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The relationship between dyslexia and anxiety/depressive symptoms among children in China is unclear. Besides, the pathways to explain the risks are also undefined.3993 primary school students from grade 2 to 6 were recruited in this study. The Dyslexia Checklist for Chinese Children and the Pupil Rating Scale-Revised Screening for Learning Disabilities were used to filter the dyslexic children. The Chinese perceived stress scale, the Screen for Child Anxiety Related Emotional Disorders, and the Children's Depression Inventory-Short Form were used separately to assess stress, anxiety symptoms, and depressive symptoms of the children. Time spent on homework was obtained by asking their parents: "How long does it take the children to complete the homework every day?". The chain mediation models were examined using SPSS PROCESS macro 3.3 software.Dyslexic children spend more time on homework (2.61±1.15), and have higher scores for depression (4.75±3.60) and stress (26.55±7.40) compared to normal children (1.87±0.77, 3.25±3.32, and 23.20±8.43, respectively). The differences are statistically significant (all P0.01). There is no direct association between dyslexia and anxiety symptoms, while dyslexia has a direct link with depressive symptoms. Dyslexia could affect anxiety/depressive symptoms via the independent mediating effect of stress and the chain mediating effect of time spent on homework and stress. The total indirect effect is 0.21 and 0.25, respectively.The data used in our study is self-reported and this is a cross-sectional study.Time spent on homework and stress could mediate the association between dyslexia and anxiety/depressive symptoms.

Background In China, coronary artery abnormalities (CAAs) secondary to Kawasaki disease (KD) tend to have an increased occurrence. We hypothesize that Chinese children with KD may possess several unique CAA risks, and the predictive efficacy of multiple scoring systems in Chinese patients are still to be further studied. Methods Two hundred and three KD patients were recruited. Using multivariable analysis, independent predictors of CAAs were combined into a scoring system. Subsequently, CAA risks of our patients were evaluated by the newly established scoring system and eight other published scoring systems. Results Seventeen (8.37%) KD patients were identified as CAAs. The newly established scoring system contained the following 5 independent predictors: days of illness at initial treatment ≥7, redness and swelling of extremities, hematocrit ≤33%, percentage of monocytes ≥8.89%, and procalcitonin ≥0.5 ng/mL. The AUC value of newly established scoring system was 0.685 with a sensitivity of 41.18% and a specificity of 84.41%, higher than Harada score, Egami score, Kobayashi score, Sato score, San Diego score, Formosa score, and Tang score, whereas lower than Hua score. Conclusions Days of illness at initial treatment ≥7 and procalcitonin are unique predictors of CAAs in newly established scoring system. Taking into account different identification criteria and analytical methodologies, there is still some heterogeneity among different scoring systems. Impact The newly established scoring system contains the five independent predictors. Days of illness at initial treatment ≥7 and PCT are unique predictors of CAAs in our study, compared with 8 other systems. The AUC value of newly established scoring system is 0.685, similar to Hua score. There is some heterogeneity among different scoring systems.

Background In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27). Methods VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1–28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1–10). The primary endpoint was median overall survival. Results In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each). Conclusions Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy., In the Japanese subgroup of VIALE-C patients (n = 27), venetoclax plus low-dose cytarabine (LDAC) was well tolerated and showed high response vs placebo plus low-dose cytarabine in patients with acute myeloid leukaemia ineligible for intensive chemotherapy.

Background Histological transformation (HT) of follicular lymphoma to a more aggressive lymphoma is a serious event affecting patients’ outcomes. To date, no strong clinical HT predictors present at diagnosis have yet been identified. The fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is highlighted as a non-invasive diagnostic tool for the detection of HT, but its ability to predict HT at early stage of disease has not been clear. Therefore, this study investigated the predictive values of the pre-transformation standardized uptake value (SUVmax) for the risk of transformation in FL. Methods This retrospective study involved 219 patients with FL between June 2008 and October 2019 who had undergone 18F-FDG PET/CT scan. One hundred and thirty-two, 64, and 78 patients underwent PET at baseline (PETbaseline), interim (PETinterim) and end-of-induction therapy (PETend), respectively. Qualitative assessment was performed using the 5-point Deauville scale. Statistical analysis was done using Cox regression models, receiver operating characteristic (ROC) analysis, and Kaplan–Meir survival curves. Results Of the 219 patients included, 128 had low-grade FL (grade 1–2) and 91 had high-grade FL (grade 3a). HT eventually occurred in 30 patients. The median time to HT was 13.6 months. Among clinical indicators, advance pathological grade was shown as the most significant predictor of HT (HR = 4.561, 95% CI 1.604–12.965). We further assessed the relationship between PET and HT risk in FL. Univariate Cox regression determined that SUVbaseline and SUVend were significant predictors for HT, while neither SUVinterim nor qualitative assessment of Deauville score has predictive value for HT. Due to the noticeable impact of high pathological grade on the HT risk, we conducted the subgroup analysis in patients with low/high pathological grade, and found SUVbaseline could still predict HT risk in both low-grade and high-grade subgroups. Multivariate analysis adjusted by FLIPI2 score showed the SUVbaseline (HR 1.065, 95% CI 1.020–1.111) and SUVend (HR 1.261, 95% CI 1.076–1.478) remained as significant predictors independently of the FLIPI2 score. According to the cut-off determined from the ROC analysis, increased SUVbaseline with a cutoff value of 14.3 and higher SUVend with a cutoff value of 7.3 were highly predictive of a shorter time to HT. Conclusions In follicular lymphoma, quantitative assessment used SUVmax at the pre-treatment and end-of-treatment PET/CT scan may be helpful for early screen out patients at high risk of transformation and guide treatment decisions.

Background The present study focuses on the associations of streptococcal infection with the clinical phenotypes, relapse/recurrence and renal involvement in Henoch-Schönlein purpura (HSP) children. Methods Two thousand seventy-four Chinese children with HSP were recruited from January 2015 to December 2019. Patients’ histories associated with HSP onset were obtained by interviews and questionnaires. Laboratory data of urine tests, blood sample and infectious agents were collected. Renal biopsy was performed by the percutaneous technique. Results (1) Streptococcal infection was identified in 393 (18.9%) HSP patients, and served as the most frequent infectious trigger. (2) Among the 393 cases with streptococcal infection, 43.0% of them had arthritis/arthralgia, 32.1% had abdominal pain and 29.3% had renal involvement. (3) 26.1% of HSP patients relapsed or recurred more than 1 time within a 5-year observational period, and the relapse/recurrence rate in streptococcal infectious group was subjected to a 0.4-fold decrease as compared with the non-infectious group. (4) No significant differences in renal pathological damage were identified among the streptococcal infectious group, the other infectious group and the non-infectious group. Conclusions Streptococcal infection is the most frequent trigger for childhood HSP and does not aggravate renal pathological damage; the possible elimination of streptococcal infection helps relieve the relapse/recurrence of HSP.

Background: We conducted this meta-analysis to compare the efficacy and safety of PARP inhibitors with or without chemotherapy versus chemotherapy alone for advanced breast cancer. Methods: A meta-analysis and trial sequential analysis were performed using RevMan 5.2 analysis software. Results: Six eligible randomized clinical trials involving 2080 patients were included. Regimens containing PARP inhibitors were significantly associated with higher objective response rate, longer progression-free survival and overall survival. The PARP inhibitor regimen group had a significantly higher rate of grade ≥3 thrombocytopenia than the chemotherapy-only group. Conclusion: Regimens containing PARP inhibitors are effective and safe for BRCA-mutated advanced breast cancer patients. The efficacy appears to be only marginal in patients with BRCA status unselected.

Objective Kawasaki disease (KD) is a common childhood vasculitis absent of the specific laboratory definitions, besides a significant elevation in several inflammatory mediators, such as procalcitonin (PCT). However, whether PCT can serve as a useful candidate for differentiating KD from sepsis, and even for predicting incomplete KD, intravenous immunoglobulin (IVIG) nonrespondsiveness and coronary artery abnormalities (CAAs) remains unclear.Methods 254 Chinese KD children were enrolled and divided into 6 subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, KD with CAAs and KD without CAAs. Blood samples were collected from all subjects within 24-h pre- and 48-h post-IVIG infusion, respectively. PCT, C-reactive protein, sedimentation rate and blood cell counts were detected. In addition, both 261 sepsis children and 251 healthy children sex- and age-matched with KD children were enrolled in the same period.Results (1) PCT experienced the highest increase in sepsis patients before antibiotic therapy, followed by acute KD patients and the healthy controls. (2) The proportion of KD patients with a PCT concentration below 0.25 ng/ml was 11 folds higher than that of sepsis patients. (3) PCT had a sensitivity of 91.7% and a specificity of 30.3% at a cut-off value of >0.15 ng/ml to predict IVIG nonresponsiveness, and the proportion of IVIG-nonresponders with a PCT concentration of 0.25-0.50 ng/ml was 2 folds higher than that of IVIG-responders. Conclusions The PCT concentrations below 0.25 ng/ml may be useful for discriminating KD from sepsis, and moreover, the PCT concentrations of 0.25-0.50 ng/ml may be helpful in predicting IVIG nonresponsiveness.

Background Anomalous origin of one pulmonary artery from the ascending aorta (AOPA) is a rare and potentially deadly anomaly. Little research, aside from case reports on APOA, has been published, especially for patients with late referrals. Methods This study was a retrospective review of 57 patients with AOPA who underwent reimplantation of the pulmonary artery (PA) from 2009 to 2019. Two different reimplantation methods were used to correct the anomaly, including direct anastomosis in 36 patients and angioplasty with autologous tissue in 21 patients. Results The median age at repair was 2.8 months (range, 8 days to 3.6 years). In-hospital death occurred in 2 patients (3.5%). Five patients (9.1%) with a median age of 9.3 months (range, 5.2 months to 3.6 years) experienced a pulmonary hypertensive crisis. Patients older than 4.9 months were more likely to have a pulmonary hypertensive crisis (P = .001). The 2-year freedom from postoperative PA stenosis rate was 75.3% in patients who underwent direct anastomosis and 46.8% in patients who underwent autologous tissue angioplasty (χ2 = 4.878; P = .027). Angioplasty with autologous tissue (hazard ratio, 5.03; 95% confidence interval, 1.61 to 15.71; P = .005) and an innately smaller diameter of the aberrant PA (hazard ratio, 0.65; 95% confidence interval, 0.45 to 0.92; P = .015) were 2 independent risk factors for postoperative PA stenosis. Conclusions Surgical reimplantation of the PA in patients with AOPA has resulted in favorable early and midterm outcomes. Pulmonary hypertensive crisis occurs more commonly in patients who receive a diagnosis after the age of 4.9 months. Reimplantation with autologous tissue augmentation and an intrinsically smaller diameter in affected PAs are 2 independent risk factors for postoperative PA stenosis.

Osteoporosis (OP) behaves in different manners in different parts of the skeleton. This study aims to investigate the effects of curcumin on bone mass of the mandibular and femur from ovariectomized OP rats and to validate whether enhancer of zeste homolog 2 (EZH2)/Wnt/β‐Catenin pathway is involved in this process. Curcumin was administered intragastrically into ovariectomized rats for 12 weeks. The bone parameters and the morphology of the trabecular bone of the left mandible and left femur were assessed by micro‐computed tomography assay. Morphological changes of the left mandible and left femur were evaluated by hematoxylin and eosin staining. The mRNA levels of EZH2, β‐Catenin, and Runx2 in the right mandible and right femur were examined by quantitative real‐time polymerase chain reaction. Immunohistochemistry was performed to assess EZH2 expression. Both the mandible and femur exhibited OP‐like changes in ovariectomized rats, while the mandible bone resorption was less than the femur bone resorption. Curcumin intragastric administration improved bone microstructure and promoted bone formation in the mandible and femur. Curcumin inhibited EZH2 mRNA level and induced that of β‐Catenin and Runx2 in the mandible and femur. Collectively, curcumin exerts protective effects against OP, possibly by regulating the EZH2/Wnt/β‐Catenin pathway.

This study reviewed the midterm outcomes of supravalvular aortic stenosis (SVAS) repair and determined the risk factors associated with postoperative aortic or pulmonary stenosis. We retrospectively reviewed 225 patients who underwent surgical correction of SVAS from 2010 to 2019. A total of 178 (79.1%), 44 (19.6%) and 3 (1.3%) patients underwent McGoon, Doty, and Brom repair, respectively. The median age at surgery was 2.2 years (interquartile range, 1.2-4.4). The median follow-up time was 3.7 years (interquartile range, 1.9-5.7). Early and late mortality rates were 3.1% and 1.4%, respectively. The overall 5-year survival rate was 97.9%. Eleven patients received reintervention, including 6 (2.8%) reoperations and 5 (2.3%) balloon dilatations. Higher preoperative pressure gradient at the distal ascending aorta or aortic arch was a risk factor for reintervention (P = 0.04). Rates of mortality and complications were not related to the surgical technique. Eleven patients (5.2%) developed sinotubular junction (STJ) stenosis. Freedom from postoperative distal artery stenosis (DAS) of type II SVAS was significantly lower than that of type I (P0.01). Higher preoperative pressure gradient at the STJ (P0.01) and concomitant bilateral or peripheral pulmonary artery (PA) stenosis (P0.01) were risk factors for postoperative DAS. Postoperative PA stenosis occurred more frequently in patients who received bilateral pulmonary arterioplasty (P0.01). Postoperative prognosis of the aortic root after SVAS repair was satisfactory. DAS and PA stenosis were common. The results of bilateral pulmonary arterioplasty were unsatisfactory. The surgical timing and technique for PA stenosis should be carefully considered.

Graphical abstract, Highlights • The hierarchical levels of TAD boundaries were tissue- and cell type-specific. • The TAD nesting level of genes in tumors is different from that in normal tissue. • Hierarchical TAD level of genes is related to abnormal transcription and prognosis in cancers., Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a “TAD hierarchical score (TH score)” for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.

Bladder cancer (BC) is among the most common tumors with a high recurrence rate, necessitating noninvasive and sensitive diagnostic methods. Accurate detection of exfoliated tumor cells (ETCs) in urine is crucial for noninvasive BC diagnosis but suffers from limited sensitivity when ETCs are rare and confounded by reactive, regenerative, or reparative cells. Single-cell sequencing (SCS) enables accurate detection of ETCs by surveying oncogenic driver mutations or genome-wide copy number alternations. To overcome the low-throughput limitation of SCS, we report a SCS-validated cellular marker, hexokinase 2 (HK2), for high-throughput screening cells in urine and detecting ETCs engaging elevated glycolysis. In the SCS-based training set, a total of 385 cells from urine samples of eight urothelial carcinoma (UC) patients were sequenced to establish a HK2 threshold that achieved >90% specificity for ETC detection. This urine-based HK2 assay was tested with a blinded patient group (n = 384) including UC and benign genitourinary disorders as a validation cohort for prospectively evaluating diagnostic accuracy. The sensitivity, specificity, positive predictive value, and negative predictive value of the assay were 90, 88, 83, and 93%, respectively, which were superior to urinary cytology. For investigating the potential to be a screening test, the HK2 assay was tested with a group of healthy individuals (n = 846) and a 6-month follow-up. The specificity was 98.4% in this health group. Three participants were found to have >5 putative ETCs that were sequenced to exhibit recurrent copy number alternations characteristic of malignant cells, demonstrating early BC detection before current clinical methods.

Cholangiocarcinoma (CCA), a cancer with a relatively low incidence rate, is usually associated with poor prognosis. Current modalities for the diagnosis and treatment of CCA patients are still far from satisfactory. In recent years, numerous long noncoding RNAs (lncRNAs) have been identified as crucial players in the development of various cancers, including CCA. Abnormally expressed lncRNAs in CCA, regulated by some upstream molecules, significantly influence the biological behavior of tumor cells and are involved in tumor development through various mechanisms, including interactions with functional proteins, participation in competing for endogenous RNA (ceRNA) regulatory networks, activation of cancer‐related signaling pathways and epigenetic modification of gene expression. Furthermore, several lncRNAs are closely associated with the clinicopathological features of CCA patients, and are promising biomarkers for diagnosing and prognostication of CCA. Some of these lncRNAs play an important role in chemotherapy drug resistance. In addition, lncRNAs have also been shown to be involved in the inflammation microenvironment of CCA and malignant outcome of CCA risk factors, such as cholestatic liver diseases. In view of the difficulty of diagnosing CCA, more attention should be paid to detectable lncRNAs in the serum or bile. This review summarizes the recent knowledge on lncRNAs in CCA and provides a new outlook on the molecular mechanisms of CCA development from the perspective of lncRNAs. Moreover, we also discussed the limitations of the current studies and differential expression of lncRNAs in different types of CCA.

The accumulation of apoptotic cells is one of the pathological characteristics of systemic lupus erythematosus (SLE). The expression of urokinase-type plasminogen activator receptor (uPAR) has been reported to be increased in SLE patients and to be involved in macrophage efferocytosis. Although the toll-like receptor 7 (TLR7) is also over-expressed in lupus, its relationship to uPAR and its role in macrophage efferocytosis in lupus is still unclear. In the present study, we revealed that apoptotic cells accumulate in the spleen, macrophage efferocytosis is impaired, and uPAR is increased in the spleen and peritoneal macrophages of the TLR7 agonist imiquimod (IMQ)-induced SLE mouse model. Moreover, TLR7 upregulated uPAR expression in the mouse macrophage RAW 264.7 cells in vitro. The same results were also obtained using peritoneal macrophages of female Balb/c mice. When uPAR levels in peritoneal macrophages were knocked down by siRNA or inhibited by the peptide inhibitor UPARANT, and cells further treated with the TLR7 agonist R848, efferocytosis of peritoneal macrophages on apoptotic cells was restored. These results indicated that TLR7 activation impaired efferocytosis via uPAR in mouse peritoneal macrophages. Furthermore, TLR7 regulated uPAR expression via ERK/JNK signaling in macrophages. These results suggest that uPAR may be an important factor related to the accumulation of apoptotic cells in SLE.

Background Nuclear protein 1 (NUPR1) plays a critical role in the development and progression of various types of human cancers. However, the role and mechanism of NUPR1 in ovarian cancer have not been elucidated. The purpose of this study was to investigate the effect of NUPR1 on ovarian cancer in vivo and in vitro. Materials and Methods Through the pretreatment of ovarian cancer cell lines, including A2780 and SKOV3 cells, the expression of NUPR1 was detected by RT-PCR and Western blot assays. When NUPR1 was overexpressed and knocked down in A2780 cells and overexpressed in SKOV3 cells, the MTT assays, colony formation assays and EdU assays were used to detect cell proliferation. Furthermore, cell invasion and migration ability were detected with the transwell assays. Cell cycle and apoptosis of A2780 cells after small interfering RNA-NUPR1 (siRNA-NUPR1) were detected by flow cytometry assays. Finally, the effect of NUPR1 gene silencing on the growth of ovarian cancer was evaluated by tumor xenograft experiment in vivo. Results The expression of NUPR1 protein in A2780 cells was significantly higher than that in ovarian surface epithelium (OSE) cells (P < 0.05). The results showed that downregulation of NUPR1 gene expression significantly inhibited the proliferation, migration and invasion ability of A2780 cells, and increased apoptosis of A2780 cells, which expressed relatively high levels of NUPR1. And the expression of apoptosis-related proteins caspase 3, caspase 9 and Bax was upregulated when NUPR1 was knocked out, while the expression of anti-apoptotic proteins of Bcl-2 and Bcl-xl was downregulated. At the same time, the opposite results were observed when NUPR1 was overexpressed in A2780 and SKOV3 cells. Notably, the effect of NUPR1 overexpression in A2780 cells could be partially or completely eliminated by treatment with the AKT inhibitor LY294002. In addition, NUPR1 knockdown could effectively inhibit tumor growth of mice in vivo. Conclusion In summary, NUPR1 has a carcinogenic effect in ovarian cancer, and the oncogenic effect of NUPR1 in ovarian cancer may be achieved by the AKT pathway.

Purpose Stage IIIC1 cervical cancer showed heterogeneous in oncologic outcomes with highly variable survival rates. Our objective was to determine the prognostic significance of removed and metastatic pelvic lymph node status and further perform risk stratification in patients with stage IIIC1p cervical cancer. Patients and methods Patients with stage IIIC1p cervical cancer and undergoing radical hysterectomy with lymphadenectomy in 2008-2018 were retrospectively analyzed. Patients' stage was classified using the revised 2018 International Federation of Gynecology and Obstetrics (FIGO) staging schema. Univariate and multivariable models were used to examine the association between removed and metastatic lymph node status and recurrence-free survival/overall survival. Results During a median follow-up of 34 months, 73 relapses and 44 deaths were observed among 273 patients with stage IIIC1p cervical cancer. Parametrial involvement and metastatic lymph node ratio (mLNR) were identified as independent predictors for recurrence-free survival. Parametrial involvement and mLNR were independent predictors for overall survival. A stratification system was then created based on parametrial involvement and mLNR. A total of 123 (45.1%), 127 (46.5%) and 23 (8.4%) patients were classified into the low-risk, intermediate-risk, and high-risk groups, with as a 5-year recurrence-free survival of 81.7%, 51.1%, 38%, respectively. Compared to the low-risk group, the intermediate- and high-risk groups had a significantly greater risk of recurrence and death. Conclusion The prognosis of stage IIIC1p patients varied significantly. A risk stratification system based on parametrial involvement and mLNR successfully separated patients into low, intermediate, and high-risk group. Our findings could facilitate the practical use of further stratification in Stage IIIC1p cervical cancer.

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.

BACKGROUND The incidence and prognostic factors of chondrosarcoma patients have been reported in early studies. However, the association between risk factors and the incidence or prognosis of chondrosarcoma patients with pulmonary metastasis remains unclear. Therefore, we assessed these risk factors among chondrosarcoma patients with pulmonary metastasis. MATERIAL AND METHODS From 1365 chondrosarcoma patients in the Surveillance, Epidemiology, and End Results (SEER) database, we collected the information of 69 patients with pulmonary metastasis at the initial diagnosis of chondrosarcoma from 2010 to 2016. We investigated the incidence, risk factors, and prognostic factors for pulmonary metastasis patients by using multivariate logistic regression and multivariate Cox regression analyses. RESULTS Data from a total of 69 (6.8%) chondrosarcoma patients with pulmonary metastasis at initial diagnosis were extracted. Patients with the following characteristics were positively associated with higher risk of pulmonary metastasis: dedifferentiated subtype, high grade of malignancy, extracompartmental tumor (Enneking B), presence of regional lymph nodes, local recurrence, large tumor size (larger than 15 cm), and being married. Older patients (older than 67 years), and patients with clear cell chondrosarcoma or large tumor size (larger than 15 cm) exhibited the worse prognosis and survival (overall and cancer-specific). Resection of the primary tumor tended to be correlated with a better prognosis. CONCLUSIONS The incidence of pulmonary metastasis in chondrosarcoma was approximately 6.8%, with poor prognosis. Identifying risk factors and their associations with the incidence and prognosis in chondrosarcoma patients with pulmonary metastasis could provide a reference for clinical surveillance and guide the design of personalized treatment plans.

Uveitis is an inflammation of the iris, ciliary body, vitreous, retina, or choroid, which has been shown to be the first manifestation of numerous systemic diseases. Studies about the immunopathogenesis and treatment of uveitis are helpful to comprehend systemic autoimmune diseases, and delay the progression of systemic autoimmune diseases, respectively. Tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, plays a pivotal role in intraocular inflammation based on experimental and clinical data. Evidence of the feasibility of using anti-TNF-α agents for uveitis management has increased. Although there are numerous studies on TNF-α in various autoimmune diseases, the pathological mechanism and research progress of TNF-α in uveitis have not been reviewed. Therefore, the objective of this review is to provide a background on the role of TNF-α in the immunopathogenesis of uveitis, as well as from bench to clinical research progress, to better guide TNF-α-based therapeutics for uveitis.

Background: The prevalence of high serum uric acid is increasingly rising in recent years, and diet behavior is perceived to be associated with it. This study aimed to explore the relationship between eating away from home (EAFH) and the risk of high serum uric acid in adults in South China.Methods: The data utilized in this study were from Guangdong Nutrition and Health Survey (NHS) 2015. Serum uric acid concentration was detected. EAFH in the past week was investigated. We defined EAFH as food consumption away from home. Dietary data were collected by 24-h recalls on 3 consecutive days. A generalized linear mixed-effects model was applied to compute the odds ratio (OR) and its corresponding 95% CI.Results: A total of 3,489 individuals were included in this study. A 1.27-fold OR (95% CI: 1.05–1.52, P = 0.012) of high serum uric acid was identified in adults with EAFH in comparison with those without EAFH. With respect to men, a 1.66-fold OR (95% CI: 1.3–2.1, P < 0.001) of high serum uric acid was observed. We also observed that men with EAFH had higher intakes of red meat, poultry, vegetable, carbohydrate, protein, fat, and total energy, while a lower grain intake than those without EAFH. However, there was a lack of significant association between EAFH and the odds ratio of high serum uric acid in women. Women with EAFH did not have higher consumptions of red meat, vegetable, fish, fat, and water than those without EAFH.Conclusions: This study found that EAFH was associated with an increased odds ratio of high serum uric acid in men, but not in women.

Contrast-enhanced ultrasound (CEUS) is a new form of ultrasound (US) that can dynamically display microvessels in a highly sensitive manner. The purpose of this study was to investigate the efficacy of CEUS for characterizing testicular lesions in comparison with conventional US. Forty-seven patients with testicular lesions were enrolled. The histopathology results revealed that 31 cases were neoplastic (11 cases of seminomas, 8 nonseminomatous germ cell tumors, 8 lymphomas, 2 Leydig cell tumors, and 2 nonspecific tumors), and 16 cases were nonneoplastic (8 cases of infarctions, 3 epidermoid cysts, and 5 inflammation). The indicators of shallow lobulated morphology and cystic-solid echogenicity on conventional US were suggestive of germ cell tumors. More indicators on CEUS were found to be useful for characterizing testicular lesions. All the neoplastic lesions showed hyperenhancement on CEUS. Moreover, germ cell tumors presented with heterogeneous enhancement (73.7%, 14/19), a twisted blood vessel pattern, rapid wash-in and wash-out, and peripheral rim hyperenhancement signs. Lymphoma was characterized by nonbranching linear vessel patterns (87.5%, 7/8), rapid wash-in and slow wash-out. In nonneoplastic lesions, infarction and epidermoid cysts showed no enhancement, and abscesses were observed with marginal irregular enhancement. The sensitivity, specificity, and accuracy of CEUS for differentiating between neoplastic and nonneoplastic lesions were 100%, 93.8%, and 97.9%, respectively, and these values were higher than those for conventional US (90.3%, 62.5%, and 80.9%, respectively). CEUS can sensitively reflect the microvascular perfusion in testicular lesions and offers high accuracy for characterizing them.

Although it is a probable human carcinogen, propylene oxide is widely applied in industry and daily life. However, data on neurodevelopmental effects of propylene oxide exposure among children are extremely limited. We aimed to determine the urinary concentrations of propylene oxide metabolite among school-aged children and evaluate the potential association of propylene oxide exposure with risk of dyslexia. A total of 355 dyslexic children and 390 controls were recruited from three cities (Jining, Wuhan, and Hangzhou) in China, between 2017 and 2020. Urinary N-acetyl-S-(2-hydroxypropyl)-L-cysteine (i.e., 2-hydroxypropyl mercapturic acid; 2-HPMA) was measured as the biomarker of propylene oxide exposure. The detection frequency of 2-HPMA was 100%. After adjusting for potential confounders, the odds ratio (OR) for dyslexia per 2-fold increase in urinary 2-HPMA was 1.19 [95% confidence interval (95% CI): 1.01, 1.40, P = 0.042]. Compared with the lowest quartile of urinary 2-HPMA concentrations, children with the highest quartile of 2-HPMA had a 1.63-fold (95% CI: 1.03, 2.56, P = 0.036) significantly increased risk of dyslexia, with a dose-response relationship (P-trend = 0.047). This study provides epidemiological data on the potential association between propylene oxide exposure and the risk of dyslexia in children. Further studies are warranted to confirm the findings and reveal the underlying biological mechanisms.

Simple Summary Successful treatment of hematological malignancies with chimeric antigen receptors T (CAR-T) cells has led to much enthusiasm for the wide clinical usage and development of novel CAR-T therapies. However, it also challenges physicians and investigators to recognize and deal with treatment-associated toxicities. We conducted a systematic review and meta-analysis from 84 eligible study and a total of 2592 patients to identify the comprehensive incidences and severity of CRS and neurological symptoms (NS) as well as the potential differences in AEs across a variety of cancer types, CAR-T targets, and other factors, thereby offering a significant implication on its future application and research. Abstract Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment., The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.

Upon antigenic stimulation, naïve CD4+T cells differentiate into different subsets and secrete various cytokines to exert biological effects. Th22 cells, a newly identified CD4+T cell subset,are distinct from the Th1, Th2 and Th17 subsets. Th22 cells secrete certain cytokines such as IL-22, IL-13 and TNF-α, but not others, such as IL-17, IL-4, or interferon-γ (IFN-γ), and they express chemokine receptors CCR4, CCR6 and CCR10. Th22 cells were initially found to play a role in skin inflammatory diseases, but recent studies have demonstrated their involvement in the development of various autoimmune diseases. Here, we review research advances in the origin, characteristics and effector mechanisms of Th22 cells, with an emphasis on the role of Th22 cells and their main effector cytokine IL-22 in the pathogenesis of autoimmune diseases. The findings presented here may facilitate the development of new therapeutic strategies for targeting these diseases.

Cervical spondylosis has gradually become a high-incidence disease in today's society. The cervical range of motion (CROM) is widely used as the evaluation criterion of cervical status, whereas the existing methods of CROM measuring are not humanized enough. Consequently, the purpose of this study was to develop a novel photogrammetric method to assess three-dimensional CROM. Three smartphone cameras were controlled to simultaneously capture three-direction photographs of the subject wearing the special designed device with three mark lines. The obtained photographs were uploaded to a PC and the mark lines in each photograph were extracted by utilizing both the Radon transform and the Hough transform. By calculating and combining the tilt angles of three mark lines, the CROM of the subject was indirectly determined. The performance of our method was compared with the goniometer-based method: the inter-instrument reliability was excellent for all six cervical movements with intraclass correlation coefficients 0.99; the degree of agreement between the two methods was high with Pearson's coefficients 0.98; and the Bland-Altman plots also revealed the validity of our method. Moreover, the concept of a cervical motion curve was put forward to describe the movement track of the neck in order to reflect the cervical health status. The proposed approach is feasible, automatic and convenient for the measurement of CROM and the generated cervical motion curve can intuitively exhibit the trajectory of the neck. This technique that can easily acquire the biomedical information of the cervical spine has tremendous potential in the diagnosis, healthcare and wellness management of the neck.

Myocardial ischemia/reperfusion (I/R) injury could lead to severe cardiovascular ischemic disease, including myocardial infarction and contractile dysfunction. Remifentanil demonstrated protective effect on myocardial I/R injury. The underlying pathophysiological mechanism was then investigated in this study. In the current study, primary cardiomyocytes were isolated from rats, and then preconditioned with remifentanil. Rats, tail vein injected with miR-205 antagomir, were subjected to infusion of remifentanil, and then subjected to regional ischemia followed by reperfusion. The results demonstrated that cell viability of hypoxia/reoxygenation-induced cardiomyocytes was increased post remifentanil, while the apoptosis was decreased accompanied with reduced cleaved caspase-3 expression. Hypoxia/reoxygenation treatment increased miR-205 and decreased PINK1 (PTEN induced putative kinase 1) expression. However, preconditioning with remifentanil reduced miR-205 and enhanced PINK1. Moreover, over-expression of miR-205 decreased PINK1 expression and counteracted the effects of remifentanil-induced increase of cell viability and decrease of cell apoptosis in hypoxia/reoxygenation-induced cardiomyocytes. Injection with miR-205 antagomir improved remifentanil-induced decrease of infarct size and LDH (lactic acid dehydrogenase) activity in rat model with I/R injury. In conclusion, miR-205 might participate in the protective effect of remifentanil in rat myocardial I/R injury via regulation of PINK1, providing a potential target for amelioration of cardiovascular ischemic disease.

Objectives Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 3-5% in non–small-cell lung cancer (NSCLC) patients who tend to be young and never/light-smokers. Echinoderm microtubule-associated protein like 4 (EML4) is the most common partner for ALK fusion, while more than 90 other partners have been reported in NSCLC. Majority of the ALK actionable rearrangements were sensitive to crizotinib, yet some rare fusion types may less benefit than EML4-ALK. Here, we reported a case of lung adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion which the breakpoints was (S6,A20). To our knowledge, this case is the first report showed clinical evidence of SRBD1-ALK fusion responding to crizotinib. Materials and Methods Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) examination and next-generation sequencing (NGS) based on a 425-gene panel was performed on the biopsy sample. Results The IHC analysis revealed positive expression of ALK and atypical FISH signals were detected. Further NGS detected a novel SRBD1-ALK fusion. The patient received crizotinib (250 mg, twice a day) as first-line treatment and partial response was observed. The progression-free survival (PFS) is already over than 10 months up to today. Conclusion To our knowledge, our case is the first case of SRBD1-ALK fusion with excellent response to crizotinib. This case merits further follow-up and provides valuable information on the response to crizotinib of NSCLC patients with SRBD1-ALK fusion.

Objective To evaluate real-world use and outcomes of apatinib treatment in platinum-resistant recurrent epithelial ovarian cancer. Methods This is an observational study. Patients with platinum-resistant recurrent epithelial ovarian cancer initiating apatinib treatment from January 2016 to December 2018 were included. The primary end point was progression-free survival. Other end points included overall survival, objective response rate, disease control rate, and toxicity. Results A total of 28 platinum-resistant epithelial ovarian cancer patients were enrolled in this study. Thirteen cases received apatinib as maintenance therapy following chemotherapy with a median progression-free survival of 6.0 months and a medium overall survival of 11.0 months. Four patients received apatinib as palliative following chemotherapy with 2 cases in progressive disease and 2 cases in stable disease. Eleven cases received apatinib alone as salvage therapy with a disease control rate of 81.8% and a median progression-free survival of 3.0 months. The most common adverse effects were hand-foot syndrome (53.57%), secondary hypertension (46.43%) and fatigue (14.29%). Five patients discontinued treatment due to grade 3 toxicities and 4 patients required dose reduction because of adverse effects. Conclusion Apatinib produced moderate improvements in progression-free survival in patients with platinum-resistant epithelial ovarian cancer both as maintenance therapy following chemotherapy and as single-agent salvage therapy. Our study suggests that apatinib may be effective for women with platinum-resistant recurrent epithelial ovarian cancer.

PURPOSE The extranodal natural killer (NK)/T-cell lymphoma (NKTCL) of non-upper aerodigestive tract (NUAT) was found to have clinical heterogeneity compared with NKTCL of the upper aerodigestive tract (UAT) in small scale studies. We conducted this study in a much larger cohort to analyze the clinical characteristics, prognostic factors, treatment modality, and clinical outcomes of patients with NUAT-NKTCL. Materials and Methods From January 2001 to December 2017, a total of 757 NKTCL patients were identified and included in this study, including 92 NUAT-NKTCL patients (12.2%) and 665 UAT-NKTCL patients (87.8%). RESULTS NUAT-NKTCL patients had relatively poorer performance status, more unfavorable prognostic factors, and more advanced stage, compared with UAT-NKTCL patients. The 5-year overall survival (OS) was 34.7% for NUAT-NKTCL, which was significantly worse than UAT-NKTCL (64.2%, p

Single-incision laparoscopic-assisted anorectoplasty (SILAARP) was compared to posterior sagittal anorectoplasty (PSARP) for treating intermediate-type anorectal malformations (ARMs) with rectobulbar fistula. Between December 2011 and January 2016, 48 children with intermediate-type ARMS were treated with SILAARP (n = 34) or PSARP (n = 14) in our centre. Data including demographics, complications, and long-term outcomes were retrospectively compared. No significant difference was observed between both groups in terms of median operative time and complications. The length of postoperative hospital stay was shorter in the SILAARP group than in the PSARP group (6.15 ± 1.10 vs 9.64 ± 4.13 days; p = 0.008). After a mean follow-up of 59.38 ± 13.68 months, the rates of voluntary bowel movements, soiling, and constipation were similar in both groups. Anorectal manometry was performed in 15 and 7 children from the SILAARP and PSARP groups, respectively. Although there were no significant differences in the presence of rectoanal relaxation reflex and high-pressure-zone length, anal canal resting pressure was higher in the SILAARP group than in the PSARP group (33.35 ± 12.95 vs 23.06 ± 8.40 mmHg; p = 0.039). Both SILAARP and PSARP seemed feasible and effective for treating intermediate-type ARMs with rectobulbar fistula in children. However, SILAARP significantly reduced the length of postoperative hospital stay and improved anal canal resting pressure.

Studies investigating the impact of polymorphisms on monocyte chemotactic protein-1 (MCP-1) and CC chemokine receptor (CCR2) on the susceptibility of Parkinson's disease (PD) have reported inconsistent results. Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the two gene polymorphisms and PD risk. We performed a meta-analysis of five eligible studies to summarize the data describing the association between PD risk and polymorphisms in MCP-1 A2518G and CCR2 V64I. The association was evaluated by calculating the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). A significant increased risk of PD was observed in the MCP-1 A2518G polymorphism in allele model (G vs. A: OR 1.12, 95% CI 1.01-1.25, p = 0.03). The dominant model of MCP-1 A2518G genotype showed no significant association with PD risk, while the risk tendency was increased (AG + GG vs. AA: OR 1.20, 95% CI 1.00-1.42, p = 0.05). In addition, CCR2 V64I polymorphism showed no significant association with PD risk (I vs. V: OR 0.33, 95% CI 0.06-1.92, p = 0.22; VI + II vs. VV: OR 1.00, 95% CI 0.83-1.21, p = 0.99). In subgroup analysis by ethnicity, no significant difference was found in both Caucasians and Asians between CCR2 V64I polymorphism and PD risk, while a significant statistical association was identified in Asians between MCP-1 A2518G polymorphism and PD risk. When the data were stratified by study area, the increased risk of PD was observed only in studies conducted in China. In summary, the present meta-analysis suggests that genetic polymorphisms of MCP-1 A2518G may influence the susceptibility of PD in Asian countries, especially in China. However, CCR2 V64I polymorphism is not correlated with PD risk. The results should be interpreted with caution due to limited sample and heterogeneity. Large scale and well-designed studies are needed to validate our findings.

Background Population movement could extend multidrug-resistant tuberculosis (MDR-TB) transmission and complicate its global prevalence. We sought to identify the high-risk populations and geographic sites of MDR-TB transmission in Shenzhen, the most common destination for internal migrants in China. Methods We performed a population-based, retrospective study in patients diagnosed with MDR-TB in Shenzhen during 2013–2017. By defining genomic clusters with a threshold of 12–single-nucleotide polymorphism distance based on whole-genome sequencing of their clinical strains, the clustering rate was calculated to evaluate the level of recent transmission. Risk factors were identified by multivariable logistic regression. To further delineate the epidemiological links, we invited the genomic-clustered patients to an in-depth social network investigation. Results In total, 105 (25.2%) of the 417 enrolled patients with MDR-TB were grouped into 40 genome clusters, suggesting recent transmission of MDR strains. The adjusted risk for student to have a clustered strain was 4.05 (95% confidence interval, 1.06–17.0) times greater than other patients. The majority (70%, 28/40) of the genomic clusters involved patients who lived in different districts, with residences separated by an average of 8.76 kilometers. Other than household members, confirmed epidemiological links were also identified among classmates and workplace colleagues. Conclusions These findings demonstrate that local transmission of MDR-TB is a serious problem in Shenzhen. While most transmission occurred between people who lived distant from each other, there was clear evidence that transmission occurred in schools and workplaces, which should be included as targeted sites for active case finding. The average residential distance between genomic-clustered cases was more than 8 kilometers, while schools and workplaces, identified as sites of transmission in this study, deserve increased vigilance for targeted case finding of multidrug-resistant tuberculosis.

SETTING The proportion of bacteriologically confirmed tuberculosis (TB) in China has decreased far below the worldwide average. OBJECTIVE To investigate whether stepwise measures to ensure sputum quality can improve the rate of bacteriologically confirmed TB. DESIGN We enrolled 980 adults with suspected TB from three counties in China during 2017 for this multicentre randomised controlled trial. Half the participants (n = 490) were randomly assigned to intervention groups that received instructions by a study nurse, and sputum induction, if necessary. In the remaining 490 patients, sputum samples were collected without observation. The primary outcome was the proportion of patients detected as bacteriologically positive on smear, culture or molecular assays (EasyNAT or Xpert). RESULTS Bacteriological confirmation rates were significantly higher in the intervention than in the control group: overall (159/490 [32%] vs. 122/490 [25%]; P = 0.009); confirmation using smear (17% vs. 11%; P = 0.010); confirmation using culture (28% vs. 21%; P = 0.021); and confirmation using molecular assays (27% vs. 18%; P = 0.001). Most of the improvement was in patients who received instruction alone, while improvement was greatest in younger patients (adjusted odds ratio 1.27, 95%CI 1.05-1.53 per 10 years). CONCLUSIONS If implemented effectively in resource-limited primary care clinics, our simple stepwise procedure combining instruction and sputum induction could increase the proportion of bacteriologically confirmed TB significantly. .

Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.To seek a potential therapeutic target in glutamine-addicted ccRCC.Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells.Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses.We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR]=2.04, cancer-specific survival [CSS] HR=2.95; all p0.001) and Shanghai (OS HR=2.07, CSS HR=3.92; all p0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor β expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells.Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC.In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23-high patients had significantly poorer survival than IL-23-low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine syndrome characterized by metabolic abnormality and reproductive dysfunction, including ovulation abnormality, hyperandrogenism and polycystic ovarian manifestations. Most PCOS patients are overweight or obese, particularly the central type. This aggravates the clinical manifestations of PCOS and ultimately increases the risk of infertility. Orlistat is the only weight loss drug approved by the US Food and Drug Administration. As a long-lasting gastrointestinal lipase inhibitor, orlistat can effectively reduce the absorption of lipid and increase lipid excretion, thereby achieving weight loss. In obese PCOS patients, orlistat can reduce weight, improve lipid metabolism and insulin resistance, improve sex hormone disorder, and have a positive effect on pregnancy outcome. This review summarizes the impact of orlistat treatment on metabolism and fertility in obese women with PCOS. Key words: hyperandrogenism; insulin resistance; obesity; orlistat; polycystic ovary syndrome; pregnancy outcome

Background: There are many methods to diagnose diabetic autonomic neuropathy (DAN); however, often, the various methods do not provide consistent results. Even the two methods recommended by the American Diabetes Association (ADA) guidelines, Ewing's test and heart rate variability (HRV), sometimes give conflicting results. The purpose of this study was to evaluate the degree of agreement of the results of the Composite Autonomic Symptom Score 31 (COMPASS-31), skin sympathetic reaction (SSR) test, Ewing's test, and HRV in diagnosing DAN.Methods: Patients with type 2 diabetes were recruited and each received the COMPASS-31, SSR, Ewing's test, and HRV for the diagnosis of DAN. Patients were categorized as DAN(+) and DAN(–) by each of the tests. Kappa consistency tests were used to evaluate the agreement of diagnosing DAN between any two methods. Spearman's correlation test was used to evaluate the correlations of the severity of DAN between any two methods. Receiver operating characteristic (ROC) analyses were used to evaluate the diagnostic value and the cutoff value of each method.Results: A total of 126 type 2 diabetic patients were included in the study. The percentages of DAN(+) results by HRV, Ewing's test, COMPASS-31, and SSR were 61, 40, 35, and 33%, respectively. COMPASS-31 and Ewing's test had the best agreement for diagnosing DAN (κ = 0.512, p < 0.001). COMPASS-31 and Ewing's test also had the best correlation with respect to the severity of DAN (r = 0.587, p < 0.001). Ewing's test and COMPASS-31 had relatively good diagnostic values (AUC = 0.703 and 0.630, respectively) in the ROC analyses.Conclusions: COMPASS-31 and Ewing's test exhibit good diagnostic consistency and severity correlation for the diagnosis of DAN. Either test is suitable for the diagnosis of DAN and treatment follow-up.

Colorectal cancer (CRC) is one of the most common human cancer types and a leading cause of cancer-related death. Accumulating evidence has confirmed that long non-coding RNAs have crucial roles in CRC progression. In the present study, the biological roles of LINC01535 were investigated and the interaction between long intergenic non-coding RNA (LINC)01535 and microRNA (miR)-761 in CRC was explored. LINC01535 expression was observed to be upregulated in CRC tissues and cell lines. A functional study suggested that LINC01535 silencing inhibited CRC cell proliferation and invasion but enhanced cisplatin sensitivity of CRC cells, while co-transfection with a miR-761 inhibitor reversed these biological effects. A luciferase reporter assay demonstrated that LINC01535 regulated miR-761 directly and RNA-binding protein immunoprecipitation further confirmed that the suppression of LINC01535 by miR-761 was via an RNA-induced silencing complex. Finally, knockdown of LINC01535 inhibited the growth of CRC cells in vivo. Collectively, the results suggested that LINC01535 exerts oncogenic functions in CRC by sponging miR-761. In conclusion, the present study indicated that LINC01535 promoted CRC progression through sponging miR-761, and may serve as a potential diagnostic biomarker and therapeutic target for CRC.

Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

ObjectiveTibet has the highest prevalence of both tuberculosis disease and multidrug-resistant tuberculosis (MDR-TB) in China. The circulated Mycobacterium tuberculosis strains from Tibet were sequenced to investigate the underlying drivers for the high burden of MDR-TB.MethodsUsing whole-genome sequencing data of 576 M. tuberculosis strains isolated from consecutive patients in Tibet, we mapped resistance-conferring mutations onto phylogenetic trees to determine their evolution and spread. The impact of drug resistance on bacterial population growth was assessed with a Bayesian (Skyline Plot) analysis. Multivariable logistic regression was used to identify risk factors for the development of rifampicin resistance.ResultsOf the 576 isolates, 284 (49.3%), 280 (48.6%), and 236 (41.0%) were, respectively, genetically resistant to isoniazid, rifampicin, or both (MDR-TB). Among the isoniazid- and rifampicin-resistant strains, the proportions in phylogenetically-inferred clusters were 77.8% (221/284) and 62.1% (174/280), respectively. Nearly half (47.2%, 134/284) of the isoniazid-resistant strains were in six major clades, which contained between 8 and 58 strains with katG S315T, katG S315N, or fabG1 promoter −15 C>T resistance mutations. These major clades exponentially expanded after emerging with isoniazid resistance and stabilized before evolving into MDR-TB twenty years later. Isoniazid-resistant isolates showed an increased risk of accumulating rifampicin resistance compared to isoniazid-susceptible strains, with an adjusted odds ratio of 3.81 (95% confidence interval 2.47-5.95).ConclusionHistorical expansion of isoniazid-resistant strains and their increased likelihood of acquiring rifampicin resistance both contributed to the high burden of MDR-TB in Tibet, highlighting the need to detect INH-resistant strains promptly and to control their transmission.

Background Tuberculosis (TB) in emerging cities is often a disease of recent immigrants, and understanding this epidemiology is crucial for designing effective control and prevention strategies. Methods We conducted a retrospective population-based genomic epidemiological study of culture-positive pulmonary TB patients diagnosed between June 2014 and November 2017 in the Bao'an District of Shenzhen, a Chinese city with dramatic recent growth. After whole genome sequencing, transmission clusters were defined as strains differing by no more than 12 SNPs. Findings Of 1696 culture-positive TB patients, 93•8% (1591/1696) were migrants, with 51•6% (821/1591) employed in housekeeping or unemployed. Of the 1460 migrants with known residence time, 47•7% (697/1460) developed TB within two years after arriving in Bao'an. Only 12•2% (207/1696) of Bao'an isolates were in genomic clusters, indicating that recent transmission was not the primary cause of TB in Bao'an. The isolates' median terminal branch length was 56 SNPs, more than could have accumulated since the arrival of the migrants in Bao'an. The migrants' isolates had genotypic distributions similar to those in their home provinces. One strain isolated in Bao'an belonged to a clade circulating in the patient's home province, providing further evidence that the strains were brought to Bao'an with the migrants. Interpretation TB in the Bao'an District is principally caused by reactivation of infections acquired by migrants in their home provinces. Nearly half developed TB within two years after arriving in Bao'an, suggesting a need for increased TB screening of migrants, especially housekeeping workers and the unemployed. Funding Sanming Project of Medicine in Shenzhen; National Science and Technology Major Project of China; Natural Science Foundation of China.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its lack of treatment options. Patients with TNBC frequently develop resistance to chemotherapy. As epigenetic-based antineoplastic drugs, histone deacetylase inhibitors (HDACis) have achieved particular efficacy in lymphoma but are less efficacious in solid tumors, and the resistance mechanism remains poorly understood. In this study, the GSE129944 microarray dataset from the Gene Expression Omnibus database was downloaded, and fold changes at the transcriptome level of a TNBC line (MDA-MB-231) after treatment with belinostat were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the critical biological processes. Construction and analysis of the protein-protein interaction (PPI) network were performed to screen candidate genes related to cancer prognosis. A total of 465 DEGs were identified, including 240 downregulated and 225 upregulated genes. The cytokine-cytokine receptor pathway was identified as being significantly changed. Furthermore, the expression of CXCL1 was implicated as a favorable factor in the overall survival of breast cancer patients. With in vitro approaches, we also showed that belinostat could induce the expression of CXCL1 in another 2 TNBC cell lines (BT-549 and HCC-1937). We speculate that belinostat-induced CXCL1 expression could be one of the results of the stress clone evolution of cells after HDACi treatment. These findings provide new insights into clone evolution during HDACi treatment, which might guide us to a novel perspective that various mutation-targeted treatments should be implemented during the whole treatment cycle.

Hepatocellular carcinoma (HCC) is a deadly tumor with high heterogeneity. Aerobic glycolysis is a common indicator of tumor growth and plays a key role in tumorigenesis. Heterogeneity in distinct metabolic pathways can be used to stratify HCC into clinically relevant subgroups, but these have not yet been well-established. In this study, we constructed a model called aerobic glycolysis index (AGI) as a marker of aerobic glycolysis using genomic data of hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) project. Our results showed that this parameter inferred enhanced aerobic glycolysis activity in tumor tissues. Furthermore, high AGI is associated with poor tumor differentiation and advanced stages and could predict poor prognosis including reduced overall survival and disease-free survival. More importantly, the AGI could accurately predict tumor sensitivity to Sorafenib therapy. Therefore, the AGI may be a promising biomarker that can accurately stratify patients and improve their treatment efficacy.

Exposure to organophosphate (OP) insecticides has been found to be related to neurodevelopmental disorders in children. However, no study has examined the association between OP insecticide exposure and the risk of dyslexia among children. We aimed to explore the association between OP insecticide exposure, indicated by urinary dialkylphosphate metabolites (DAPs), and the risk of dyslexia among Chinese Han children from three cities. A total of 845 children (422 dyslexics and 423 non-dyslexics) from Tongji Reading Environment and Dyslexia research program were included in the current case-control study. We measured six DAPs in urine samples, collected from November 2017 to December 2020. Logistic regression models were used to estimate odds ratios (ORs) for the association between DAPs and dyslexia risk, adjusting for potential confounders. The detection frequencies of DAPs were above 97.5%, except for diethyldithiophosphate (DEDTP) and dimethyldithiophosphate (DMDTP). Diethyl phosphate metabolites (DEs) were significantly associated with the risk of dyslexia. Compared with the lowest quartile, the adjusted ORs of dyslexia risk for the highest quartile of urinary diethylthiophosphate (DETP) and diethylphosphate (DEP) were 1.82 (1.04, 3.20) and 1.85 (1.08, 3.17). In addition, the adjusted ORs for dyslexia per 10-fold of urinary DEP, DETP, and ∑DEs concentration were 1.87 (1.12, 3.13), 1.55 (1.03, 2.35), and 1.91 (1.13, 3.21), respectively. Analyses stratified by gender indicated that such associations were more significant among boys. This study suggested that exposure to OP insecticides may be related to dyslexia among Chinese Han children from the three studied cities. However, our results should be interpreted with caution because of the case-control design and the fact that only one-spot urine sample was collected from the children. More studies with children living in China are necessary concerning the relatively high levels of urinary OP metabolites in our study.

Background: Targeted delivery to the Rheumatoid arthritis (RA) which is characterized by destruction and degeneration of bones due to chronic inflammation is of great need. RA being a chronic autoimmune disorder might result in severe disability and morbidity. A targeted delivery system is designed to deliver methotrexate (MTX) for RA. Methods: Here, we synthesized folic acid (FA) conjugated hydrophobically modified glycol chitosan (GC) self-assembled nanoparticles (FA-GC-SA) for the targeted delivery of MTX to RA. The FA conjugation and hydrophobic modification of GC by stearic acid (SA) was confirmed by Fourier-transform infrared spectroscopy (FTIR). The FA-GC-SA was exploited for developing targeted nanoparticles encapsulating MTX by the ionic gelation method. The particles were characterized and evaluated for their targeting potential in in vitro cell culture studies. Further their in vivo efficacy in arthritis induced rats using collagen was also evaluated. Results: FTIR confirms the successful modification of GC-SA and FA-GC-SA. The FA-GC-SA-MTX of size 153 ± 9 nm were prepared with high encapsulation efficiency of MTX. The FA-GC-SA-MTX size was further confirmed by transmission electron microscopy (TEM). In vitro cell studies revealed the superior efficacy of FA-GC-SA-MTX in cell cytotoxicity. Also, significantly higher cellular uptake of FA functionalized FA-GC-SA-MTX was observed in comparison to non-functionalized GC-SA-MTX attributed to folate receptors (FRs) mediated endocytosis. In vivo results confirms the potential of FA-GC-SA-MTX which reduces reduces the pro-inflammatory cytokines, paw thickness, and arthritis score in collagen induced rats. Conclusion: The results shows that FRs targeted FA-GC-SA-MTX has superior efficacy in the treatment of RA.

Objectives To evaluate the effect of dyslipidemia on the incidence of moderate and severe Ovarian hyperstimulation syndrome (OHSS) in the duration of assisted reproduction technique (ART). Methods The study included 233 moderate and severe OHSS patients who received hospitalization after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles to avoid severe complications. They were divided into dyslipidemia group and normal lipid metabolism group to evaluate whether dyslipidemia contributes to the development of severe OHSS. Subgroup analysis was set to avoid deviation including the freeze-all group and fresh embryo transfer (ET) group according to whether the eligible women chose fresh embryo transfer immediately after their IVF or ICSI cycles. The main outcome measures included the incidence of moderate OHSS and severe OHSS, total gonadotropin dose, number of oocytes retrieved, age and body mass index (BMI). In the ET groups, the rate of pregnancy is also included for analysis. Results In the freeze-all group, lipid metabolism was ultimately identified as the factor affecting the morbidity of severe OHSS and the ones with dyslipidemia were more likely to develop to severe OHSS (P < 0.05), while the incidence of severe OHSS among the ET groups had no statistical significance (P > 0.05). Conclusion The findings of this study suggested that dyslipidemia might contribute to the development of OHSS, especially for those patients who chose the cryopreservation of all embryos. It is essential to consider the risk of OHSS in patients with dyslipidemia although they required cryopreservation of all embryos.

Background and aims Observational studies have suggested that plasma lipids contribute substantially to cardiovascular disease, but “cholesterol paradox” in atrial fibrillation (AF) remains. We sought to investigate the causal effects of lipid profiles on the risk of AF. Methods and results Two-sample Mendelian randomization (MR) framework was implemented to examine the causality of association. Summary estimations of genetic variants associated with low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol, triglycerides, lipoprotein-a [Lp(a)], apolipoprotein A1 (ApoA 1), and apolipoprotein B (ApoB) were 81, 99, 96, 61, 30, 10, and 23 single nucleotide polymorphisms, respectively. Genetic association with AF were retrieved from a genome-wide association study that included 1,030,836 individuals. The complications for AF were predefined as cardioembolic stroke (CES) and heart failure (HF). In the multivariable MR, the odds ratios for AF per standard deviation (SD) increase were 1.030 (95% confidence interval (CI) 0.979–1.083; P = 0.257) for LDL-cholesterol, 0.986 (95% CI 0.931–1.044; P = 0.622) for HDL-cholesterol, 0.965 (95% CI 0.896–1.041; P = 0.359) for triglycerides, 1.001 (95% CI 1.000–1.003; P = 0.023) for Lp(a), 1.017 (95% CI 0.966–1.070; P = 0.518) for ApoA1, and 1.002 (95% CI 0.963–1.043; P = 0.923) for ApoB. There was no evidence that other lipid components were causally associated with AF, CES, or HF, other than for a marginal association between triglycerides and HF. Conclusions This MR study provides robust evidence that high Lp(a) increases the risk of AF, suggesting that interventions targeting Lp(a) may contribute to the primary prevention of AF.

BACKGROUND At the end of the last century, genome-wide association studies revealed a significant genetic association between bipolar disorder and autoimmune diseases. Subsequently, the theory of immune pathogenesis of bipolar disorder gradually formed, and the research on autoimmune diseases and bipolar comorbidities began to extend to other diseases, but their correlation is still controversial. To explore the differences in the prevalence of bipolar disorder in patients with autoimmune disease and normal healthy people through meta-analysis, and to examine the relationship between bipolar disorder and autoimmune disease by reviewing the relevant literature. METHODS The Cochrane, PubMed, and Embase databases were searched by computer from the date of inception of the database to July 2020. The main topics of the search were based on common autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, pemphigus, and Sjogren's syndrome. The databases were comprehensively searched for controlled studies regarding the prevalence of bipolar disorder in patients with autoimmune diseases. Review Manager 5.3 software was used for meta-analysis. RESULTS In total, 10 cohort and case control studies were included. From these, 16 control groups were extracted based on nine autoimmune diseases. The meta-analysis demonstrated that the incidence of bipolar disorder was significantly increased in patients with autoimmune disease compared to patients without autoimmune disease, [mean difference (MD) =1.54, 95% confidence interval (CI): 1.28-1.86, P