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Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell–specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with p53 and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.

Imatinib is a nontoxic tyrosine kinase inhibitor, used in the treatment of advanced renal cell carcinoma. However, some patients with renal cell carcinoma develop resistance to imatinib. Protein disulfide isomerase family 6 (PDIA6) was involved in the chemo-resistance of lung adenocarcinoma. In this study, the effect of PDIA6 on imatinib-resistance of renal cell carcinoma was investigated. First, PDIA6 was found to be up-regulated in the imatinib-resistant renal cell carcinoma tissues and cells. Functional assays showed that knockdown of PDIA6 sensitized imatinib-resistant renal cell carcinoma cells to imatinib through decreasing the half-maximal inhibitory concentration (IC50) of imatinib-resistant renal cell carcinoma cells. Secondly, cell proliferation of imatinib-resistant renal cell carcinoma cells was suppressed by PDIA6 silencing, and the apoptosis was promoted with reduced Bcl-2, enhanced Bax and cleaved caspase-3. Moreover, the interference of PDIA6 increased phosphorylation of H2A histone family member X (γH2AX), while decreased Rad51 and phosphorylated DNA-dependent protein kinase (DNA-PK) (p-DNA-PK) in imatinib-resistant renal cell carcinoma cells. Lastly, protein expression levels of Wnt3a and Frizzled1 (FZD1) in imatinib-resistant renal cell carcinoma cells were down-regulated by silencing of PDIA6. Over-expression of FZD1 attenuated PDIA6 silencing-induced increase in cell apoptosis and decrease in cell proliferation in imatinib-resistant renal cell carcinoma cells. In conclusion, knockdown of PDIA6 sensitized imatinib-resistant renal cell carcinoma cells into imatinib through inactivation of Wnt3a-FZD1 axis.

Purpose To compare the diagnostic performance of double contrast-enhanced ultrasound (DCEUS) and multi-detector row computed tomography (MDCT) in the gross classification of gastric cancer (GC) preoperatively. Methods 54 patients with histology proved GC were included in this retrospective study. The sensitivity and specificity of DCEUS and MDCT for the gross classification of GC was calculated and compared. The area under the curve (AUC) from a receiver operating characteristic curve analysis was used to evaluate the difference of the diagnostic performance between these two methods. Results There were no significant differences between DCEUS and MDCT in terms of AUC for early gastric cancer (EGC), Borrmann I, II, III and Borrmann (III + IV) (P = 0.248, 0.317, 0.717, 0.464 and 0.594, respectively). The accuracy of DCEUS in diagnosing EGC, Borrmann I, II and Borrmann (III + IV) was higher than that of MDCT (96% vs 92%; 96% vs 94%; 87% vs 80%; 83% vs 73%), while in determining Borrmann III and IV, that of DCEUS was lower than that of MDCT (72% vs 74%; 89% vs 96%). Conclusion Considering the revolution in clinical decision, prognosis evaluation, safety and non-invasion aspects, DCEUS can be used as the main alternative method for Borrmann classification of GC preoperatively.

Background This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). Methods This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. Results Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥ 23 kg/m2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037–8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Common Estimate OR: 2.531; 95% CI: 1.388–4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772–9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398–6.210; P = 0.004) after the adjustments of the BMI and diabetes. Conclusions Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.

Background This study aimed to identify the differences in clinical characteristics, puncture efficacy, antibiotic use, treatment duration, breastfeeding post-illness, and recurrence of patients with breast abscesses caused by methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-susceptible Staphylococcus aureus (MSSA) infection during lactation. Methods The clinical data of patients with breast abscesses during lactation who were treated from January 2014 to February 2017 at Haidian Maternal and Child Health Hospital, Beijing, were reviewed. According to bacterial culture results, they were divided into MRSA (n = 260) and MSSA (n = 962) groups. Hospitalization (whether or not the patients were hospitalized), postpartum period, maternal age, location of abscess cavities, number of abscess cavities, amount of pus, frequency of needle aspiration, failure of needle aspiration, antibiotic use, treatment duration, cessation of breastfeeding and recurrence were compared between the two groups using a t-test and a chi-squared test. Results We noted that only the cessation of breastfeeding was statistically significantly different between the two groups (P = 0.018). Hospitalization, postpartum period, maternal age, location of abscess cavities, number of abscess cavities, amount of pus, number of needle aspiration, failure of needle aspiration, antibiotic use, treatment duration and recurrence showed no statistically significant differences (P = 0.488, P = 0.328, P = 0.494, P = 0.218, P = 0.088, P = 0.102, P = 0.712, P = 0.336, P = 0.512, P = 0.386 and P = 0.359, respectively). Conclusions There was no difference in clinical characteristics between breast abscesses infected by MRSA and those infected by MSSA. Ultrasound-guided needle aspiration could be the first choice for MRSA-infected breast abscess treatment. There is no need to increase antibiotic use because of MRSA infection, unless it is necessary. The reason why more patients with MRSA infected breast abscesses terminated breastfeeding is unclear from this study.

Two new triucallane triterpenoids, polystanin F (1) and polystanin G (2), along with eight known compounds (3-10) were isolated from the fruits of Aphanamixis polystachya. Their structures were established on the basis of extensive spectroscopic analysis. Moreover, eight compounds were evaluated for their in vitro cytotoxicity against three cancer cell lines (liver cancer RT112, colon cancer HCT-116 and breast cancer M231) using the MTT method. Compound 7 showed significant cytotoxic activity against HCT-116 with IC50 1.27 µM.

Objectives The new antituberculous drugs delamanid and bedaquiline form the last line of defence against drug-resistant tuberculosis (TB). Understanding the background prevalence of resistance to new drugs can help predict the lifetime of these drugs’ effectiveness and inform regimen design. Methods Mycobacterium tuberculosis without prior exposure to novel anti-TB drugs were analysed retrospectively. Drug susceptibility testing for bedaquiline, delamanid, linezolid, clofazimine and widely used first- and second-line anti-TB drugs was performed. All TB isolates with resistance to new or repurposed drugs were subjected to whole-genome sequencing to explore the molecular characteristics of resistance and to perform phylogenetic analysis. Results Overall, resistance to delamanid, bedaquiline, linezolid and clofazimine was observed in 0.7% (11/1603), 0.4% (6/1603), 0.4% (7/1603) and 0.4% (6/1603) of TB isolates, respectively. Moreover, 1.0% (1/102), 2.9% (3/102), 3.9% (4/102) and 1.0% (1/102) of multidrug-resistant TB (MDR-TB) were resistant to bedaquiline, delamanid, linezolid and clofazimine, respectively. Whereas 22.2% (2/9) of extensively-drug resistant tuberculosis (XDR-TB) isolates were resistant to both delamanid and linezolid, and none was resistant to bedaquiline or clofazimine. Phylogenetic analysis showed that recent transmission occurred in two XDR-TB with additional resistance to delamanid and linezolid. None known gene mutation associated with delamanid resistance was detected. All four isolates with cross-resistance to bedaquiline and clofazimine had a detected gene mutation in Rv0678. Three of five strains with linezolid resistance had a detected gene mutation in rplC. Conclusion Detection of resistance to new anti-TB drugs emphasises the pressing need for intensive surveillance for such resistance before their wide usage.

BACKGROUND: Traditional Chinese medicine (TCM) has shown excellent therapeutic effects in the treatment of heart diseases. This meta-analysis was to evaluate the therapeutic effects of TCM on patients with atrial fibrillation (AF). METHODS: Four databases were searched from their establishment to 1 April 2021 for randomized controlled trials (RCTs) on the treatment of AF using TCM. The Cochrane Handbook 5.0.2 was used to perform to bias risk assessment, and RevMan 5.3 was used for meta-analysis. RESULTS: A total of 7 references were included. It was found that compared with conventional Western medicine, the effective rate of TCM or the combined therapy of TCM and Western medicine was higher [mean difference (MD) =1.85; 95% confidence interval (CI): 1.28 to 2.68; Z=3.26; P=0.001]; the success rate of conversion was increased (MD =1.58; 95% CI: 1.02 to 2.44; Z=2.06; P=0.04), the conversion time was shortened (MD =-224.82; 95% CI: -262.56 to -187.08; Z=11.68; P

OBJECTIVE The published studies regarding the relationships between zinc finger 365 (ZNF365) polymorphisms and inflammatory bowel disease (IBD) risk in Caucasians have yielded conflicting results. Therefore, we performed a meta-analysis to clarify this issue. METHODS The Electronic databases of PubMed, Web of Science, Wiley Online Library, and EMBASE were searched for eligible studies up to 31 November 2020. The quality of eligible studies was evaluated using the Newcastle-Ottawa Scale. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) under different genetic models were calculated to assess the strength of associations. RESULTS A total of 22 relevant case-control studies with 9542 ulcerative colitis (UC) patients and 13,886 controls, as well as 13,651 Crohn's disease (CD) patients and 15,256 controls, were involved in our meta-analysis. rs10761659 polymorphism significantly decreased CD and UC risk (except for the heterozygous model and the dominant model in UC), and rs10995271 polymorphism was significantly associated with UC (except for the heterozygous model and dominant model) rather than CD. CONCLUSIONS The meta-analysis demonstrated that the rs10761659 polymorphism might be a protective factor for both UC and CD in Caucasians, while the rs10995271 polymorphism might be a risk factor for UC rather than CD in Caucasians.

Background Both natural killer (NK) and CD3+CD56+natural killer T (NKT)-like cells play critical roles in the antitumor response. This study aimed to explore the effects of stereotactic body radiotherapy (SBRT) on peripheral NK and NKT-like cells in patients with hepatocellular carcinoma (HCC), and to identify possible surface markers on these cells that correlate with the prognosis. Methods Twenty-five HCC patients were prospectively enrolled in our study, and 10 healthy individuals were served as healthy controls. Flow cytometry was used to determine the counts and the percentages of peripheral NK and NKT-like cells, cells with certain receptors, and cells with intracellular interferon-γ and TNF-α secretion at different time points, including time points of prior to SBRT, at post-SBRT, and 3-month and 6-month after treatment. The Kaplan-Meier method with the log-rank test was applied for survival analysis. Results The peripheral NKT-like cells was increased at post-SBRT. Meanwhile, elevated levels of inhibitory receptors and reduced levels of activating receptors of NK cells were also observed in NK cells at post-SBRT, but the levels was not significantly different at 3-month and 6-month as compared with the baseline levels. Lower percentage of NKp30+NK cells before SBRT and higher percentage of CD158b+NK cells after SBRT were associated with poor progression-free survival. In addition, higher percentage of CD3+CD56+ NKT-like cells was associated with a higher overall survival rate in HCC patients. Conclusions SBRT has an apparent effect on both peripheral NK and CD3+CD56+NKT-like cells. Lower percentage of NKp30+NK cells before SBRT and higher percentage of CD158b+NK cells after SBRT are correlated with poor patients' PFS. Higher percentage of CD3+CD56+ NKT-like cells is associated with higher OS in HCC patients.

Background The coronavirus disease 2019 (COVID-19) has quickly spread across the world. However, the nutritional status of COVID-19 patients has not yet been extensively examined. Objectives The aim of this study was to evaluate the nutritional status of COVID-19 patients and to identify factors independently associated with malnutrition risk. Methods In this single-center, cross-sectional study, we analyzed data from 760 hospitalized COVID-19 patients between 29 January 2020 and 15 March 2020. Based on the Nutrition Risk Screening (NRS) 2002 score, we divided patients into the normal nutrition group (NRS score

BACKGROUND Sepsis usually causes hemodynamic abnormalities. Hemodynamic index is one of the factors to identify the severity of sepsis and an important parameter to guide the procedure of fluid resuscitation. The present study investigated whether the assessment of hemodynamic indices can predict the outcomes of septic patients undergoing resuscitation therapy. AIM To evaluate the prognostic value of hemodynamic indices in patients with sepsis after fluid resuscitation. METHODS A retrospective study was conducted in 120 patients with sepsis at Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University between October 2016 and October 2019. All patients were treated with sodium chloride combined with dextran glucose injection for fluid resuscitation. Patients' hemodynamic parameters were monitored, including heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), mean arterial pressure (MAP), central venous pressure (CVP), and central venous oxygen saturation. The prognostic value of hemodynamic indices was determined based on the prognosis status. RESULTS During fluid resuscitation, 86 patients developed septic shock and 34 did not. Ninety-nine patients survived and 21 patients died at 28 d after the treatment. Heart rate, CI, mean arterial pressure, SVRI, and CVP were higher in patients with septic shock and patients who died from septic shock than in non-shock patients and patients who survived, and central venous oxygen saturation was lower in patients with shock and patients who died than in non-shock patients and the survivors (P < 0.05). When prognosis was considered as a dependent variable and hemodynamic parameters was considered as independent variables, the results of a logistic regression analysis showed that CI, SVRI, and CVP were independent risk factors for septic shock, and CI was an independent risk factor for 28-d mortality (P < 0.05). CONCLUSION Hemodynamic indices can be used to evaluate the prognosis of septic patients after fluid resuscitation.

Background Comorbidity has been established as one of the important predictors of poor prognosis in lung cancer. In this study, we analyzed the prevalence of main comorbidities and its association with hospital readmission and fatality for lung cancer patients in China. Methods The analyses are based on China Urban Employees’ Basic Medical insurance (UEBMI) and Urban Residents’ Basic Medical Insurance (URBMI) claims database and Hospital Information System (HIS) Database in the Beijing University Cancer Hospital in 2013–2016. We use Elixhauser Comorbidity Index to identify main types of comorbidities. Results Among 10,175 lung cancer patients, 32.2% had at least one comorbid condition, and the proportion of patients with one, two, and three or more comorbidities was 21.7, 8.3 and 2.2%, respectively. The most prevalent comorbidities identified were other malignancy (7.5%), hypertension (5.4%), pulmonary disease (3.7%), diabetes mellitus (2.5%), cardiovascular disease (2.4%) and liver disease (2.3%). The predicted probability of having comorbidity and the predicted number of comorbidities was higher for middle elderly age groups, and then decreased among patients older than 85 years. Comorbidity was positively associated with increased risk of 31-days readmission and in-hospital death. Conclusion Our study is the first to provide an overview of comorbidity among lung cancer patients in China, underlines the necessity of incorporating comorbidity in the design of screening, treatment and management of lung cancer patients in China.

Background/Aims Depressive symptom is one of the most common symptoms in patients with irritable bowel syndrome (IBS), but its pathogenetic mechanisms remain unclear. As a voxel-level graph theory analysis method, degree centrality (DC) can provide a new perspective for exploring the abnormalities of whole-brain functional network of IBS with depressive symptoms (DEP-IBS). Methods DC, voxel-wise image and clinical symptoms correlation and seed-based functional connectivity (FC) analyses were performed in 28 DEP-IBS patients, 21 IBS without depressive symptoms (nDEP-IBS) patients and 36 matched healthy controls (HC) to reveal the abnormalities of whole brain FC in DEP-IBS. Results Compared to nDEP-IBS patients and HC, DEP-IBS patients showed significant decrease of DC in the left insula and increase of DC in the left precentral gyrus. The DC’s z-scores of the left insula negatively correlated with depression severity in DEP-IBS patients. Compared to nDEP-IBS patients, DEP-IBS patients showed increased left insula-related FC in the left inferior parietal lobule and right inferior occipital gyrus, and decreased left insula-related FC in the left precentral gyrus, right supplementary motor area (SMA), and postcentral gyrus. In DEP-IBS patients, abstracted clusters’ mean FC in the right SMA negatively correlated with depressive symptoms. Conclusions DEP-IBS patients have abnormal FC in brain regions associated with the fronto-limbic and sensorimotor networks, especially insula and SMA, which explains the vicious circle between negative emotion and gastrointestinal symptoms in IBS. Identification of such alterations may facilitate earlier and more accurate diagnosis of depression in IBS, and development of effective treatment strategies.

Background and Aims Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. Methods A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. Results Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004–5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083–9.725, p

Background Evidence‐based policy making for delivering affordable lung cancer care relies on the breadth, depth and quality of knowledge of its treatment costs. This study estimates the annual prevalence, medical service utilization and direct treatment costs of lung cancer in urban China. Materials and Methods Using claim data from China's urban basic medical insurance between 2013 and 2016, we constructed a nationally representative sample of lung cancer patients in urban China. Weighted descriptive analyses, Poisson regressions and generalized linear modelling were used to analyse lung cancer medical service utilization and costs and their associations with patient characteristics. Results In urban China, the annual prevalence of lung cancer was 87.65/100000, with nearly 0.65% of total health expenditures of urban residents spent on lung cancer treatments. Weighted average annual total medical costs of lung cancer was RMB33.78 (US$5.36) thousand, with annual out‐of‐pocket costs of RMB10.26 (US$1.63) thousand. The average yearly number of lung cancer‐related outpatient visits was 2.42 and inpatient admissions was 2.07, with an average cost of RMB0.75 (US$0.12) thousand for outpatients and RMB 15.67 (US$2.49) thousand for inpatients. Inpatient expenses were the major component (95%) of lung cancer medical costs, with roughly 67% of inpatient services occurring in high‐level tertiary hospitals. Medical care utilization and direct medical costs were associated with sex, age and insurance status. Western medicine costs were the major contributor (39.4%) to average lung cancer‐related medical costs. Conclusion Lung cancer imposed a significant economic burden on China's health system and a financial cost on lung cancer sufferers and their families. Specific policies are required to efficiently allocate health resources, contain health expenditure and decrease the individual financial burden of lung cancer., In urban China, the annual prevalence of lung cancer was 87.65/100000, with nearly 0.65% of total health expenditures of urban residents spent on lung cancer treatments. Inpatient expenses were the major component (95%) of lung cancer medical costs.Western medicine cost contributes 39.4% for lung cancer medical costs.

Overexpression of AKR1C3, an aldo-keto reductase, was recently discovered in liver cancers. In this study, an inverse correlation between AKR1C3 expression and survival of patients with liver cancer was observed. AKR1C3 inhibitors, however, failed to suppress liver cancer cell growth. The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. In patient-derived mouse xenograft models, TH3424 at doses as low as 1.5 mg/kg eliminated liver tumors with no apparent toxicity. Therefore, TH3424 is a promising drug candidate for liver cancer and other types of cancers overexpressing AKR1C3.

Objective The aim of this work was to characterize the genetic abnormalities and prenatal diagnosis indications in one fetus with Cri-du-Chat syndrome with codependent 10q24.2-q26.3 duplication in prenatal screening. Materials and methods A 31-year-old woman had a second trimester serum screening that indicated the fetus was at low risk. During this pregnancy, the woman underwent amniocentesis at 18+4 weeks' gestation because of adverse fertility history and nuchal fold thickening. Cytogenetic analysis and next-generation sequencing analysis were simultaneously performed to provide genetic analysis of fetal amniotic fluid. According to abnormal results, parental chromosome karyotype of peripheral blood was performed to analysis. Results CNV-seq detected a 14.00 Mb deletion at 5p15.33-p15.2 and a 34.06 Mb duplication at 10q24.2-q26.3 in the fetus. Cytogenetic analysis of the fetus revealed a karyotype of 46, XY, der(5) t(5;10) (p15.2;q26.3). The karyotype of pregnant women was 46,XX,t(5;10) (p15.2;q24.2). The pregnancy was subsequently terminated after sufficient informed consent. Conclusion This is the first study that reports prenatal diagnosis of a Cri-du-Chat syndrome with concomitant 10 q24.2-q26.3 duplication. Adverse pregnancy history has to be as an important indicator for prenatal diagnosis, and the genetic factors of abnormal pregnancy should be identified before next pregnancy. Nuchal fold thickening is closely related to fetal abnormalities. Combined with ultrasonography, the use of CNV-seq will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.

Background Hypoxaemia in post-surgical patients of esophageal cancer (EC) is common in thoracic departments. However, few studies have investigated the role of high-flow nasal cannula (HFNC) compared with conventional oxygen therapy (COT). Methods A retrospective study was implemented to enroll hypoxemic patients after esophagectomy who were treated by HFNC or COT immediately after extubation between January 2019 and December 2019. We compared the effect of HFNC or COT in patients regarding the vital signs and arterial blood gases, the incidence of anastomotic leakage, postoperative pulmonary complications (PPCs), sore throat/nose, and reintubation, length of stay, and sputum production. We also 3D reconstructed the postoperative chest CT, and compared the amount of lung volume loss caused by PPCs (pneumothorax, atelectasis, pulmonary consolidation and pleural effusion) between the two groups. Results Compared to patients in COT group, sore throat/nose in HFNC group was lower, the sputum production was higher, and the total hospital stay was shorter. Compared to COT, HFNC treatment decreased systolic blood pressure (SBP) at day 1, diastolic blood pressure (DBP) at day 1-4, and heart rate (HR) at day 2-4, increased arterial partial pressure of oxygen (PaO2) at day 1-4, and arterial oxygen saturation (SaO2%) at day 1-2. In addition, the rate of PPCs and anastomotic leakage in HFNC group were lower than those in COT group. Compared to COT, HFNC treatment significantly decreased the amount of lung volume loss caused by PPCs. Conclusions HFNC can improve the hypoxemia of patients after esophagectomy, increase the flow of sputum, reduce the incidence of PPC and anastomotic leakage.

Vascular calcification (VC) is highly prevailing in cardiovascular disease, diabetes mellitus, and chronic kidney disease and, when present, is associated with cardiovascular events and mortality. The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is regarded as the foundation for mediating VC. Related transcriptional enhancer factor (RTEF-1), also named as transcriptional enhanced associate domain (TEAD) 4 or transcriptional enhancer factor-3 (TEF-3), is a nuclear transcriptional factor with a potent effect on cardiovascular diseases, apart from its oncogenic role in the canonical Hippo pathway. However, the role and mechanism of RTEF-1 in VC, particularly in calcification of VSMCs, are poorly understood. Our results showed that RTEF-1 was reduced in calcified VSMCs. RTEF-1 significantly ameliorated β-glycerophosphate (β-GP)-induced VSMCs calcification, as detected by alizarin red staining and calcium content assay. Also, RTEF-1 reduced alkaline phosphatase (ALP) activity and decreased expressions of osteoblast markers such as Osteocalcin and Runt-related transcription factor-2 (Runx2), but increased expression of contractile protein, including SM α-actin (α-SMA). Additionally, RTEF-1 inhibited β-GP-activated Wnt/β-catenin pathway which plays a critical role in calcification and osteogenic differentiation of VSMCs. Specifically, RTEF-1 reduced the levels of Wnt3a, p-β-catenin (Ser675), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β (Ser9), but increased the levels of p-β-catenin (Ser33/37). Also, RTEF-1 increased the ratio of p-β-catenin (Ser33/37) to β-catenin proteins and decreased the ratio of p-GSK-3β (Ser9) to GSK-3β protein. LiCl, a Wnt/β-catenin signaling activator, was observed to reverse the protective effect of RTEF-1 overexpression on VSMCs calcification induced by β-GP. Accordingly, Dickkopf-1 (Dkk1), a Wnt antagonist, attenuated the role of RTEF-1 deficiency in β-GP-induced VSMCs calcification. Taken together, we concluded that RTEF-1 ameliorated β-GP-induced calcification and osteoblastic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling pathway.

N6-methyladenosine (m6A) is the most abundant and prevalent epigenetic modification of mRNA in mammals. This dynamic modification is regulated by m6A methyltransferases and demethylases, which control the fate of target mRNAs through influencing splicing, translation and decay. Recent studies suggest that m6A modification plays an important role in the progress of cardiac remodeling and cardiomyocyte contractile function. However, the exact roles of m6A in cardiovascular diseases (CVDs) have not been fully explained. In this review, we summarize the current roles of the m6A methylation in the progress of CVDs, such as cardiac remodeling, heart failure, atherosclerosis (AS), and congenital heart disease. Furthermore, we seek to explore the potential risk mechanisms of m6A in CVDs, including obesity, inflammation, adipogenesis, insulin resistance (IR), hypertension, and type 2 diabetes mellitus (T2DM), which may provide novel therapeutic targets for the treatment of CVDs.

The effect of postmastectomy radiotherapy (PMRT) on patient outcomes after neoadjuvant chemotherapy (NAC) remains controversial. We aimed to establish a model to identify the subsets benefiting from PMRT and to examine the effect of PMRT according to molecular subtype. We retrospectively analyzed 1118 cT1-4cN0-3M0 breast cancer patients treated with NAC and mastectomy. A nomogram predicting locoregional recurrence (LRR) was established based on 418 unirradiated patients, and X-tile analysis was performed to divide the patients into two risk groups. The effect of PMRT on LRR, distant recurrence (DR), and breast cancer mortality (BCM) was estimated for patients with different molecular subtypes in two risk groups. A nomogram predicting LRR was developed using six factors: histologic classification, lymphovascular invasion, ypT stage, ypN stage, estrogen receptor status, and Ki-67 expression. Our study found that PMRT correlated with lower 5-year LRR, DR, and BCM rates for the high-risk group; however, no significant improvement in these endpoints was observed in the low-risk group. Among patients with high risk, subgroup analysis showed that LRR control was improved after PMRT for the human epidermal growth factor receptor 2 (HER2)-negative/hormone receptor (HR)-positive (HER2−/HR+), HER2-positive (HER2+)/HR+, and HER2−/HR-negative (HR−) subtypes, with hazard ratios of 0.113 (95% confidence [CI] 0.034–0.379; p

Background Sepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified. Methods RAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively. Results Our results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression. Conclusions MAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.

Resistin, a cysteine-rich secretory protein, has a pleiotropic role in humans. Resistin usually presents as trimer or hexamer in plasma, and targets specific receptors Toll Like Receptor 4 (TLR4) or Adenylyl Cyclase-Associated Protein 1 (CAP1). Upon binding to TLR4 and CAP1, resistin can trigger various intracellular signal transduction pathways to induce vascular inflammation, lipid accumulation, and plaque vulnerability. These pro-atherosclerotic effects of resistin appear in various cell types, including endothelial cells, vessel smooth muscle cells and macrophages, which cause diverse damages to cardiovascular system from dyslipidemia, atherosclerosis rupture and ventricular remodeling. In this review, we gather recent evidence about the pro- atherosclerotic effects of resistin and highlight it as a candidate therapeutic or diagnostic target for cardiovascular disease.

Leptospirosis, caused by pathogenic Leptospira species, has emerged as a widespread zoonotic disease worldwide. Macrophages mediate the elimination of pathogens through phagocytosis and cytokine production. Scavenger receptor A1 (SR-A1), one of the critical receptors mediating this process, plays a complicated role in innate immunity. However, the role of SR-A1 in the immune response against pathogenic Leptospira invasion is unknown. In the present study, we found that SR-A1 is an important nonopsonic phagocytic receptor on murine macrophages for Leptospira. However, intraperitoneal injection of leptospires into WT mice presented with more apparent jaundice, subcutaneous hemorrhaging, and higher bacteria burdens in blood and tissues than that of SR-A1-/- mice. Exacerbated cytokine and inflammatory mediator levels were also observed in WT mice and higher recruited macrophages in the liver than those of SR-A1-/- mice. Our findings collectively reveal that although beneficial in the uptake of Leptospira by macrophage, SR-A1 might be exploited by Leptospira to modulate inflammatory activation and increase the susceptibility of infection in the host. These results provide our new insights into the innate immune response during early infection by L. interrogans.

Background Sleeve lobectomy has been reported to be a safe procedure after neoadjuvant chemotherapy. We aim to evaluate the oncological and surgical outcomes of neoadjuvant chemoimmunotherapy (IO+C) for local advanced non-small cell lung cancer (NSCLC) patients who underwent sleeve lobectomy. Methods NSCLC patients that underwent sleeve lobectomy between December 2016 and December 2019 were retrospectively included. Patients were divided into two groups: neoadjuvant IO+C and chemotherapy. Oncological, intraoperative and postoperative variables were compared. Results In total, 20 patients underwent sleeve lobectomy after neoadjuvant IO+C (n=10) or chemotherapy (n=10). In the neoadjuvant IO+C group, 8/10 (80%) patients achieved a partial response (PR), 1/10 (10%) patients had a complete pathological response (CPR), and 5/10 (50%) patients achieved a major pathological response (MPR). In the neoadjuvant chemotherapy group, only 3/10 (30%) patients had PR, and 3/10 (30%) patients achieved MPR. No complications were found in the neoadjuvant IO+C group, 1 chylothorax occurred in the neoadjuvant chemotherapy group. Other peri- and postoperative outcomes were similar: bleeding volume (365.00 vs. 347.50 mL; P=0.267), operation time (291.88 vs. 287.50 min; P=0.886), chest tube duration (5.40 vs. 5.00 day; P=0.829), total drainage volume (815.50 vs. 842.50 mL; P=0.931) and the length of hospital-stay (7.00 vs. 6.56 day; P=0.915). In addition, less N1 (average number 4.70 vs. 7.40) and N2 (average number 9.80 vs. 20.10) lymph nodes were acquired in the neoadjuvant IO+C group than the neoadjuvant chemotherapy group. The number of lymph nodes positive for tumor cells was also less in the neoadjuvant IO+C group than the neoadjuvant chemotherapy group, both in N1 (0.40 vs. 1.60) and N2 (0.10 vs. 1.30). The positive lymph node ratio (LNR) was lower in the neoadjuvant IO+C group, both in N1 (0.05 vs. 0.15) and N2 (0.01 vs. 0.09). A greater destruction on elastic fiber of the blood vessels, vascular wall degeneration, fibrinoid necrosis and fibrosis, and greater pulmonary interstitial exudation were found in neoadjuvant IO+C patients compared to the neoadjuvant chemotherapy patients. Conclusions Sleeve lobectomy for advanced NSCLC following IO+C is feasible, although the operations become more complex, neoadjuvant IO+C did not delay postoperative recovery.

Bone targeting is one of the most potentially valuable therapeutic methods for medically treating bone diseases, such as osteoarthritis, osteoporosis, nonunion bone defects, bone cancer, and myeloma-related bone disease, but its efficacy remains a challenge due to unfavorable bone biodistribution, off-target effects, and the lack of cell specificity. To address these problems, we synthesized a new dual-targeting nanocarrier for delivery to bone by covalently modifying the G4.0 PAMAM dendrimer with the C11 peptide and the CH6 aptamer (CH6-PAMAM-C11). The molecular structure was confirmed using 1H-NMR and FT-IR spectroscopy. CLSM results showed that the novel nanocarrier could successfully accumulate in the targeted cells, mineralized areas and tissues. DLS and TEM demonstrated that CH6-PAMAM-C11 was approximately 40-50 nm in diameter. In vitro targeting experiments confirmed that the C11 ligand had a high affinity for HAP, while the CH6 aptamer had a high affinity for osteoblasts. The in vivo biodistribution analysis showed that CH6-PAMAM-C11 could rapidly accumulate in bone within 4 h and 12 h and then deliver drugs to sites of osteoblast activity. The components of CH6-PAMAM-C11 were well excreted via the kidneys. The accumulation of many more CH6-PAMAM-C11 dual-targeting nanocarriers than single-targeting nanocarriers was observed in the periosteal layer of the rat skull, along with aggregation at sites of osteoblast activity. All of these results indicate that CH6-PAMAM-C11 may be a promising nanocarrier for the delivery of drugs to bone, particularly for the treatment of osteoporosis, and our research strategy may serve as a reference for research in targeted drug, small molecule drug and nucleic acid delivery.

Scaffold proteins play crucial roles in orchestrating synaptic signaling and plasticity in the excitatory synapses by providing a structural link between glutamatergic receptors, signaling molecules, and neuronal cytoskeletons. FRMPD4 is a neural scaffold protein that binds to metabotropic glutamate receptors via its FERM domain. Here, we determine the crystal structure of the FERM domain of FRMPD4 at 2.49 Å resolution. The structure reveals that the canonical target binding groove of FRMPD4 FERM is occupied by a conserved fragment C-terminal to the FERM domain, suggesting that the FRMPD4–mGluR interaction may adopt a distinct binding mode. In addition, FRMPD4 FERM does not contain a typical phosphoinositide binding site at the F1/F3 cleft found in ERM family FERM domains, but it possesses a conserved basic residue cluster on the F2 lobe which could bind to lipid effectively. Finally, analysis of mutations that are associated with X-linked intellectual disability suggests that they may compromise the biological function of FRMPD4 by destabilizing the FERM structure.

Apoptosis is an important programmed cell death process involved in ischemia/reperfusion injury. MicroRNAs are considered to play an important role in the molecular mechanism underlying the regulation of cerebral ischemia and reperfusion injury. However, whether miR-670 can regulate cell growth and death in cerebral ischemia/reperfusion and the underlying mechanism are poorly understood. In this study, we established mouse models of transient middle artery occlusion and Neuro 2a cell models of oxygen-glucose deprivation and reoxygenation to investigate the potential molecular mechanism by which miR-670 exhibits its effects during cerebral ischemia/reperfusion injury both in vitro and in vivo. Our results showed that after ischemia/reperfusion injury, miR-670 expression was obviously increased. After miR-670 expression was inhibited with an miR-670 antagomir, cerebral ischemia/reperfusion injury-induced neuronal death was obviously reduced. When miR-670 overexpression was induced by an miR-670 agomir, neuronal apoptosis was increased. In addition, we also found that miR-670 could promote Yap degradation via phosphorylation and worsen neuronal apoptosis and neurological deficits. Inhibition of miR-670 reduced neurological impairments after cerebral ischemia/reperfusion injury. These results suggest that microRNA-670 aggravates cerebral ischemia/reperfusion injury through the Yap pathway, which may be a potential target for treatment of cerebral ischemia/reperfusion injury. The present study was approved by the Institutional Animal Care and Use Committee of China Medical University on February 27, 2017 (IRB No. 2017PS035K).

Summary: Background: More research is needed to understand the long-term effects of prenatal exposure to adverse events, such as floods and other natural disasters, on cognitive outcomes in childhood. We aimed to explore the risk of cognitive impairment in children following maternal exposure to the 1998 Yangtze River flood in China during pregnancy. Methods: For this study we obtained and analysed individual-level data from the second China National Sample Survey on Disability (CNSSD), which was done in 2006. We defined the flood period as June–August, 1998. The analytical sample comprised children from four birth cohorts, defined according to their month of birth: the post-partum exposed cohort (children born between June, 1997, and May, 1998), the prenatal exposed cohort (children born between June, 1998, and May, 1999), the preconception exposed cohort (children born between June 1999, and May, 2000), and the unexposed cohort (children born between June, 2000, and May, 2001). In the CNSSD, cognitive impairment was assessed and diagnosed by validated screening tools and procedures. Difference-in-difference models were used to examine variations in the effects of maternal flood exposure on cognitive impairment in childhood across the different birth cohorts and regions. Findings: 108 175 children born between June, 1997, and May, 2001, and aged 4–8 years at the time of the survey, were included in our analysis. 1131 children had a cognitive impairment; the prevalence of cognitive impairment was 1·05% (95% CI 0·99–1·11). Maternal exposure to flood during pregnancy increased the risk of cognitive impairment among children (adjusted odds ratio [OR] 2·18 [95% CI 1·54–3·08]; p

Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in HepG2 cells was assayed along with the qPCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program LibDock of Discovery Studio 2018 software. The results showed that puerarin improved HepG2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.

Introduction Cytochrome P450 (CYP) 2J2 is a major enzyme that controls epoxyeicosatrienoic acids biosynthesis, which may play a role in chronic obstructive pulmonary disease (COPD) development. In this study, we aimed to assess the influence of CYP2J2 polymorphisms with COPD susceptibility. Material and methods A case–control study enrolled 313 COPD cases and 508 controls was to investigate the association between CYP2J2 polymorphisms and COPD risk. Agena MassARRAY platform was used to genotype CYP2J2 polymorphisms. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the association between CYP2J2 polymorphisms and COPD risk. Results We observed rs11207535 (homozygote: OR = 0.08, 95%CI = 0.01–0.96, p = 0.047; recessive: OR = 0.08, 95%CI = 0.01–0.94, p = 0.044), rs10889159 (homozygote: OR = 0.08, 95%CI = 0.01–0.92, p = 0.043; recessive: OR = 0.08, 95%CI = 0.01–0.90, p = 0.040) and rs1155002 (heterozygote: OR = 1.63, 95%CI = 1.13–2.36, p = 0.009; dominant: OR = 1.64, 95%CI = 1.15–2.35, p = 0.006; additive: OR = 1.45, 95%CI = 1.09–1.92, p = 0.011) were significantly associated with COPD risk. Allelic tests showed T allele of rs2280274 was related to a decreased risk of COPD and T allele of rs1155002 was associated with an increased COPD risk. Stratified analyses indicated the effects of CYP2J2 polymorphisms and COPD risk were dependent on gender and smoking status (p Conclusion It suggested CYP2J2 polymorphisms were associated with COPD susceptibility in the Chinese Han population.

To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). This prospective clinical trial ( ClinicalTrials.gov : NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016–10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (Cmax) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3–4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher’s exact test, and Pearson correlation. Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-Cmax increased from 1 segment (DOX-Cmax, 83.94 ± 75.09 ng/mL; DN-DOX-Cmax, 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX-Cmax, 139.66 ± 117.73 ng/mL; DN-DOX-Cmax, 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX-Cmax, 334.35 ± 215.18 ng/mL; DN-DOX-Cmax, 7.11 ± 4.24 ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-Cmax were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-Cmax and tumor response after cTACE in liver cancer. • Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (Cmax). • Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin Cmax after conventional TACE. • ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.

Background We aimed to examine the risk factors for chronic kidney disease (CKD) stage 3 among adults with ASK from unilateral nephrectomy. Methods We retrospectively collected data from adult patients with ASK between January, 2009 and January, 2019, identified from a tertiary hospital in China. The clinical data were compared between patients who developed CKD stage 3 and those who did not develop CKD stage 3 during follow-up. Results In total, 172 patients with ASK (110 men; median 58.0 years) were enrolled, with a median follow-up duration of 5.0 years. During follow-up, 91 (52.9%) and 24 (14.0%) patients developed CKD stage 3 and end-stage renal disease, respectively. Multiple regression analyses showed that age (odds ratio [OR] 1.076, 95% confidence interval [CI] 1.039–1.115, p p = 0.002), hyperuricemia (OR 2.733, 95% CI 1.104–6.764, p = 0.03), a history of cardiovascular disease (CVD) (OR 5.583, 95% CI 1.884–18.068, p = 0.002), and ASK due to renal tuberculosis (OR 8.816, 95% CI 2.92–26.62, p Conclusions Regular follow-up of renal function is needed among adult patients with ASK. Optimal management of diabetes, hyperuricemia, and CVD may reduce their risk of CKD stage 3, especially among those that undergo unilateral nephrectomy for renal tuberculosis.

Chronic obstructive pulmonary disease (COPD) is a high incidence in the elderly and significantly affects the quality of life. CYP2C9 and CYP2C19 play an important role in tobacco-related diseases ...

We aimed to reveal clinicopathological features and explore survival-related factors of colorectal signet ring cell carcinoma (SRCC). A population-based study was carried out to investigate colorectal SRCC by using data extracted from the surveillance, epidemiology and end results (SEER) database between 2004 and 2015. In total, 3,278 patients with colorectal SRCC were identified, with a median age of 63 (12–103) years old. The lesions of most patients (60.49%) were located in the cecum–transverse colon. In addition, 81.27% patients had advanced clinical stage (stage III/IV), and 76.69% patients had high pathological grade. The 3–, 5–year cancer‐specific survival and overall survival rate was 35.76%, 29.32% and 32.32%, 25.14%. Multivariate analysis revealed that primary site in cecum–transverse colon, married, received surgery, lymph node dissections ≥ 4 regional lymph nodes were independent favorable prognostic. Meanwhile, aged ≥ 65 years, higher grade, tumor size ˃5 cm and advanced AJCC stage were associated with poor prognosis. Patient age, tumor grade, marital status, tumor size, primary tumor location, AJCC stage, surgery and number of dissected lymph node had significant correlation with prognosis of colorectal SRCC.

Cancer therapeutic strategies based on angiogenesis attract great attention from fundamental and clinical research. Blocking oxygen and nutrition supply to tumor cells could inhibit the growth of tumors based on occlusion of blood vessels in the tumor. Herein, we report a dual-responsive peptide-based nanoparticle, mimicking the laminin fibrillogenesis specifically and highly efficiently in tumor vessels, resulting in the blockage of tumor vessels and the growth inhibition of tumors. The laminin mimic peptide (LMMP) is designed with a fibrillation sequence, a pH-responsive sequence, and a targeting sequence. The LMMP in nanoformulations is delivered to blood vessels in the tumors, where the microenvironment (pH and microthrombus) enable LMMP to process laminin fibrillogenesis, constructing fibrous networks. The laminin-like fibrous networks capture red blood cells etc., forming occlusion specifically in the tumor blood vessels to inhibit the growth of the tumor.

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

Background It is evident that comorbidity exacerbate the complexity of the management of lung cancer, however, limited research has been conducted to investigate the impact of comorbidity on health service utilization and cost, as well as the treatment choice among lung cancer patients. We examined the association of comorbidity with medical service utilization, cost and treatment choice among lung cancer patients in China. Methods We used claims data from China Urban Employees’ Basic Medical Insurance (UEBMI) and Urban Residents’ Basic Medical Insurance (URBMI) between 2013 to 2016 and data from Hospital Information System (HIS) Database in Beijing Cancer Hospital (BCH). Elixhauser Comorbidity Index was used to assess comorbidity. Negative binomial regression, generalized linear model (GLM) with a gamma distribution and a log link, and logistic regression was applied to assess the associations between comorbidity and medical service utilization, cost and treatment choice, respectively. Results Among 8655 patients with lung cancer, 31.3% of had at least one comorbid conditions. Having comorbidity was associated with increased number of annual outpatient visits (1.6, 95%CI: 1.3, 1.9) and inpatients admissions (0.8, 95%CI, 0.70, 0.90), increased outpatient (USD635.5, 95%CI: 490.3, 780.8) and inpatient expenditure (USD2 470.3, 95CI%: 1998.6, 2941.9), as well as increased possibility of choosing radio therapy (OR: 1.208, 95%CI:1.012–1.441) and chemotherapy (1.363, 1.196–1.554), and decreased possibility of choosing surgery (0.850, 0.730–0.989). The medical utilization and expenditure, the possibility of choosing radiotherapy increases, and the possibility of choosing surgery decreases with the increasing number of chronic conditions. There are variations in the association with medical service utilization and expenditure, and treatment choice among individuals with different types of comorbid conditions. Conclusion Comorbidity among lung cancer patients restricts the potential treatment choices and poses an extra substantial health care burden. Our findings provide implications for both the clinical management and health service planning and financing for lung cancer patients.

Purpose Hearing loss has not received sufficient attention, especially in low- and middle-income countries where more than 80% of the people with hearing loss reside. Little is known about the preference for hearing aids among people with hearing loss in developing countries. The aim of this study is to elicit the preferences for hearing aid attributes among rural Chinese adults with moderate or greater hearing loss and examine how preferences vary across different individual socioeconomic characteristics. Patients and methods We interviewed 125 adults in two rural counties in Shandong province in China. A discrete choice experiment (DCE) with eight attributes, comprising out-of-pocket (OOP) costs, hearing aid style, effective in quiet settings and noisy settings, feedback (whistling), connectivity, water/sweat resistance and battery life, were employed to examine participants' preference for hearing aids. Mixed logit models were used for the statistical analyses. Results While OOP costs, effectiveness in quiet settings, water/sweat resistance and battery life were significantly associated with choosing a hearing aid, rural Chinese adults with moderate or greater hearing loss valued effectiveness in noisy settings above other attributes of hearing aids, followed closely by lack of feedback. The preference of the attributes of OOP costs, in the canal hearing aids, effectiveness in noisy settings, connectivity and battery life varied across individual socioeconomic characteristics including sex, marriage, employment, income and education level. Conclusion Our study supported the view that the development of noise suppression and feedback cancellation systems remained the main challenge for the hearing aid industry. Since OOP costs were also associated with choosing a hearing aid, the policy advice is to improve reimbursements from insurance schemes and/or reduce the costs of hearing aids.

Background: Congenital pyriform sinus fistula (CPSF) is a rare branchial cleft deformity. The characteristics and management of CPSF in neonates are different from those in children or adults, and a comprehensive understanding of the imaging features of neonatal CPSF can facilitate its preoperative diagnosis. Thus, the aim of this study was to summarize the ultrasonography (US) and CT imaging findings of CPSF in neonates.Methods: Forty-five full-term neonates with CPSF, confirmed by pathology after surgical resection from January 2012 to October 2020, were included in this retrospective study. All patients underwent preoperative cervical US and contrast-enhanced CT examinations, and the imaging findings were analyzed.Results: Forty-six cervical cystic masses were found in 45 neonates, including one case with bilateral lesions, three cases with lesions on the right side, and 41 cases on the left side. Both US and CT detected neck abnormality among all cases, while the diagnostic accuracy of US (15/46, 32.6%) was lower than that of CT (42/46, 91.3%). Moreover, CT showed significantly higher detection rates of intralesional air bubbles, involvement of the ipsilateral thyroid, deviation of the airway, and expansion into the mediastinal and retropharyngeal space compared with the US. As the age increased, it was more likely to present some features including the absence of air-containing, thick cyst wall, and poorly defined border (ρ Conclusion: CPSF in the neonates showed distinctive imaging findings on contrast-enhanced CT scan, which provides important supplementary information for the diagnosis of CPSF after the initial US examination.

Purpose: Pancreatic cancer (PC) is an inflammatory tumor. Tumor microenvironment (TME) plays an important role in the development of PC. This study aims to explore hub genes of TME and establish a prognostic prediction system for PC.Methods: High throughput RNA-sequencing and clinical data of PC were downloaded from TCGA and ICGC database, respectively. PC Patients were divided into High- and low-score group by using stromal, immune scores system based on ESTIMATE. Differentially expressed genes (DEGs) between High- and low-score patients were screened and survival related DEGs were identified as candidate genes by univariate COX regression analysis. Final variables for establishment of the prognostic prediction system were determined by LASSO analysis and multivariate COX regression analysis. The predictive power of the prognostic system was evaluated by internal and external validation. Results: A total of 210 candidate genes were identified by stromal, immune scores system and survival analyses. Finally, the prognostic risk score system was constructed by the following genes: FAM57B, HTRA3, CXCL10, GABRP, SPRR1B, FAM83A, LY6D. In process of internal validation, Harrell's C-index of this prognostic risk score system was 0.73, and the area under the receiver operating characteristic curve (AUC) value of 1-year, 2-year and 3-year OS period was 0.67, 0.76 and 0.86, respectively. In the external validation set, the survival prediction C-index was 0.71, and the AUC was 0.81, 0.72, 0.78 at 1-year, 2-year and 3-year, respectively.Conclusion: This prognostic risk score system based on TME demonstrated a good predictive capacity to the prognosis of PC.

As a frequently occurring infectious disease mainly caused by Candida albicans, vulvovaginal candidosis (VVC) affects more than 100 million women worldwide every year. Multiple factors that influence C. albicans colonisation have been linked to the incidence of VVC, including high levels of circulating oestrogen due to pregnancy, the use of oral contraceptives, and hormone replacement therapy. This review provides an overview of the current understanding of the mechanism(s) by which oestrogen contributes to VVC, which might provide meaningful guidance to the prevention and treatment of this disease.

Objective Evidence suggested that traumatic events, including pandemics, can be associated with psychiatric symptoms like increased anxiety and depression. However, there were many unknowns concerning the emergent global coronavirus-19 (COVID-19), including its impact on psychiatric health within the United States. Our study aimed to track trends of mental health problems in individuals who presented with psychiatric complaints in an emergent setting. Methods A total of 1776 patients and 1610 patients presented to Emergency Department (ED) with psychiatric complaints between January 1 – July 9 of the years of 2019 and 2020, respectively, in Millcreek Community Hospital (MCH) Erie, PA. This study was an electronic medical record review (EMR), therefore the data were collected exclusively from EMR over the two-year span. ED prevalence was calculated as the number of total psychiatric MCH ED cases divided by the total number of all MCH ED patients, and prevalence ratio (PR) between 2019 and 2020 was used to reflect change of overall ED psychiatric prevalence. Results Clinical notes revealed increased ED psychiatric chief complaint prevalence, as indicated by a PR greater than one, in multiple categories in comparison to before the COVID-19 outbreak. Concerning primary psychiatric disorders, there was increased ED prevalence in chief complaint of total mood disorders (PR = 1.21) with major depressive disorder (PR = 1.23) and bipolar disorder (PR = 1.47), neurodevelopment disorders (PR = 1.25) with attention deficit hyperactivity disorder (ADHD) (PR = 1.19) and intellectual disability (PR = 1.52), trauma- and stressor-related disorders (PR = 1.56) with post-traumatic stress disorder (PTSD) (PR = 1.39) and adjustment disorder (PR = 1.73), substance abuse and addiction disorders (PR = 1.29), and personality disorders (PR = 1.56). Conclusions The pandemic outbreak dramatically impacted mental health in an ER setting. Further research on mental health disparities in conjunction with the COVID-19 pandemic is critical to help predict and address risk for chronic symptoms and sequela to help anticipate and improve psychiatric patient care and well-being during potential future pandemics.

Background Mood and anxiety are widely associated with physical conditions, but research and treatment are complicated by their overlap, clinical heterogeneity, and manifestation on a spectrum rather than as discrete disorders. In contrast to previous work relying on threshold-level disorders, we examined the association between empirically-derived profiles of mood and anxiety syndromes with physical conditions in a nationally-representative sample of US adolescents. Methods Participants were 2,911 adolescents (aged 13-18) from the National Comorbidity Survey-Adolescent Supplement who provided information on physical conditions and reported at least one lifetime mood-anxiety ‘syndrome’ based on direct interviews with the Composite International Diagnostic Interview Version 3.0. Mood-anxiety syndromes reflected 3-level ratings from subthreshold to severe distress/impairment, and subtyped mood episodes. Stepwise latent profile analysis identified mood-anxiety profiles and tested associations with physical conditions. Results Three mood-anxiety profiles were identified: “Mood-GAD” (25.6%)—non-atypical depression, mania, generalized anxiety; “Atypical-Panic” (11.3%)—atypical depression, panic; and “Reference” (63.1%)—lower mood and anxiety except specific phobia. Headaches were more prevalent in Mood-GAD and Atypical-Panic than Reference (47.9%, 50.1%, and 37.7%, respectively; p=0.011). Heart problems were more common in Mood-GAD than Atypical-Panic (7.4% v 2.2%, p=0.004) and Reference, with back/neck pain more prevalent in Mood-GAD than Reference (22.5% v 15.3%, p=0.016). Limitations Broad categories of physical conditions without information on specific diagnoses; replication regarding specificity is recommended. Conclusions Heart problems and pain-related conditions were differentially associated with specific mood-anxiety profiles. Subtyping depression and anxiety—inclusive of subthreshold syndromes—and their patterns of clustering may facilitate etiologic and intervention work in multimorbidity.

OBJECTIVE: The purpose of this review is to clarify the potential roles of forkhead box transcription factor M1 (FoxM1) in the occurrence and progression of breast cancer, as well as the predictive value of FoxM1 as a prognostic biomarker and potential therapeutic target for breast cancer. BACKGROUND: Breast cancer, well-known as a molecularly heterogeneous cancer, is still one of the most frequently diagnosed malignant tumors among females worldwide. Tumor recurrence and metastasis are the central causes of high mortality in breast cancer patients. Many factors contribute to the occurrence and progression of breast cancer, including FoxM1. FoxM1, widely regarded as a classic proliferation-related transcription factor, plays pivotal roles in the occurrence, proliferation, invasion, migration, drug resistance, and epithelial-mesenchymal transition (EMT) processes of multiple human tumors including breast cancer. METHODS: The PubMed database was searched for articles published in English from February 2008 to May 2021 using related keywords such as “forkhead box transcription factor M1”, “human breast cancer”, “FoxM1”, and “human tumor”. About 90 research papers and reports written in English were identified, most of which were published after 2015. These papers mainly concentrated on the functions of FoxM1 in the occurrence, development, drug resistance, and treatment of human breast cancer. CONCLUSIONS: Considering that the abnormal expression of FoxM1 plays a significant role in the proliferation, invasion, metastasis, and chemotherapy drug resistance of breast cancer, and its overexpression is closely correlated with the unfavorable clinicopathological characteristics of breast tumor patients, it is considerably important to comprehend the regulatory mechanism of FoxM1 in breast cancer. This will provide strong evidence for FoxM1 as a potential biomarker for the targeted treatment and prognostic evaluation of breast cancer patients.

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFβ superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV+ SDE+ (n = 15), HIV- SDE+ (n = 15) and HIV+ SDE- (n = 10) subjects were enrolled in our study. All HIV+ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF-α, IFN-γ, IL-4, IL-13, IL-6, CXCL9, and CCL17 were quantified by ELISA. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT-qPCR. CD4, CD8, Th1, Th2, TNF-α-CD8, and IFN-γ-CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV+ SDE+ patients were significantly different from in HIV- SDE+ patients (P < .05). EBV and CMV viral loads were significantly higher in HIV+ SDE+ patients, but not in HIV- SDE+ patients (P < .05). Inflammatory cytokines TNF-α and IFN-γ were significantly elevated in HIV+ SDE+ patients (P < .05). Th2/Th1 populations and TNF-α secreting or IFN-γ secreting CD8+ T cells, were significantly up-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). Conversely, the CD4/CD8 ratio was significantly down-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8+ T cells mediating a pro-inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV+ SDE+ patients.

This study examined the prevalence, sociodemographic features, patterns of comorbidity, and impact on functional impairment of excessive sleepiness (Ex.S) and associated symptoms in a nationally representative sample of adults using the National Comorbidity Survey Replication (NCS-R) dataset.Participants ≥18 years (n = 5,962) were queried about their sleep using the Composite International Diagnostic Interview (CIDI). Specifically, respondents were questioned about feeling sleepy during the day and falling asleep in permissive situations, feelings of insufficient sleep despite adequate time in bed, and/or difficulty waking up. Those endorsing daytime sleepiness and at least one additional symptom were considered to have Ex.S plus associated symptoms. Associations between Ex.S plus associated symptoms and sociodemographics, Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) mental disorders, chronic physical conditions, and functional impairment were examined.The prevalence of Ex.S plus associated symptoms in U.S. adults was 23.34% (standard error [SE] = 0.88) and significantly co-occurred with insomnia-related symptoms after adjusting for confounders (Odds ratio [OR] = 5.65; 95% confidence interval [CI] = 4.55-7.02). The presence of Ex.S and associated symptoms was more common in women, particularly younger women, those with lower family income, and the unemployed (all P.001). After controlling for demographic characteristics and other confounders, Ex.S plus associated symptoms was associated with having a DSM-IV mental disorder (OR = 4.25; 95% CI = 3.53-5.10), a chronic physical condition (OR = 2.57; 95% CI = 1.94-3.42) and greater disability (P.001).Ex. S with associated symptoms was common, frequently co-occurred with other mental and physical conditions, and was associated with substantial disability. Dissipation of some associations after controlling for insomnia-related symptoms indicated that physical-mental comorbidity and disability were greater among individuals with more pervasive sleep disturbances.

Rhesus monkeys (Macaca mulatta) are valuable experimental animals for studies on neurodegenerative diseases due to their evolutionarily close relationship to humans ( Zhang et al., 2014 ). Rhesus monkeys also display similar hallmarks of aging and neurodegeneration as humans, including formation of senile plaques in the brain ( Beckman et al., 2019 ; Paspalas et al., 2018 ). However, changes in formaldehyde (FA) levels in the cerebrospinal fluid (CSF) of rhesus monkeys with aging have not been reported. Additionally, whether changes in CSF FA are correlated with changes in amyloid-β (Aβ) concentrations have not yet been explored. Here, the CSF levels of Aβ40, Aβ42, and FA were measured in 56 rhesus monkeys of different ages, ranging from 4 to 26 years old. Results revealed significant declines in Aβ40 and Aβ42, and an increase in FA with age. Interestingly, the increase in FA levels was negatively correlated with Aβ40 and Aβ42 concentrations in aged rhesus monkeys but not in young and middle-aged monkeys. These results appear to parallel changes seen within human aging, i.e., decreased levels of CSF Aβ and increased levels of FA in normal aged adults and Alzheimer’s disease (AD) patients. These findings further indicate that rhesus monkeys are a reliable model for studying age-related neurological disorders such as AD and suggest that FA is an important factor in AD development and may be used as a diagnostic indicator of such disease.