pathological process in age-related macular degeneration (AMD), causes retinal pigment epithelium (RPE) degeneration driven mostly by oxidative stress. However, despite intense investigations, the extent to which overoxidation contributes to Aβ-mediated RPE damage and its potential mechanism has not been fully elucidated. Methods: We performed tandem mass-tagged (TMT) mass spectrometry (MS) and bioinformatic analysis of the RPE-choroid complex in an Aβ1-40-induced mouse model of retinal degeneration to obtain a comprehensive proteomic profile. Key regulators in this model were confirmed by reactive oxygen species (ROS) detection, mitochondrial ROS assay, oxygen consumption rate (OCR) measurement, gene knockout experiment, chromatin immunoprecipitation (ChIP), and luciferase assay. Results: A total of 4243 proteins were identified, 1069 of which were significantly affected by Aβ1-40 and found to be enriched in oxidation-related pathways by bioinformatic analysis. Moreover, NADPH oxidases were identified as hub proteins in Aβ1-40-mediated oxidative stress, as evidenced by mitochondrial dysfunction and reactive oxygen species overproduction. By motif and binding site analyses, we found that the transcription factor PU.1/Spi1 acted as a master regulator of the activation of NADPH oxidases, especially the NOX4-p22phox complex. Also, PU.1 silencing impeded RPE oxidative stress and mitochondrial dysfunction and rescued the retinal structure and function. Conclusion: Our study suggests that PU.1 is a novel therapeutic target for AMD, and the regulation of PU.1 expression represents a potentially novel approach against excessive oxidative stress in Aβ-driven RPE injury.

Lemur tyrosine kinase-2 (LMTK2), a newly identified serine/threonine kinase, is a potential regulator of cell survival and apoptosis. However, little is known about its role in regulating neuronal survival during cerebral ischemia/reperfusion injury. The present study aimed to explore the potential function of LMTK2 in regulating neuronal survival using an in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury. Herein, we found that LMTK2 expression was markedly decreased in neurons following OGD/R exposure. Gain-of-function experiments demonstrated that LMTK2 overexpression significantly improved the viability and reduced apoptosis of neurons with OGD/R-induced injury. Moreover, LMTK2 overexpression reduced the production of reactive oxygen species (ROS) in OGD/R-exposed neurons. Notably, our results elucidated that LMTK2 overexpression reinforced the activation of nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response element (ARE) antioxidant signaling associated with increased glycogen synthase kinase-3β (GSK-3β) phosphorylation. GSK-3β inhibition by its specific inhibitor significantly reversed LMTK2-inhibition-linked apoptosis and ROS production. Additionally, silencing Nrf2 partially reversed the LMTK2-overexpression-mediated neuroprotective effect in OGD/R-injured neurons. Taken together, our results demonstrated that LMTK2 overexpression alleviated OGD/R-induced neuronal apoptosis and oxidative damage by enhancing Nrf2/ARE antioxidant signaling via modulation of GSK-3β phosphorylation. Our study suggests LMTK2 is a potential target for neuroprotection during cerebral ischemia/reperfusion.

Objectives: There have been reports of unexplained visual loss following intra-ocular silicone oil (SiO) tamponade in retinal detachment patients, yet the underlying mechanism is unknown. The aim of this study was to investigate the mechanisms behind retinal toxicity following intra-ocular SiO tamponade in retinal detachment patients.Methods and Results: Vitreous fluid samples were acquired from 27 patients (27 eyes). Twelve eyes for data-independent acquisition (DIA) were divided into four groups: pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RD group), SiO removal after successful retinal reattachment (SO group), cataract surgery after successful retinal reattachment with sterilized air tamponade (FA group), and PPV for epiretinal membrane (ERM group). The remaining 15 eyes were used for enzyme-linked immunosorbent assay analysis. DIA was combined with two-dimensional liquid chromatography–tandem mass spectrometry to find expression changes in the proteome of vitreous. Mean number mass spectra, statistically differentially expressed proteins, gene ontology (GO), pathway representations, and protein interactions were analyzed. GO analysis showed that the protein categories of synapse organization, cell adhesion, and regulation of cell migration in the SO group were differentially expressed compared to the control or FA groups (p < 0.05). Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, lysosome and cell adhesion were found to be significantly enriched in the SO group compared to the FA and control groups (p < 0.05). Cadherin 2, transferrin, and lysosome function may partially contribute to silicone oil-related vision loss.Conclusion: Vision loss-inducing novel molecular signatures and pathways that may be associated with SiO toxicity were identified. Transferrin may be a potential visual outcome biomarker for SiO tamponade.

Objective: This study aims to explore the influence of patient activation (PA) and relational aspects on the quality of life (QoL) in patients with Atrial Fibrillation (AF) for developing measures to improve PA and QoL.Methods: A cross-sectional study was undertaken in 2021 among 190 AF patients in Nanjing, China. Research instruments included a self-designed social-demographic characteristics scale, the Patient Activation Measure (PAM), the Atrial Fibrillation Effect on Quality of Life (AFEQT). The data analysis was performed using IBM SPSS 25.0. Spearman correlation analysis, multiple linear regression analysis, and Wilcoxon rank-sum tests were used to assess the association accordingly.Results: The average AFEQT score for the 190 AF patients was 69.32 ± 14.52. The distribution of activation Levels 1, 2, 3, and 4, were where 4.7, 34.2, 47.4, and 13.7%, respectively. The multiple linear regression analysis revealed that patient activation, work status, and cardiac rehabilitation of AF patients predicted AF-related QoL (β = 0.270, −0.205, and 0.183, respectively; all P < 0.05). The influences of PA level on subdimensions of AF-related QoL were as follows: symptoms, daily activities and treatment concern.Conclusion: The level of QoL of patients with AF was moderate. Higher levels of patient activation in those with AF were associated with milder symptoms, more positive daily activities and fewer treatment concern. Based on our findings, we suggest that healthcare personnel should encourage AF patients to take active participation in cardiac rehabilitation, disease self-management and foster progression of PA level. Future research is warranted to develop tailor-made interventions aimed at the activation level.

Background: P53 has different prognostic cut-off values in different mantle cell lymphoma (MCL) studies, and p53 immunohistochemistry (IHC) interpretation is still based on semiquantitative estimation，which might be inaccurate. This study aimed to investigate the optimal cut-off value of p53 for predicting prognosis and the possibility of computer image analysis identifying the positive rate of p53 in patients with mantle cell lymphoma (MCL). Methods: We used QuPath software to determining the p53 positive rate and compared it to the data obtained by manual counting and semiquantitative estimation. Using Youden index and Kaplan-Meier survival curve analysis, we generated survival curves. Chi-squared (χ2) test was used to compared MCL cell morphology with p53. Spearman rank correlation test and Bland-Altman analysis were used to compared manual counting, computer image analysis and semiquantitative estimation.Results: The optimal cut-off value of p53 for predicting prognosis was 20% in MCL patients. Patients with p53 ≥ 20% had a significantly worse overall survival (OS) compared to p53 < 20% (P < 0.0001). MCL patients with blastoid/pleomorphic variant cell morphology had more p53 ≥ 20% than classical type (P < 0.0001). And a strong correlation between computer image analysis and manual counting p53 in the same areas in MCL patients (spearman's rho = 0.966, P < 0.0001). Conclusions: MCL patients with p53 ≥ 20% have a shorter OS, and a blastoid/pleomorphic variant tendency. Computer image analysis could reflect the actual positive rate of p53 and is a more attractive alternative than semiquantitative estimation in MCL.

BackgroundDiabetic foot ulcers characterized by delayed healing are one of the main complications of diabetes. Epidermal keratinocyte dysfunction has been found to play a pivotal role in the poor healing ability of diabetic wounds. In this study, we aimed to explore the relationship between c-Myc and its O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) modification and keratinocyte dysfunction in diabetic wounds.MethodsClinical wound samples were collected and a full-thickness skin defect wound model of diabetic rats was established. Re-epithelialization of wounds was observed by H&E staining and expressions of proliferating cell nuclear antigen, transglutaminase 1, loricrin, c-Myc and O-GlcNAc were measured by immunohistochemistry. The functional changes of proliferation, migration and differentiation of human immortalized epidermal cells (HaCaT) cells after overexpression or knockdown of c-Myc were observed. O-GlcNAcylation of c-Myc was confirmed using immunoprecipitation and proximity ligation assay. Stability of the c-Myc protein was measured using cycloheximide. Wound healing was observed after topical application of compounds that inhibited c-Myc or O-GlcNAc on diabetic wounds.ResultsKeratinocytes at the diabetic wound margin were characterized by active proliferation and division, slow migration and poor differentiation. Similar phenomena were observed in HaCaT cells cultured in 30 mM glucose and keratinocytes at the wound margin of the diabetic rats. The expression of c-Myc was increased in keratinocytes at the wound margin of diabetic rats, patients, and in HaCaT cells cultured with 30 mM glucose. Increased expression of c-Myc promoted the proliferation while inhibiting the migration and differentiation of the HaCaT cells, and inhibition of c-Myc promoted diabetic wound healing. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing.ConclusionsIncreased expression of c-Myc promoted abnormal proliferation and inhibited migration and differentiation of keratinocytes at the diabetic wound margin. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of c-Myc or O-GlcNAc alleviated delayed diabetic wound healing. These findings make c-Myc and O-GlcNAc potential therapeutic targets for diabetic wounds.

ObjectivePrevious studies have mostly discussed the clinical manifestations and prognosis of mucinous breast carcinoma with a micropapillary pattern. The purposes of this study were to investigate the sonographic features of pure mucinous breast carcinoma with micropapillary pattern (MUMPC) and to identify the role of ultrasound in the differential diagnosis between MUMPC and conventional pure mucinous breast carcinoma (cPMBC).Materials and MethodsWe obtained written informed consent from all patients, and the Ethics Committee of West China Hospital approved this retrospective study. The study was conducted between May and August 2020. We enrolled 133 patients with 133 breast lesions confirmed as mucinous breast carcinoma (MBC) histopathologically between January 2014 and January 2020.We retrospectively assessed sonographic features (margin, shape, internal echogenicity, calcification, posterior acoustic feature, invasive growth, blood flow grade, and rate of missed diagnosis) and clinical characteristics (age, tumor size, tumor texture, initial symptom, and lymph node metastasis). Bivariable analyses were performed using SPSS version 19.0.ResultsThe 133 lesions included 11 MUMPCs, 65 cPMBCs, and 57 mixed MBCs (MMBCs). There were significant differences in margin, shape, calcification, posterior acoustic feature, invasive growth, rate of missed diagnosis, average tumor size, and lymph node metastasis among the three groups (p < 0.05). The subsequent pairwise comparisons showed that there were significant differences in lymph node metastasis, margin, and invasive growth between MUMPC and cPMBC (p < 0.05). In patients aged >45 years, there was a significant difference in tumor size among the three groups (p = 0.045), and paired comparison showed that the average tumor size in the cPMBC group was larger than that in the MMBC group (p = 0.014).ConclusionMUMPC showed a non-circumscribed margin and invasive growth more frequently than cPMBC did. Lymphatic metastasis was more likely to occur in MUMPC than cPMBC. Ultrasound is helpful to distinguish MUMPC from cPMBC.

Background: Sepsis is the leading cause of mortality in intensive care units (ICUs). However, early diagnosis and prognosis of sepsis and septic shock are still a great challenge. Pentraxin-3 (PTX3) was shown to be associated with the severity and outcome of sepsis and septic shock. This study was carried out to investigate the diagnostic and prognostic value of PTX3 in patients with sepsis and septic shock based on Sepsis 3.0 definitions. Methods: In this single-center prospective observational study, all patients’ serum was collected for biomarker measurements within 24 h after admission. Logistic and Cox regression analyses were used to identify the potential biomarkers of diagnosis, severity stratification, and prediction. Results: Serum levels of PTX3 were significantly increased on the first day of ICU admission, while septic shock patients had highest PTX3 levels than other groups. A combination between PTX3 and procalcitonin (PCT) could better discriminate sepsis and septic shock, and PTX3 was an independent predictor of mortality in sepsis and septic shock patients. Conclusion: PTX3 may be a robust biomarker to classify the disease severity and predict the 90-day mortality of sepsis and septic shock based on the latest Sepsis 3.0 definitions.

Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or FAM175A LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 vs. 10.1 months, p < 0.05), or FAM175A LOH (16.5 vs. 9.2 months, p < 0.05), or negative WGD (16.5 vs. 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.

PURPOSE Thyroid cancer (TC) is the most common malignancy of the endocrine system and its incidence is gradually rising. Research has demonstrated a close link between autophagy and thyroid cancer. We constructed a prognostic model of autophagy-related long non-coding RNA (lncRNA) in thyroid cancer and explored its prognostic value. METHODS The data used in this study were all obtained from The Cancer Genome Atlas (TCGA) database and the Human Autophagy Database (HADb). We construct a co-expression network by autophagy-related genes and lncRNA to obtain autophagy-related lncRNAs. After univariate Cox regression analysis and multivariate Cox regression analysis, autophagy-related lncRNAs significantly associated with prognosis were identified. Based on the risk score of lncRNA, thyroid cancer patients are divided into high-risk group and low-risk group. RESULTS A total of 14,142 lncRNAs and 212 autophagy-related genes (ATGs) were obtained from the TCGA database and the HADb, respectively. We performed lncRNA-ATGs correlation analysis and finally obtained 1,166 autophagy-associated lncRNAs. Subsequently, we conducted univariate Cox regression analysis and multivariate Cox regression analysis, nine autophagy-related lncRNAs (AC092279.1, AC096677.1, DOCK9-DT, LINC02454, AL136366.1, AC008063.1, AC004918.3, LINC02471 and AL162231.2) significantly associated with prognosis were identified. Based on these autophagy-related lncRNAs, a risk model was constructed. The area under the curve (AUC) of the risk score was 0.905, proving that the accuracy of risk signature was superior. In addition, multiple regression analysis showed that risk score was a significant independent prognostic risk factor for thyroid cancer. CONCLUSION In this study, nine autophagy-related lncRNAs in thyroid cancer were established to predict the prognosis of thyroid cancer patients.

Objective The ectopic expression of Homeobox (HOX) gene cluster-embedded long non-coding RNAs (LncRNAs) have been involved several carcinogenic development and progressions. This meta-analysis aimed to summarize the LncRNAs to validate the functions and the prognostic values in several kinds of cancer. Methods The retrospective study was conducted to analyze the association between HOX gene-related LncRNAs and the survival outcomes. Cochran's Q and I2 test were used for calculated heterogeneity, and I2 > 50%, P Results Total 15,315 patients extracting from 121 studies focused on assessing the association between LncRNAs and the survival outcomes and 12,110 participants were enrolled to address the clinicopathological features. The results demonstrated that the overexpression of HOX gene cluster-embedded LncRNAs revealed notable association among tumor size (pooled OR = 1.80), lymph node metastasis (LNM) stage (pooled OR = 3.00), tumor node metastasis (TNM) stage (pooled OR = 2.86), histological differentiation (pooled OR = 1.59) and distant metastasis (pooled OR = 2.49). Additionally, the up-regulated LncRNAs predicted a poor prognosis in overall survival (pooled HR = 1.95, 95%CI = 1.86-2.04), and also disclosed worse prognosis among the stratified analysis included HOX clusters, LncRNAs, ethnicity, and tumor classification (pooled HRs >1). Conclusion In summary, the findings proved that HOX gene cluster-embedded LncRNAs acted as potential biomarkers for clinical treatment of several tumors and the overexpression might be a candidate hallmark for prognosis outcome.

Background Pregnancy exposure to titanium dioxide nanoparticles (TiO2NPs) is a vital consideration due to their inadvertent ingestion from environmental contamination. The potential health effects of TiO2NPs on the neurodevelopmental process should be seriously concerned in health risk assessment, especially for the pregnant women who are susceptible to the neurodevelopmental toxicity of nano-sized particles. However, the available evidence of neurodevelopmental toxicity of TiO2NPs remains very limited. Methods In the present study, the pregnant mice were intragastric administered with 150 mg/kg TiO2NPs from gestational day (GD) 8 to 21, the maternal behaviors and neurodevelopment-related indicators in offspring were all assessed at different time points after delivery. The gut microbial community in both dams and their offspring were detected by using 16S ribosomal RNA (rRNA) gene sequencing. The gut-brain axis related indicators were also determined in the offspring. Results The results clearly demonstrated that exposure to TiO2NPs did not affect the maternal behaviors of pregnant mice, or cause the deficits on the developmental milestones and perturbations in the early postnatal development of offspring. Intriguingly, our data revealed that pregnancy exposure of TiO2NPs did not affect locomotor function, learning and memory ability and anxiety-like behavior in offspring at postnatal day (PD) 21, but resulted in obvious impairments on these neurobehaviors at PD49. Similar phenomena were obtained in the composition of gut microbial community, intestinal and brain pathological damage in offspring in adulthood. Moreover, the intestinal dysbiosis induced by TiO2NPs might be highly associated with the delayed appearance of neurobehavioral impairments in offspring, possibly occurring through disruption of gut-brain axis. Conclusions This is the first report elucidated that pregnancy exposure to TiO2NPs caused delayed appearance of neurobehavioral impairments in offspring when they reached adulthood, although these perturbations did not happen at early life after delivery. These findings will provide valuable insights about neurodevelopmental toxicity of TiO2NPs, and call for comprehensive health risk assessment of TiO2NPs on the susceptible population, such as pregnant women. Graphical abstract

Although lymphatic endothelial cells (LECs) serve a positive role in tumor lymphatic metastasis, the regulation of LECs undergoing migration similar to that of tumor cells remains poorly understood. A previous study revealed that semaphorin 4C (Sema4C) could be a marker of LECs in cervical cancer. Thus, the present study aimed to understand the mechanism via which Sema4C could promote the development of tumor-associated characteristics in LECs in cervical cancer. Primary tumor-associated LECs (TLECs) were distinguished from cervical cancer by flow cytometry. The promigratory ability was assessed using the Transwell assay. Lentivirus infection was used to alter the expression of Sema4C in TLECs. Confocal laser scanning was used to determine the infection efficiency of lentivirus infection. Sema4C/ERK/E-cadherin pathway was measured by reverse transcription-quantitative PCR and western blotting. The co-localization of Sema4C and the lymphatic marker lymphatic vessel endothelial hyaluronan receptor 1 was verified. Primary tumor-associated LECs (TLECs) were isolated from a mouse xenograft cervical tumor model. It was revealed that overexpressing Sema4C stimulated the migratory ability of TLECs, downregulated E-cadherin expression and stimulated ERK phosphorylation, whereas knocking down Sema4C had the opposite effects. The treatment of PD98059 (ERK inhibitor) blocked the pro-migratory ability of TLECs, which indicated a dependence on the ERK signaling pathway. It was identified that the Sema4C/ERK/E-cadherin pathway may be critical for the migration of TLECs, which may promote lymph node metastasis. Therefore, Sema4C could be a promising target for the treatment of cervical cancer with lymphatic metastasis.

Nephrogenic proteins are re-expressed after ischemia/reperfusion (I/R) injury; however, the role of these proteins is still unknown. We found that sine oculis homeobox 1 (SIX1), a developmentally regulated homeoprotein, is reactivated in tubular epithelial cells after I/R injury associated with cell proliferation/migration and anti-inflammation. We demonstrated that SIX1 promoted cell proliferation by upregulating cyclin and glycolytic genes, and might increase cell migration by upregulating the expression of matrix metalloproteinase 9 (MMP9) directly or indirectly in the cell model. Notably, SIX1 targeted the promoters of the amino-terminal enhancer of split (AES) and fused in sarcoma (FUS), which are cofactors of nuclear factor-κB (NF-κB) subunit RELA, and then inhibited the transactivation function of RELA. The expression of monocyte chemotactic protein-1 (MCP-1) was decreased by the SIX1-mediated NF-κB pathway. Our results showed that the expression of cyclin, glycolytic genes, and MMP9 were significantly increased, and the infiltration of monocytes/macrophages (Mophs) was suppressed in SIX1 overexpression kidney at 1, 2, and 3 days after reperfusion. The overexpression of SIX1 resulted in reducing kidney damage from I/R injury in mice by promoting cell proliferation and migration and by inhibiting inflammation. Our study provides evidence that SIX1 involved in cell proliferation, migration, and anti-inflammation in the I/R model, which might be a potential therapeutic target that could be used to ameliorate kidney damage.

BackgroundPrimary peritoneal serous carcinoma (PPSC) is a rare tumor that lacks a prognostic prediction model. Our study aims to develop a nomogram to predict overall survival (OS) of PPSC patients.MethodsPatients confirmed to have PPSC between 2004 and 2012 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. LASSO and multivariate Cox regression analyses were used to screen for meaningful independent prognostic factors to construct a nomogram model for 3-, 5-, and 10-year OS among patients with PPSC. The nomogram compared the discrimination, calibration, and net benefits with the International Federation of Gynecology and Obstetrics (FIGO) staging system of PPSC patients.ResultsEight variables were selected to establish the nomogram for PPSC. The established nomogram performed significantly better than the FIGO staging system (p ConclusionsPPSC patients have distinct characteristics with respect to their presentation and survival outcomes. A prognostic nomogram constructed by various clinical indicators can provide better and more accurate predictions for patients with PPSC.

Simple Summary Breast cancer (BC) is a typical global cancer and the second leading cause of cancer-related deaths among women worldwide. BC is a heterogeneous disease with several subtypes, and it is a challenge to use multi-omic data effectively to find suitable drugs for patients. In this paper, we used the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drug combinations that could be used to treat different BC subtypes. Our results showed that this precision drug discovery strategy identified important disease-related genes in individuals and specific groups, supporting its efficiency, high reliability, and practical application value in drug discovery. Abstract Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

Background: Hereditary spherocytosis (HS), characterized by the presence of spherocytic red cells in peripheral blood, hemolysis, splenomegaly, jaundice, and gallstones, is a common form of inherited hemolytic anemia (HA). To date, five causative genes associated with HS have been identified, including ANK1, SPTB, SPTA1, SLC4A1, and EPB42.Methods: Clinically suspected patients with HS or undiagnosed HA from 14 Chinese families were enrolled in this study. We presented the patients’ clinical features and identified the causative gene variants in these patients using whole exome sequencing (WES), with 10 novel and four reported mutations in the ANK1 and SPTB genes (seven mutations in ANK1 and seven in SPTB), individually. Then, we reviewed all available literature on Chinese HS patients from 2000 to 2020 in PubMed and Chinese Journals with genetic results and clinical information, to delineate gene mutation spectrum and potential correlation with phenotypes.Results: A total of 158 variants (including 144 in previous reports and 14 in this study) indicated that ANK1 (46%) and SPTB (42%) were the most frequently mutated genes in Chinese HS patients, followed by SLC4A1 (11%) and SPTA1 (1%), while no mutations in EPB42 was reported. Most of the mutations in ANK1 and SPTB were nonsense (26/73 in ANK1 and 32/66 in SPTB) and frameshift (20/73 in ANK1 and 15/66 in SPTB), while missense mutations (14/18) accounted for the majority in SLC4A1. The higher mutation frequency of ANK1 was found in its exon 8, 9, 26, and 28. The majority of mutations in SPTB were located in its exon 13, 15, and 18–30, whereas mutations in SLC4A1 were scattered throughout the entire region of the gene.Conclusion: Our study expanded the mutation spectrum of ANK1 and SPTB. Furthermore, we clarified the mutational characteristics of causative genes by reviewing all available literature on Chinese patients with HS.

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p

Transient Receptor Potential Melastatin-2 (TRPM2) is a nonselective cation channel mediating Ca2+ influx in response to oxidative stress. Given that insulin resistance-related endothelial dysfunction in obesity attributes to fatty-acid-induced reactive oxygen species (ROS) overproduction, in this study, we addressed the possible role of TRPM2 in obesity-related endothelial insulin resistance and the underlying mechanisms. Whole-cell patch clamp technique, intracellular Ca2+ concentration measurement, western blot, vasorelaxation assay, and high-fat diet (HFD)-induced obese model were employed to assess the relationship between TRPM2 and endothelial insulin response. We found that both the expression and activity of TRPM2 were higher in endothelial cells of obese mice. Palmitate rose a cationic current in endothelial cells which was inhibited or enlarged by TRPM2 knockdown or overexpression. Silencing of TRPM2 remarkably improved insulin-induced endothelial Akt activation, nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production, while TRPM2 overexpression resulted in the opposite effects. Furthermore, TRPM2-mediated Ca2+ entry, CaMKII activation and the following activation of PERK/ATF4/TRB3 cascade were involved in the mechanism of obesity or palmitate-induced endothelial insulin resistance. Notably, in vivo study, knockdown of TRPM2 with adeno-associated virus harboring short-hairpin RNA (shRNA) against TRPM2 alleviated endothelial insulin resistance and ameliorated endothelium-dependent vasodilatation in obese mice. Thus, these results suggest that TRPM2-activated Ca2+ signaling is necessary to induce insulin resistance-related endothelial dysfunction in obesity. Downregulation or pharmacological inhibition of TRPM2 channels may lead to the development of effective drugs for treatment of endothelial dysfunction associated with oxidative stress state.

Long noncoding RNAs (lncRNAs) are a new class of potential biomarkers and therapeutic targets for cancer. In this study, we chose four single nucleotide polymorphisms (SNPs) in lncRNA-PCAT1 (rs1026411 G>A, rs12543663 A>C, rs710886 T>C, and rs16901904 T>C) to investigate the association between genetic variant in lncRNA-PCAT1 and susceptibility to lung cancer. The study was a hospital-based case–control study including 561 cancer-free controls and 468 lung cancer cases. Genotyping of four SNPs was conducted by using Taqman® allelic discrimination methods. All statistical analyses were performed by using IBM SPSS Statistics 22 software. We failed to find significant associations between four SNPs and lung cancer risk in all models. However, polymorphisms in rs1026411 and rs710886 were observed to have significant associations with susceptibility to non-small cell lung cancer (AG vs. GG: odds ratio [OR]a = 0.701, p* = 0.020 and AA+AG vs. GG: ORa = 0.711 [superscript “a” refers to OR adjusted by age, gender, and smoking], p* = 0.017 [asterisks “*” refers to p adjusted by age, gender, and smoking] for rs1026411; CT vs. TT: ORa = 0.723, p* = 0.047 and CC+CT vs. TT: ORa = 0.729, p* = 0.038 for rs710886). Besides, the rs1026411 polymorphism had a similar association with lung adenocarcinoma risk (AG vs. GG: ORa = 0.663, p* = 0.019 and AA+AG vs. GG: ORa = 0.685, p* = 0.020). Polymorphisms in rs710886 and rs16901904 were observed to be associated with lung squamous cell carcinoma risk (CC+CT vs. TT: ORa = 0.638, p* = 0.040 for rs710886; CC vs. TT: ORa = 2.582, p* = 0.033 and CC vs. TT+CT: ORa = 2.381, p* = 0.048 for rs16901904). In addition, there were no significant results in gene–environmental interactions in both additive and multiplicative models. Our results suggested that polymorphisms in lncRNA-PCAT1 might be associated with lung cancer susceptibility in a northeastern Chinese population. The results of gene–environmental interactions were not significant in lung cancer.