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To present a case series of the exstrophy-epispadias complex (EEC) with isolated ectopic bowel segment (IEBS) with the literature review, highlighting the clinical findings and treatments.We present 3 cases of bladder exstrophy (BE) with IEBS in our institute and reviewed the literature in PubMed with the terms "("bladder exstrophy" OR "epispadias") AND ("visceral sequestration" OR "sequestered" OR "ectopic bowel")."There were 2 males and 1 female. The IEBS was detected by physical examination in 2 cases and by ultrasonography in another one. All cases were BE accompanying with lower abdominal mass which adhered to the bladder wall but was separated from the digestive system. All cases underwent the IEBS excision and BE repair simultaneously. Pathological result of IEBS suggested the histological structures of colon. There were totally 13 cases of EEC with IEBS reported in the literature, including 2 (15%) epispadias, 9 (69%) covered BE, 1 (8%) duplicate BE and 1 (8%) classic bladder exstrophy. Although their clinical manifestations were various, IEBS excision were safely conducted in all cases.EEC with IEBS is an extremely rare congenital malformation. Physical and imaging examinations are important for diagnoses. Surgical excision is safe and effective for managing IEBS.

This study examined the associations of fine particulate matter (PM

Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Developmental dysplasia of the hip (DDH) is a debilitating condition that affects 1–7% of newborns. Children with DDH, not treated early and effectively, will easily lead to disability. A better understanding of the biology of DDH is critical to the development of prognostic biomarkers and novel therapies. The purpose of this study was to establish a biobank of DDH genetic resources, to facilitate clinical and basic scientific research. The biological specimen and clinical data of DDH were collected in Shanghai Children’s Hospital from 2014 to 2021. The collection of blood samples was performed at definitive diagnosis and review, tissue specimens were performed at definitive surgery. The clinical data was collected at the whole stage of DDH patients at diagnosis, treatment and follow-up. A total of 528 patients with DDH were enrolled in this study, 90 were men and 438 were women, with the mean age of 4.67 years. The numbers of tissue and blood specimens reached 2172 and 1490, respectively. The quality test results showed that the DNA concentration decreased slightly with the extension of storage time, but the DNA purity did not change. Meanwhile, the extension of storage time slightly affected the stability of protein of tissue samples but did not affect the expression of the housekeeping gene. The DDH biobank built has the potential of monitoring disease pathogenesis and progress, which could provide specimens to the researchers improving the biological understanding and provide guidance of clinical treatment of this disease to clinicians.

The objective of the study was to explore the role of SDC1 in breast cancer cells. Our study also investigated the regulatory relationship between SDC1 and the microRNA (miRNA) miR-335-5p as well as the impact of these two genes on the progression of breast cancer. Bioinformatic approaches were employed to analyze the differentially expressed messenger RNAs (mRNAs) and miRNAs (DE-mRNAs and DE-miRNAs) in breast cancer tissue. Then mRNA SC1 was obtained. Differentially downregulated mRNAs were intersected with target miRNAs predicted by databases, and miR-335-5p was determined as the study object. Quantitative reverse transcription polymerase chain reaction was applied to assess the expressions of SDC1 and miR-335-5p in each cell line. Next, Western blot assay was conducted to detect the protein level of SDC1 and dual-luciferase assay was performed to verify the binding relationship between miR-335-5p and SDC1. Finally, we conducted methyl thiazolyl tetrazolium (MTT), colony formation, and Transwell assays and flow cytometry to further investigate the impacts of SDC1 and miR-335-5p on the progression of breast cancer. SDC1 was significantly highly expressed while miR-335-5p was remarkably lowly expressed in human breast cancer. Silencing SDC1 in breast cancer blocked the proliferation, migration and invasion of the cells. In breast cancer, SDC1 was a target gene of miR-335-5p and silencing miR-335-5p notably increased SDC1 expression. Compared with the silence of miR-335-5p, simultaneous silences of miR-335-5p and SDC1 significantly reduced the proliferative, migratory and invasive abilities of breast cancer cells. The result revealed the interaction between miR-335-5p and SDC1 in the progression of breast cancer, which may contribute to the treatments for this cancer.

BackgroundFerroptosis and iron-metabolism are regulated by Long non-coding RNAs (lncRNAs) in ovarian cancer (OC). Therefore, a comprehensive analysis of ferroptosis and iron-metabolism related lncRNAs (FIRLs) in OC is crucial for proposing therapeutic strategies and survival prediction.MethodsIn multi-omics data from OC patients, FIRLs were identified by calculating Pearson correlation coefficients with ferroptosis and iron-metabolism related genes (FIRGs). Cox-Lasso regression analysis was performed on the FIRLs to screen further the lncRNAs participating in FIRLs signature. In addition, all patients were divided into two robust risk subtypes using the FIRLs signature. Receiver operator characteristic (ROC) curve, Kaplan–Meier analysis, decision curve analysis (DCA), Cox regression analysis and calibration curve were used to confirm the clinical benefits of FIRLs signature. Meanwhile, two nomograms were constructed to facilitate clinical application. Moreover, the potential biological functions of the signature were investigated by genes function annotation. Finally, immune microenvironment, chemotherapeutic sensitivity, and the response of PARP inhibitors were compared in different risk groups using diversiform bioinformatics algorithms.ResultsThe raw data were randomized into a training set (n = 264) and a testing set (n = 110). According to Pearson coefficients between FIRGs and lncRNAs, 1075 FIRLs were screened for univariate Cox regression analysis, and then LASSO regression analysis was used to construct 8-FIRLs signature. It is worth mentioning that a variety of analytical methods indicated excellent predictive performance for overall survival (OS) of FIRLs signature (p p p ConclusionThe FIRLs signature can independently predict overall survival and therapeutic effect in OC patients.

Myofascial pelvic pain (MFPP) caused by myofascial trigger points (MTrPs) is a major contributor to chronic pelvic pain in women. However, the effect of the patient's self-myofascial release (SMFR) is unclear. This study aimed to investigate the effect of SMFR combined with biofeedback and electrical stimulation (BES) therapy in comparison with BES alone in patients with MFPP.A prospective randomized controlled study was conducted. Sixty-eight patients were randomly allocated into BES-SMFR group (n = 34) and BES group (n = 34). Every patient received 4 weeks of treatment, evaluated at baseline (T0), 4 weeks post-intervention (T4) and 12-week follow-up (T12). The primary outcome was pain intensity. The secondary outcomes were degree of activation of MTrPs, surface electromyography (sEMG) levels and Patient Global Impression of Improvement (PGI-I).Compared with the effect of BES, BES-SMFR treatment significantly decreased pain intensity and the degree of activation of MTrPs in the levator ani (p = 0.02) and obturator internus (p = 0.03), as well as the sEMG levels of the pre-test resting baseline and post-test resting baseline (all p 0.01). The degree of activation of MTrPs in the piriformis and coccygeus (all p 0.05) and the sEMG levels of the quick flicks and endurance contraction were not significantly different. The BES-SMFR treatment improved the PGI-I scale at T4 (p = 0.02) but not at T12 (p = 0.40).This study confirmed that the addition of SMFR to BES treatment resulted in superior outcomes compared with those with BES alone in patients with MFPP.Myofascial pelvic pain (MFPP) is a major contributor of female chronic pelvic pain. Myofascial release has been used commonly for better pain release; however, poor therapeutic effect due to poor patient compliance is common in clinical practice. Therefore, in future research, there is a need to investigate the effect of patient's self-myofascial release (SMFR) technique, which can eliminate the need for frequent office visits and improve patient compliance to some extent, in patients with MFPP.

Background: We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and coronavirus disease 2019 (COVID-19). Second, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. Methods: We conducted a cohort study using eight routinely collected health care databases from Spain and the United States, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: (i) diagnosed with COVID-19, (ii) hospitalized with COVID-19, and (iii) hospitalized with influenza in 2017 to 2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes. Results: We included 366,050 and 119,597 patients diagnosed and hospitalized with COVID-19, respectively. Prostate and breast cancers were the most frequent cancers (range: 5%–18% and 1%–14% in the diagnosed cohort, respectively). Hematologic malignancies were also frequent, with non-Hodgkin's lymphoma being among the five most common cancer subtypes in the diagnosed cohort. Overall, patients were aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 2% to 14% and from 6% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n = 67,743) had a similar distribution of cancer subtypes, sex, age, and comorbidities but lower occurrence of adverse events. Conclusions: Patients with a history of cancer and COVID-19 had multiple comorbidities and a high occurrence of COVID-19-related events. Hematologic malignancies were frequent. Impact: This study provides epidemiologic characteristics that can inform clinical care and etiologic studies.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p

BACKGROUND The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. METHODS A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. RESULTS The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P

What is known and objective Optimal airway management is crucial in strabismus surgery due to the inaccessibility of the airway throughout the procedure. Laryngeal mask airway offers advantages over tracheal intubation in ophthalmic surgery as it does not increase the intraocular pressure. The purpose of this study was to determine the median effective dose of propofol required, when combined with 0.2 µg/kg of sufentanil, for smooth insertion of Ambu AuraFlex in the first attempt in children undergoing strabismus surgery, and to compare it with that for Ambu AuraOnce. Methods Forty-three paediatric patients undergoing strabismus surgery under general anaesthesia were recruited. For induction, the initial dosage of propofol was 2 mg/kg in the AuraOnce group or 3 mg/kg in the AuraFlex group. In accordance with Dixon's up-and-down method, the dose of propofol for consecutive patients in each group was adjusted in increments or decrements of 0.25 mg/kg based on the previous patient's "three-point, six-category scale" response to the first attempt of insertion of the randomized device. Insertion of the device was attempted when the bispectral index was ≤60 for 5 s after propofol administration without the use of neuromuscular blocking agents. Results and discussion The median effective dose (95% confidence interval) of propofol was significantly lower in the Ambu AuraOnce group than in the Ambu AuraFlex group (1.92 [1.50-2.32] mg/kg vs. 2.98 [2.49-3.94] mg/kg; p = 0.002). The incidence of dislodgement of the device was significantly higher with the use of the Ambu AuraOnce than with the use of AuraFlex (p = 0.023), whereas insignificant differences were observed between the two groups in the incidence of other perioperative adverse events. What is new and conclusion Ambu AuraFlex requires a significantly higher dose of propofol for insertion and provides more effective and stable airway management in strabismus surgery than AuraOnce.

Perioperative neurocognitive disorders (PNDs) refer to cognitive decline identified in the preoperative or postoperative period. It has been reported that the incidence of postoperative neurocognitive impairment after noncardiac surgery in patients older than 65 at 1 week was 25.8∼41.4%, and at 3 months 9.9∼12.7%. PNDs will last months or even develop to permanent dementia, leading to prolonged hospital stays, reduced quality of life, and increased mortality within 1 year. Despite the high incidence and poor prognosis of PNDs in the aged population, no effective clinical prediction model has been established to predict postoperative cognitive decline preoperatively. To develop a clinical prediction model for postoperative neurocognitive dysfunction, a prospective observational study (Clinical trial registration number: ChiCTR2000036304) will be performed in the Shanghai General Hospital during January 2021 to October 2022. A sample size of 675 patients aged >65 years old, male or female, and scheduled for elective major noncardiac surgery will be recruited. A battery of neuropsychological tests will be used to test the cognitive function of patients at 1 week, 1 month, and 3 months postoperatively. We will evaluate the associations of PNDs with a bunch of candidate predictors including general characteristics of patients, blood biomarkers, indices associated with anesthesia and surgery, retinal nerve-fiber layer thickness, and frailty index to develop the clinical prediction model by using multiple logistic regression analysis and least absolute shrinkage and the selection operator (LASSO) method. The k-fold cross-validation method will be utilized to validate the clinical prediction model. In conclusion, this study was aimed to develop a clinical prediction model for postoperative cognitive dysfunction of old patients. It is anticipated that the knowledge gained from this study will facilitate clinical decision-making for anesthetists and surgeons managing the aged patients undergoing noncardiac surgery.

BACKGROUND AND AIMS Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P

The alterations in the gut microbiota have been reported to be correlated with the development of depression. The purpose of this study was to investigate the changes of intestinal microbiota in depressed patients after antidepressant treatment. We recruited 30 MDD patients (MDD group) and 30 healthy controls (control group). The MDD group received individualized treatment with escitalopram at a maximum dose of 20 mg/day. After depressive symptoms improved to a HAMD scale score > 50%, a fecal sample was collected again and used as the follow-up group. The differences of gut microbiota between patients and controls, the characteristics of gut microbiota under treatment and the potential differences in metabolic functions were thus investigated. The Firmicutes/Bacteroidetes ratio was significantly different within three groups, and the ratio of follow-up group was significantly lower than those of the other two groups. Alpha diversity was significantly higher in MDD group than those of the other groups, and the alpha diversity was not significantly different between control and follow-up groups. The beta diversity of some patients resembled participants in the control group. The metabolic function of gut microbiota after treatment was still different from that of the control group. This study suggests that the intestinal flora of depressed patients has a tendency to return to normal under escitalopram treatment.

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Cancer-associated fibroblasts (CAFs) are a major contributor to tumor stromal crosstalk in the tumor microenvironment (TME) and boost tumor progression by promoting angiogenesis and lymphangiogenesis. This study aimed to identify prognostic genes associated with CAFs that lead to high morbidity and mortality in ovarian cancer (OC) patients. We performed bioinformatics analysis in 16 multicenter studies (2,742 patients) and identified CAF-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify COL16A1, COL5A2, GREM1, LUM, SRPX, and TIMP3 and construct a prognostic signature. Subsequently, a series of bioinformatics algorithms indicated risk stratification based on the above signature, suggesting that high-risk patients have a worse prognosis, weaker immune response, and lower tumor mutational burden (TMB) status but may be more sensitive to routine chemotherapeutic agents. Finally, we characterized prognostic markers using cell lines, immunohistochemistry, and single-cell sequencing. In conclusion, these results suggest that the CAF-related signature may be a novel pretreatment guide for anti-CAFs, and prognostic markers in CAFs may be potential therapeutic targets to inhibit OC progression.

Graphical abstract, Introduction A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. Objectives We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. Methods Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. Results We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. Conclusion This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

Dysregulation of transcriptome expression has been reported to play an increasingly significant role in AD. In this study, we firstly identified a vital gene module associated with the accumulation of β-amyloid (Aβ) and phosphorylated tau (p-tau) using the WGCNA method. The vital module, named target module, was then employed for the identification of key transcriptome biomarkers. For coding RNA, GNA13 and GJA1 were identified as key biomarkers based on ROC analysis. As for non-coding RNA, MEG3, miR-106a-3p, and miR-24-3p were determined as key biomarkers based on analysis of a ceRNA network and ROC analysis. Experimental analyses firstly confirmed that GNA13, GJA1, and ROCK2, a downstream effector of GNA13, were all increased in 5XFAD mice, compared to littermate mice. Moreover, their expression was increased with aging in 5XFAD mice, as Aβ and p-tau pathology developed. Besides, the expression of key ncRNA biomarkers was verified to be decreased in 5XFAD mice. GSEA results indicated that GNA13 and GJA1 were respectively involved in ribosome and spliceosome dysfunction. MEG3, miR-106a-3p, and miR-24-3p were identified to be involved in MAPK pathway and PI3K-Akt pathway based on enrichment analysis. In summary, we identified several key transcriptome biomarkers, which promoted the prediction and diagnosis of AD.

Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA–arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. Experimental Design: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). Results: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. Conclusions: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Background Revealing the impacts of endogenous and exogenous mutagenesis processes is essential for understanding the etiology of somatic genomic alterations and designing precise prognostication and treatment strategies for cancer. DNA repair deficiency is one of the main sources of endogenous mutagenesis and is increasingly recognized as a target for cancer therapeutics. The role and prevalence of mechanisms that underly different forms of DNA repair deficiencies and their interactions remain to be elucidated in gynecological malignancies. Methods We analyzed 1231 exomes and 268 whole-genomes from three major gynecological malignancies including uterine corpus endometrial carcinoma (UCEC) as well as ovarian and cervical cancers. We also analyzed data from 134 related cell lines. We extracted and compared de novo and refitted mutational signature profiles using complementary and confirmatory approaches and performed interaction analysis to detect co-occurring and mutually exclusive signatures. Results We found an inverse relationship between homologous recombination deficiency (HRd) and mismatch repair deficiency (MMRd). Moreover, APOBEC co-occurred with HRd but was mutually exclusive with MMRd. UCEC tumors were dominated by MMRd, yet a subset of them manifested the HRd and APOBEC signatures. Conversely, ovarian tumors were dominated by HRd, while a subset represented MMRd and APOBEC. In contrast to both, cervical tumors were dominated by APOBEC with a small subsets showing the POLE, HRd, and MMRd signatures. Although the type, prevalence, and heterogeneity of mutational signatures varied across the tumor types, the patterns of co-occurrence and exclusivity were consistently observed in all. Notably, mutational signatures in gynecological tumor cell lines reflected those detected in primary tumors. Conclusions Taken together, these analyses indicate that application of mutation signature analysis not only advances our understanding of mutational processes and their interactions, but also it has the potential to stratify patients that could benefit from treatments available for tumors harboring distinct mutational signatures and to improve clinical decision-making for gynecological malignancies. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03259-0.

Salt-inducible kinase 2 (SIK2) is a promising target for ovarian cancer therapy due to its critical role in tumorigenesis and progression. Currently available SIK2 inhibitors have shown remarkable therapeutic effects on ovarian cancers in preclinical studies. However, direct administration of the SIK2 inhibitors may bring significant off-target effect, limiting their clinical applications. In this work, by rational design of a hydrogelator Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser-Ser-Ser-Asn-Leu-OH (Nap-S) to coassemble a SIK2 inhibitor HG-9-91-01 (HG), a SIK2-responsive supramolecular hydrogel (Gel Nap-S+HG) for local administration and SIK2-responsive release of HG is reported to efficiently suppress ovarian cancer metastasis. Under the activation of SIK2 overexpressed in ovarian cancers, Nap-S in the hydrogel is phosphorylated to yield hydrophilic Nap-Phe-Phe-Glu-Glu-Leu-Tyr-Arg-Thr-Gln-Ser(H

The purpose of this study was to analyze the acute effect of ambient temperature on hospitalization due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), stroke, and myocardial infarction (MI) in Shenyang, China. We used the distributed delayed nonlinear model to evaluate the impact of ambient temperature on respiratory and cardiovascular diseases. The study population was divided into four groups: < 65 group and ≥ 65 age groups, female and male groups. The < 65 age group of AECOPD patients was more likely to be affected by high ambient temperature, while the ≥ 65 age group of AECOPD patients was more sensitive to low ambient temperature. The hospitalization risk of MI admission increased in the ≥ 65 age group at 1–8 days delay under low ambient temperature conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-020-11934-2.

Objective To improve the accuracy of clinical diagnosis by analyzing different contrast-enhanced ultrasound (CEUS) imagines of specific subtypes of uterine leiomyomas. Methods A total of 147 female patients received preoperative CEUS examination. The scanning plane of the biggest tumors for CEUS was found by common B-mode ultrasonographic scanning on pelvic cavity, then 1.5 mL SonoVue were injected into the median cubital vein. According to the CEUS images, the lesion enhanced time, enhanced level and enhanced morphology were recorded. The time-intensity curve was acquired and analyzed, meanwhile, the relevant parameters were calculated, including rise time (RT), peak intensity (PI), time to peak (TTP) and mean transit time (MTT). Results In cellular uterine leiomyoma group, the percentage of high enhancement, early enhancement was higher, equal enhancement and synchronic enhancement were lower than those in the common uterine leiomyomas group. In hysteromyoma with hyaline degeneration group, the percentage of high enhancement, early enhancement was lower, while low enhancement and delayed enhancement were higher than those in the common uterine leiomyomas group. The ratio of PI in cellular uterine leiomyoma group was the highest, but the ratios of RT, TTP and MTT were the lowest of the three benign groups. The ratio of PI in hysteromyoma with hyaline degeneration group was the lowest, while the ratios of RT and TTP was the highest among the three benign groups. Conclusion Different pathological types of uterine leiomyomas have their own signal performance on CEUS. CEUS can be used to infer their pathological types and help differential diagnosis.

Background and objectives miRNAs play a crucial role in regulating immune responses. However, the effect of miR-124-3p on type 2 inflammation in allergic rhinitis (AR) is unclear. We aimed to study the immune regulation of miR-124-3p in AR and the mechanisms involved. Methods The direct interaction between miR-124-3p and IL-4Rα was confirmed through a dual-luciferase reporter assay. In vitro splenic lymphocytes from mice and peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured and treated with miR-124-3p mimic/inhibitor. Twenty-four female C57BL/C mice were divided into four groups: control, AR model, miR-124-3p agomir, and miR-124-3p antagomir groups (n = 6 per group). The allergic responses were evaluated based on the number of sneezing and nasal scratching, the serum HDM-specific IgE (sIgE) levels, and the degree of nasal mucosa eosinophil infiltration. The expression of IL-4Rα, p-STAT6, and type 2 inflammatory cytokines (IL-4, IL-5 and IL-13) in lymphocytes or nasal mucosa was determined by qPCR, western blotting, flow cytometry, immunohistochemistry and immunofluorescence. Results miR-124-3p directly targets the 3'UTR of IL-4Rα. The miR-124-3p mimic lowered the IL-4Rα, p-STAT6, IL-4, IL-5, and IL-13 expression levels in both mouse splenic lymphocytes and human PBMCs in vitro, and the miR-124-3p inhibitor rescued these changes. Furthermore, the miR-124-3p agomir decreased the levels of IL-4Rα and IL-4 in nasal mucosa, Th2 differentiation in spleen, and allergic response in AR mice. Moreover, the miR-124-3p antagonist increased the IL-4Rα and IL-4 levels and further aggravated the allergic responses. Conclusions miR-124-3p might attenuate type 2 inflammation in AR by regulating IL-4Rα signaling, and miR-124-3p may be a promising new target in AR treatment.

Stereoscopic viewing has an impact on ocular dynamics, but its effects on accommodative functions are not fully understood, especially for autostereoscopic viewing. This study aimed to investigate the changes in dynamic accommodative response, accommodative amplitude, and accommodative facility of myopes after autostereoscopic visual training.We enrolled 46 adults (men = 22 and women = 24; age = 21.5 ± 2.5 [range = 18-25] years, spherical equivalent: -4.52 ± 1.89 [-8.88 to -1.75] diopters [D]) who visited the EyeENT Hospital of Fudan University. The study population was randomly divided into three-dimensional (3D) and two-dimensional (2D) viewing groups to watch an 11-minute training video displayed in 3D or 2D mode. Dynamic accommodative response, accommodative facility, and accommodative amplitude were measured before, during, and immediately after the training. Accommodative lag and the variability of accommodation were also analyzed. Visual fatigue was evaluated subjectively using a questionnaire.Accommodative lag decreased from 0.54 ± 0.29 D to 0.42 ± 0.32 D (P = 0.004), whereas accommodative facility increased from 10.83 ± 4.55 cycles per minute (cpm) to 13.15 ± 5.25 cpm (P0.001) in the 3D group. In the 2D group, there was no significant change in the accommodative lag (P = 0.163) or facility (P = 0.975), but a decrease in accommodative amplitude was observed (from 13.88 ± 3.17 D to 12.71 ± 2.23 D, P = 0.013). In the 3D group, the accommodative response changed with the simulated target distance. Visual fatigue was relatively mild in both groups.The immediate impact of autostereoscopic training included a decrease in the accommodative lag and an increase in the accommodative facility. However, the long-term effects of autostereoscopic training require further exploration.

PurposeThe hypoxic microenvironment is involved in the tumorigenesis of ovarian cancer (OC). Therefore, we aim to develop a non-invasive radiogenomics approach to identify a hypoxia pattern with potential application in patient prognostication.MethodsSpecific hypoxia-related genes (sHRGs) were identified based on RNA-seq of OC cell lines cultured with different oxygen conditions. Meanwhile, multiple hypoxia-related subtypes were identified by unsupervised consensus analysis and LASSO–Cox regression analysis. Subsequently, diversified bioinformatics algorithms were used to explore the immune microenvironment, prognosis, biological pathway alteration, and drug sensitivity among different subtypes. Finally, optimal radiogenomics biomarkers for predicting the risk status of patients were developed by machine learning algorithms.ResultsOne hundred forty sHRGs and three types of hypoxia-related subtypes were identified. Among them, hypoxia-cluster-B, gene-cluster-B, and high-risk subtypes had poor survival outcomes. The subtypes were closely related to each other, and hypoxia-cluster-B and gene-cluster-B had higher hypoxia risk scores. Notably, the low-risk subtype had an active immune microenvironment and may benefit from immunotherapy. Finally, a four-feature radiogenomics model was constructed to reveal hypoxia risk status, and the model achieved area under the curve (AUC) values of 0.900 and 0.703 for the training and testing cohorts, respectively.ConclusionAs a non-invasive approach, computed tomography-based radiogenomics biomarkers may enable the pretreatment prediction of the hypoxia pattern, prognosis, therapeutic effect, and immune microenvironment in patients with OC.

Background Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. Methods A total of 12,901 breast cancer cases and 12,583 controls from 12 case–control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15–55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. Results We did not observe associations between any HLA allele and breast cancer risk at P P = 1.08e−3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). Conclusions No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

Fibroblast growth factors (FGFs) 21 and 23 are recently identified hormones regulating metabolism of glucose, lipid, phosphate and vitamin D. Here we conducted a genome-wide association study (GWAS) for circulating FGF21 and FGF23 concentrations to identify their genetic determinants. We enrolled 5,000 participants from Taiwan Biobank for this GWAS. After excluding participants with diabetes mellitus and quality control, association of single nucleotide polymorphisms (SNPs) with log-transformed FGF21 and FGF23 serum concentrations adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for body mass index (BMI) and a third model additionally adjusted for BMI and estimated glomerular filtration rate (eGFR) were used. A total of 4,201 participants underwent GWAS analysis. rs67327215, located within RGS6 (a gene involved in fatty acid synthesis), and two other SNPs (rs12565114 and rs9520257, located between PHC2-ZSCAN20 and ARGLU1-FAM155A respectively) showed suggestive associations with serum FGF21 level (P = 6.66 × 10–7, 6.00 × 10–7 and 6.11 × 10–7 respectively). The SNPs rs17111495 and rs17843626 were significantly associated with FGF23 level, with the former near PCSK9 gene and the latter near HLA-DQA1 gene (P = 1.04 × 10–10 and 1.80 × 10–8 respectively). SNP rs2798631, located within the TGFB2 gene, was suggestively associated with serum FGF23 level (P = 4.97 × 10–7). Additional adjustment for BMI yielded similar results. For FGF23, further adjustment for eGFR had similar results. We conducted the first GWAS of circulating FGF21 levels to date. Novel candidate genetic loci associated with circulating FGF21 or FGF23 levels were found. Further replication and functional studies are needed to support our findings.

Objective The objective of this study was to evaluate the outcomes of open surgery (OS) and endovascular surgery (ES) for extracranial carotid aneurysm (ECCA) in the authors' centre. Methods Fifty-seven consecutive patients who were diagnosed with ECCA and underwent intervention from January 2005 to July 2019 at Zhongshan Hospital, Fudan University, were reviewed retrospectively. Patient characteristics and surgical outcomes for OS and ES were analysed. ECCAs were divided into three morphological subgroups: subgroup Ⅰ, no severe tortuosity of the internal carotid artery (ICA) or common carotid artery (CCA) proximal to the aneurysm, tortuosity of the aneurysm and 1 cm of peri-aneurysmal carotid artery ≤ 90°; subgroup Ⅱ, severe ICA or CCA tortuosity proximal to the aneurysm, tortuosity of the aneurysm and 1 cm of peri-aneurysmal carotid artery ≤ 90°; subgroup Ⅲ, aneurysm tortuosity and 1 cm peri-aneurysmal carotid artery > 90°. Results 35 patients underwent OS, 20 patients underwent ES and 2 patients underwent OS after the failure of ES. Thirty-six cases were classified in subgroup Ⅰ, 11 cases in subgroup Ⅱ, and 10 cases in subgroup Ⅲ. ES was achieved successfully in all 18 cases of subgroup I, but failed in three of four cases in subgroups Ⅱ and Ⅲ. With a mean duration of 62.9 ± 44.5 months of follow up, five deaths were recorded in the OS group, two of which were caused by ipsilateral stroke and three were not neurologically related. There was no stroke or death in the ES group during follow up. One case of stroke and two cases of death occurred in symptomatic patients, while one case of stroke and three cases of death occurred in asymptomatic patients. Conclusion This series demonstrates that ES may be a safe and durable option for ECCA in subgroup Ⅰ, while in subgroups Ⅱ and Ⅲ, ES alone may be difficult to apply. A 30 day stroke rate around 5% existed in ECCAs with interventions, which should be considered before the intervention.

Background and aims The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines. Approach and results AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns. Conclusions The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.

Cervical cancer (CC) is a malignant tumor that could seriously endanger women's life and health, of which cervical squamous cell carcinoma (CESC) accounts for more than 80%. High-risk human papillomavirus (HR-HPV) infection is the primary cause of CC. The 5-year survival rate is low due to poor prognosis. We need to explore the pathogenesis of CC and seek effective biomarkers to improve prognosis. The purpose of this research is to construct an HR-HPV-related long non-coding RNA (lncRNA) signature for predicting the survival and finding the biomarkers related to CC prognosis. First, we downloaded the CESC data from The Cancer Genome Atlas (TCGA) database to find HR-HPV-related lncRNAs in CC. Then, the differentially expressed lncRNAs were analyzed by univariate and multivariate Cox regression. Six lncRNAs were found to be associated with the prognosis and can be used as independent prognostic factors. Next, based on these prognostic genes, we established a risk score model, which showed that patients with higher score had poorer prognosis and higher mortality. Moreover, the Kaplan-Meier curve of the model indicated that the model was statistically significant (

Background In previous studies, the growth rate and diameter of infrarenal aorta was paucity of Chinese data. This study aim to evaluate the normal inside diameter and growth rate of the infrarenal aorta and common iliac artery in Chinese adult population and to explore the relationship between related factors and the arterial diameter. Methods A retrospective study was performed among 1,340 hospitalized adult patients undergoing contrast-enhanced abdominopelvic computed tomography from April 2017 to March 2018 in our hospital. The inside diameter of infrarenal aorta and common iliac artery was measured. Linear regression was used to analyze the relationship between various factors and arterial diameter. Kruskal-Wallis H test was used to analyze the relationship between the arterial diameter and age. Mann-Whitney U test was used to analyze the relationship between arterial diameter and sex. Results The inside diameter of the infrarenal aorta was 16.49 ± 2.12 mm in male patients and 14.50 ± 1.73 mm in female patients. In male patients, the right common iliac artery was 9.77 ± 1.75 mm, and the left was 9.65 ± 1.76 mm. In female patients, the right common iliac artery was 8.59 ± 1.31 mm and the left was 8.45 ± 1.28 mm. Comparing the oldest group with the youngest, the infrarenal aortic diameter increased 27.32% in male patients and 30.11% in female patients. Right common iliac artery increased 25.13% in male patients and 30.30% in female patients. Left common iliac artery increased 25.19% in male patients and 34.26% in female patients. The growth rate increased at the beginning, reached its peak at the age of 50–60 years, and then decreased. Multiple linear regression analysis results showed that sex, age, body surface area (BSA), hypertension, and cancer were significantly correlated with the diameter of infrarenal aorta. Sex, age, BSA, and hypertension were correlated with the diameter of right common iliac artery. Sex, age, BSA, and cancer were correlated with the diameter of left common iliac artery. Conclusions The diameter of the infrarenal abdominal aorta and common iliac artery of Chinese people is smaller than that of other countries. The abdominal aortic aneurysm (AAA) guideline might be developed based on the basic diameter to suit patients with AAA and a different basic abdominal aortic diameter. Artery diameter was increased by the age, and female patients have smaller diameter and larger arterial growth rate than male patients. Female and young patients with AAA may choose more oversize grafts for endovascular AAA repair.

Purpose: The aim of this study was to compare visual outcomes after small incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) for high myopia. Methods: In this prospective, comparative study, a total of 52 eyes of 34 consecutive highly myopic patients with spherical equivalent within the range of –8.00 to –10.00 diopters were recruited. Twenty-three eyes of 16 patients were in the FS-LASIK group and 29 eyes of 18 patients were in the SMILE group. Visual outcomes and wavefront aberrations were analyzed preoperatively and 6 months postoperatively. Results: At the postoperative 6-month visit, 96.6% in the SMILE group and 91.3% in the FS-LASIK group achieved unchanged or better corrected distance visual acuity (CDVA). As for uncorrected distance visual acuity (UDVA), 96.6% in the SMILE group and 95.7% in the FS-LASIK group achieved UDVA of 20/20 or better. As for wavefront aberrations, high-order aberrations (HOAs) and spherical aberrations increased significantly after surgery in both groups relative to corresponding preoperative values (p < 0.001), and vertical coma increased after SMILE (p < 0.001). No statistically significant differences in changes of HOAs (p =0.90), spherical aberrations (p = 0.07), horizontal coma (p = 0.56), coma (p =0.08), horizontal trefoil (p =0.19), vertical trefoil (p = 0.90), and trefoil (p = 0.45) were detected between the 2 groups, except for vertical coma (p < 0.01). Conclusions: SMILE is as effective as FS-LASIK in correcting high myopia, but attention should be paid to the induction of vertical coma in highly myopic patients following a SMILE procedure.

Background Parasympathetic nerve hypersensitivity contributes to the severity of allergic rhinitis (AR), but the precise mechanism underlying neuroimmune regulation in patients with AR remains unclear. This study investigated the effect of cholinergic nerve inhibition on AR CD4+ T-helper (Th)2-cell polarization and the underlying regulatory mechanism in vitro. Methods An in-vitro neuroimmune coculture model of D-U87 cells and CD4+ T cells was established. D-U87 cells with cholinergic neuron characteristics were used as cholinergic neuron models. CD4+ T cells were derived from peripheral blood monocytes from AR patients (n = 60) and control subjects (n = 40). Th1- and Th2-cell percentages were measured by flow cytometry. Proteins involved in related signaling pathways were analyzed by protein chip assay and Western blotting. Results The Th2-cell percentage among CD4+ T cells from AR patients was significantly increased after coculture with D-U87 cells and was decreased by ipratropium bromide (IB) treatment. In contrast, the Th1-cell percentage among control CD4+ T cells was significantly increased after coculture with D-U87 cells, but was unaltered by IB treatment. Furthermore, phosphorylated Akt (p-Akt) protein levels increased in CD4+ T cells from both controls and AR patients after coculture with D-U87 cells and decreased after IB treatment. However, higher p-Akt levels were observed in cells from AR patients than in cells from control subjects. Moreover, Akt inhibition decreased Th2-cell percentage in AR patients. Conclusion In-vitro cholinergic nerve inhibition with IB decreased AR CD4+ T-cell polarization into Th2 cells partially through an Akt-dependent mechanism.

Purpose Ovarian cancer (OC) is the most common malignancy in women with high mortality. Increasing studies have revealed that long non-coding RNA (lncRNA) MNX1-AS1 has a promoting effect on various cancers. However, the mechanisms of MNX1-AS1 in OC are still unclear. Therefore, this study focused on exploring the mechanisms of MNX1-AS1 in OC. Materials and methods The expression of SOX12 at the protein level was detected by western blot. Cell proliferation was detected by CCK8 assay and colony formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. Wound-healing assay, transwell assay and western blot were used to detect the ability of cell migration and invasion. The target binding was confirmed through the luciferase reporter assay. Results The expression of MNX1-AS1 was increased in OC tumor tissues and cells. Elevated MNX1-AS1 expression is associated with advanced stage and lower overall survival rate. Knockdown of MNX1-AS1 inhibited cell proliferation, migration and invasion, blocked cell cycle, and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. MNX1-AS1 was competitively binding with miR-744-5p, and its downstream target gene was SOX12. miR-544-5p expression was decreased, while SOX12 expression was increased in OC tumor tissues and cells. Overexpression of miR-744-5p inhibited cell proliferation, migration, invasion and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. Conclusion MNX1-AS1 promoted the development of OC through miR-744-5p/SOX12 axis. This study revealed a novel mechanism of MNX1-AS1 in OC, which may provide a new treatment or scanning target for OC.

Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

The incidence rate of human uterine leiomyomas is over 70% in the women of childbearing age, which has caused serious health and financial burden. Our previous study confirmed that Bisphenol A (BPA)，representative environmental estrogen, promoted the proliferation of human uterine leiomyomas and up-regulated the expression of cell proliferation-related genes. In this study, by combining ChIP-seq and RNA-seq, it was shown that after BPA intervention, H3K27ac modification levels and gene expression levels were altered in uterine leiomyomas cells. Moreover experimental verification found that BPA can regulate ITGA2 through the transcription factor XBP1, activate the downstream PI3K/AKT signaling pathway, eventually promote the proliferation of uterine leiomyomas. The present study provides new insights into the pathogenesis associated with exposure to BPA and other endocrine disruptors with similar effects by defining XBP1 as an important regulator, and which may act as an intervention and treatment target for uterine leiomyomas.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.

Background The aim of this study was to analyze the risk factors, causes, and management of intestinal obstruction after pediatric liver transplantation. Methods Retrospective analysis was performed on pediatric liver transplantation recipients from January 1st 2013 to December 31st 2019 at Organ Transplant Center, Tianjin First Central Hospital. The cases of intestinal obstruction were analyzed. Results A total of 1034 pediatric liver transplantations were performed during the study period, 66 intestinal obstructions were diagnosed in 61 recipients. Three recipients suffered intestinal obstructions twice, and one recipient suffered three times. Forty of the 66 cases were treated with non-surgical treatment, including fasting, gastrointestinal decompression, purgation, enema, and parenteral nutrition. Surgical intervention was performed in 26 cases. Diaphragmatic hernia, intestinal inflammatory stenosis, PTLD, and intestine perforation are essential causes of intestinal obstruction in pediatric liver transplant recipients. Diaphragmatic hernia was independent risk factors for intestinal obstruction. The 1-, 2- and 3-year survival rate of the recipients with or without intestinal obstruction were 98.4%, 96.5%, 96.5% and 95.3%, 94.4%, 94.0%, respectively, without significant difference. Conclusions Most cases of intestinal obstruction after liver transplantation in children can be remitted by non-surgical treatment, but there are still some cases need to be treated by surgery. Both measures are related to ideal outcomes, intestinal obstruction does not increase the mortality rate in pediatric liver transplantation.

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.

Preventive intervention can significantly reduce the human and economic costs of postpartum depression (PPD) compared with treatment post-diagnosis. However, identifying women with a high PPD risk and making a judgement as to the benefits of preventive intervention is a major challenge.This is a retrospective study of parturients that underwent a cesarean delivery. Control group was used as development cohort and validation cohort to construct the risk prediction model of PPD and determine a risk threshold. Ketamine group and development cohort were used to verify the risk classification of parturients by evaluating whether the incidence of PPD decreased significantly after ketamine treatment in high-risk for PPD population.The AUC for the development cohort and validation cohort of the PPD prediction model were 0.751 (95%CI:0.700-0.802) and 0.748 (95%CI:0.680-0.816), respectively. A threshold of 19% PPD risk probability was determined, with a specificity and sensitivity in the validation cohort are 0.766 and 0.604, respectively. After matching the high-risk group and the low-risk group by propensity score, the results demonstrated that PPD incidence significantly reduced in the high-risk group following ketamine, versus non-ketamine, intervention (p0.01). In contrast, intervention in the low-risk group showed no significant difference in PPD outcomes (p0.01).Randomized trials are needed to further verify the feasibility of the model and the thresholds proposed.This prediction model developed in this study shows utility in predicting PPD risk. Ketamine intervention significantly lowers PPD incidence in parturients with a risk classification threshold greater than 19%.

BACKGROUND AND AIMS Interferon-γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex-specific liver injury and inflammation induced by IFNγ. APPROACH AND RESULTS A lentiviral autophagy-related 5 (Atg5) knockdown was performed to decrease autophagy-sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL-1β or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ-induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ-induced hepatocyte death in autophagy-deficient AML12 cells and female mice. The mechanism of death is STAT1-induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. CONCLUSIONS Decreased hepatocyte autophagy sensitizes mice to IFNγ-induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex-specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ-mediated immune diseases.

Background This study was aimed to discover more biomarkers associated with spinal cord injury (SCI) by constructing a competing endogenous RNA (ceRNA) network. Methods The transcriptome expression profile data related to SCI (GSE45006 GSE20907) were downloaded from GEO database. The differentially expressed RNAs (DERs), including lncRNAs, miRNAs, and mRNAs, between SCI and control groups were selected, which were then performed function enrichment analyses. Following that, a SCI-related ceRNA regulatory network was constructed. PCA analysis was performed on the genes constituting the ceRNA regulatory network directly related to SCI. Results In GSE45006 and GSE20907 datasets, there were respectively 3336 and 1453 DERs. Venn analysis showed that there were 429 DERs which had consistent differential expression direction. RGD1564534-miR-29b-5p relation pair and 103 miRNA-target regulatory pairs were integrated to construct the ceRNA regulatory network. Then a SCI-related ceRNA regulatory network including 8 mRNAs of IFNGR1, STAT2, CYBB, NFATC1, FCGR2B, HMOX1, TLR4, and HK2, a lncRNA of RGD1564534, and a miRNA of miR-29b-5p was constructed. Additionally, two pathways, osteoclast differentiation, and HIF-1 signaling pathway, were involved in this network. PCA indicated the samples before and after injury can be significantly distinguished based on the genes in the ceRNA network. Conclusion A total of 8 SCI-related mRNAs have been identified in the ceRNA network, including IFNGR1, STAT2, CYBB, NFATC1, FCGR2B, HMOX1, TLR4, and HK2. Moreover, RGD1564534 may serve as ceRNA by competitively binding to miR-29b-5p to regulate the expression of 8 SCI-related mRNAs. Therefore, these genes may serve as key biomarkers of SCI.

Excessive bone resorption induced by increased osteoclast activity in postmenopausal women often causes osteoporosis. Although the pharmacological treatment of osteoporosis has been extensively developed, a safer and more effective treatment is still needed. Here, we found that curcumenol (CUL), an antioxidant sesquiterpene isolated from Curcuma zedoaria, impaired receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis in vitro, whereas the osteoblastogenesis of MC3T3-E1 cells was not affected. We further demonstrated that CUL treatment during RANKL-induced osteoclastogenesis promotes proteasomal degradation of TRAF6 by increasing its K48-linked polyubiquitination, leading to suppression of mitogen-activated protein kinases (MAPKs) and NF-κB pathways and the production of reactive oxygen species (ROS). We also showed that inositol polyphosphate multikinase (IPMK) binds with TRAF6 to reduce its K48-linked polyubiquitination under RANKL stimulation. Concurrently, IPMK deficiency inhibits osteoclast differentiation. The binding between IPMK and TRAF6 blocked by CUL treatment was found in our study. Finally, we confirmed that CUL treatment prevented ovariectomy (OVX)-induced bone loss in mice. In summary, our study demonstrates that CUL could impair the stability of TRAF6 enhanced by IPMK and suppress excessive osteoclast activity in estrogen-deficient mice to treat osteoporosis. © 2021 American Society for Bone and Mineral Research. © 2021 American Society for Bone and Mineral Research (ASBMR).

Background Highly upregulated in liver cancer (HULC) is a long non-coding RNA (lncRNA) which has recently been identified as a key regulator in hepatocellular carcinoma (HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown. Aim To explore the mechanism by which HULC promotes the secretion of exosomes from HCC cells. Methods Serum and liver tissue samples were collected from 30 patients with HCC who had not received chemotherapy, radiotherapy, or immunotherapy before surgery. HULC expression in serum exosomes and liver cancer tissues of patients was measured, and compared with the data obtained from healthy controls and tumor adjacent tissues. The effect of HULC upregulation in HCC cell lines and the relationship between HULC and other RNAs were studied using qPCR and dual-luciferase reporter assays. Nanoparticle tracking analysis was performed to detect the quantity of exosomes. Results HULC expression in serum exosomes of patients with HCC was higher than that in serum exosomes of healthy controls, and HULC levels were higher in liver cancer tissues than in tumor adjacent tissues. The expression of HULC in serum exosomes and liver cancer tissues correlated with the tumor-node-metastasis (TNM) classification, and HULC expression in tissues correlated with that in serum exosomes. Upregulation of HULC promoted HCC cell growth and invasion and repressed apoptosis. Notably, it also facilitated the secretion of exosomes from HCC cells. Moreover, qPCR assays showed that HULC repressed microRNA-372-3p (miR-372-3p) expression. We also identified Rab11a as a downstream target of miR-372-3p. Dual-luciferase reporter assays suggested that miR-372-3p could directly bind both HULC and Rab11a. Conclusion Our findings illustrate the importance of the HULC/miR-372-3p/Rab11a axis in HCC and provide new insights into the molecular mechanism regulating the secretion of exosomes from HCC cells.

Summary Background Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. Methods In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology–Oncology Programs Evaluation System in China. Young patients (16–60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61–80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1–5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01852435 . Findings From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6–77·6) and in the R-CEOP70 group was 72·4% ([66·5–77·5]; HR 1·00 [0·73–1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1–93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7–82·3]; 0·44 [0·25–0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4–83·7%]; 0·49 [0·27–0·86]; p=0·017). Grade 3–4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. Interpretation R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. Funding National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

BACKGROUND Osteopontin (OPN) is a molecule expressed in numerous cancers including colorectal cancer (CRC) that correlates disease progression. The interaction of OPN that promotes CRC cell migration, invasion, and cancer stem-like cells (CSCs) have not been elucidated. Hence, we aimed to investigate the mechanisms that might be involved. MATERIAL AND METHODS Expression of OPN in tumor tissues derived from patients was monitored with real-time quantitative polymerase chain reaction and western blot. Wound healing and Transwell assay were used to test the differences in migration and invasion in an OPN enriched environment and OPN knockdown condition. Aldehyde dehydrogenase 1 (ALDH1) positive stem cells were isolated using fluorescence-activated cell sorting (FACS) following the protocol of the ALDEFLUOR™ kit. The expression of protein participation in the PI3K-Akt-GSK/3ß-ß/catenin pathway was detected by western blot. RESULTS OPN exhibited increased levels in CRC tumor tissue compared with non-tumor normal tissue and the high level of which correlated with lymphatic metastasis and late TNM stage. Additional rhOPN co-cultured low-expression CRC cells demonstrated more aggressive capability of proliferation, migration, and invasion. For knockdown of OPN in high-expression CRC cells, the bioactivities of proliferation, migration, and invasion were significantly inhibited. Interestingly, the percentage of ALDH1 labeled stem cells was dramatically decreased by OPN inhibition. The phosphorylation of PI3K-Akt-GSK/3ß-ß/catenin pathway was involved in the OPN signaling. Furthermore, Ly294002, a specific PI3K inhibitor, can reverse the promotion of bioactivities and stem cell proportion among rhOPN treated CRC cells. CONCLUSIONS OPN promoted cell proliferation, migration, and invasion, and was accompanied by upregulation of ALDH1-positive CSC in CRC through activation of PI3K-Akt-GSK/3ß-ß/catenin pathway.

Aim To study the molecular mechanism of G protein-coupled receptor 30-epidermal growth factor receptor (GPR30-EGFR) signaling pathway on the proliferation of leiomyoma cells exposed with bisphenol A. Methods Primary cultures and subcultures of human uterine leiomyoma (UL) cells. The expressions of messenger RNA and proteins of GPR30 and EGFR in 15 leiomyoma tissue specimens and all groups were detected by real-time quantitative polymerase chain reaction assay and Western blot assay. The protein of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK)/c-fos signaling pathway members was detected by Western blot assay. Results Bisphenol A promoted the growth of UL cells and the expressions of GPR30, EGFR, c-fos and p-ERK1/2. Conclusion Bisphenol A was found to be a promoter specifically to proliferate the human UL cells by activating the transcription and translation of GPR30-EGFR and MAPK/ERK/c-fos signaling pathway members.

Background Relaxin is a small peptide hormone that regulates extracellular matrix remodeling and reduces fibrosis in a number of organs. Little is known about its impact on chronic rhinosinusitis with nasal polyps (CRSwNP); thus, we aimed to determine the expression of human H2 relaxin (relaxin-2) and its role in tissue remodeling in CRSwNP. Methods Patients were enrolled and divided into the following groups: CRS with NP (CRSwNP; n = 20), CRS without NP (CRSsNP; n = 20), and controls (n = 15). Tissue samples were analyzed by Masson trichrome staining for collagen, while the location and expression of relaxin-2, transforming growth factor beta 1 (TGF-β1), and phosphorylated (p) Smad2/Smad3 were analyzed by immunohistochemistry and Western blot. The expression of relaxin-2, Smad2, Smad3, and TGF-β1 mRNA was tested by quantitative polymerase chain reaction (qPCR). Ex vivo NP were treated with relaxin-2 (n = 15) or TGF-β1 (n = 15). Collagen type I (collagen I), relaxin-2, and TGF-β1 levels in the culture supernatants were examined by enzyme-linked immunosorbent assay, while pSmad2/Smad3 in culture pellets was analyzed by Western blot, and the expression of Smad2 and Smad3 mRNA was tested by qPCR. Results The collagen, relaxin-2, TGF-β1, and pSmad2/Smad3 protein expression levels were significantly decreased in the CRSwNP group compared with the CRSsNP group ( P Conclusions The antifibrotic effects of relaxin-2 may play a role in tissue remodeling in CRSwNP, but the detailed mechanism deserves further study.