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Diagnosis and classification of tumors is increasingly dependent on biomarkers. RNA expression profiling using next-generation sequencing provides reliable and reproducible information on the biology of cancer. This study investigated targeted transcriptome and artificial intelligence for differential diagnosis of hematologic and solid tumors. RNA samples from hematologic neoplasms (N = 2606), solid tumors (N = 2038), normal bone marrow (N = 782), and lymph node control (N = 24) were sequenced using next-generation sequencing using a targeted 1408-gene panel. Twenty subtypes of hematologic neoplasms and 24 subtypes of solid tumors were identified. Machine learning was used for diagnosis between two classes. Geometric mean naïve Bayesian classifier was used for differential diagnosis across 45 diagnostic entities with assigned rankings. Machine learning showed high accuracy in distinguishing between two diagnoses, with area under the curve varying between 1 and 0.841. Geometric mean naïve Bayesian algorithm was trained using 3045 samples and tested on 1415 samples, and showed correct first-choice diagnosis in 100%, 88%, 85%, 82%, 88%, 72%, and 72% of acute lymphoblastic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, colorectal cancer, lung cancer, chronic lymphocytic leukemia, and follicular lymphoma cases, respectively. The data indicate that targeted transcriptome combined with artificial intelligence are highly useful for diagnosis and classification of various cancers. Mutation profiles and clinical information can improve these algorithms and minimize errors in diagnoses.

Complete tracheal obliteration after tracheostomy remains a considerable challenge for otolaryngologists and pulmonologists. Here, we report for the first time a novel method of interventional bronchoscopy to successfully recanalize complete tracheal obliteration. Three patients with suprastomal tracheal obliteration and tracheostomy dependence were referred to our center for further management. Using interventional bronchoscopy, a TBNA needle was retrogradely inserted from the stoma to locate the original passage through the occlusion, and then its stylet was left as a guide wire for the sequential dilations. Once the tracheal lumen was restored, endoprosthesis would be implanted to maintain the airway patency. All cases achieved successful recanalization with effortless breathing after the treatment and restored phonation. Bronchoscopic retrograde recanalization using a TBNA needle is a promising and effective treatment for complete tracheal obliteration.

Objective The present systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to investigate the effects of pulmonary rehabilitation in individuals with chronic obstructive pulmonary disease (COPD). Methods The RCTs of pulmonary rehabilitation programs published between 1999 and 2021 were retrieved from electronic databases (PubMed, Cochrane Library, and Embase). Two reviewers independently assessed the topical relevance and trial quality and extracted data for meta-analysis using the Stata software version 14.0. Results A total of 39 trials involving 2,397 participants with COPD were evaluated. We found that patients who received pulmonary rehabilitation program had significant improvement in the 6-min walk test (6MWT), St. George Respiratory Questionnaire score, and the modified British Medical Research Council score as compared to those who received usual care. Yoga and Tai Chi showed significant improvement in the forced expiratory volume (FEV1)% in 1 s predicted value. However, no significant difference was detected in the modified Borg score, forced vital capacity (FVC), and FEV1/FVC predicted value between the pulmonary rehabilitation and usual care groups. Conclusion Yoga and Tai Chi showed a significant improvement in the FEV1% predicted value. Also, pulmonary rehabilitation program improved the exercise capacity, the quality of life, and dyspnoea in patients with COPD.Key messagesA total of 39 trials involving 2,397 participants with COPD were evaluated.We found that patients who received pulmonary rehabilitation program had significant improvement in the 6MWT, St. George Respiratory Questionnaire score, and the modified British Medical Research Council score as compared to those who received usual care.Yoga and Tai Chi showed significant improvement in the FEV1% predicted value.No significant difference was detected in the modified Borg score, FVC, and FEV1/FVC predicted value between the pulmonary rehabilitation and usual care groups.

Prolactinomas have harmful effects on human health. Bromocriptine is the only commercially available drug in China, but about 25% of prolactinoma patients do not respond to it in clinic, its pathogenesis remains unknown. Thus, its pathogenesis needs to be determined to develop new therapeutic methods for prolactinomas. The expression of ERβ, TLR4, and prolactin (PRL) in the pituitary gland of C57BL/6 mice and human prolactinoma specimen was examined by immunofluorescence or immunohistochemistry. The role of TLR4 in prolactinoma was determined using estradiol-induced models of C57BL/6 wild-type and TLR4−/− mice. MMQ cells were treated with estradiol, fulvestrant, and lipopolysaccharide (LPS) or transfected with TLR4 siRNA to study the expression of ERβ, TLR4, and PRL in these cells. Furthermore, the interaction between ERβ and TLR4 was investigated by immunoprecipitation analysis. The expression of PRL and TLR4 was co-located and increased in the pituitary gland of mice and human prolactinoma specimen compared to that in the control specimen. Meanwhile, TLR4 knockout or treatment with the TLR4 inhibitor TAK242 not only significantly inhibited tumor overgrowth but also decreased the expression of PRL in estradiol-treated mice through p38 MAPK pathway regulation. However, MMQ treated with estradiol and LPS enhanced PRL expression than treated with estradiol or LPS alone. Finally, ERβ or TLR4 inhibition prevented the estradiol-induced PRL increase by regulating the TLR4/p38 MAPK pathway in vitro. Estradiol promoted prolactinoma development by activating the TLR4/p38 MAPK pathway through ERβ, and TLR4 is a potential therapeutic target for prolactinoma treatment.

IgA nephropathy (IgAN) is characterized by deposition of galactose-deficient IgA1 (Gd-IgA1) in glomerular mesangium associated with mucosal immune disorders. Since environmental pollution has been associated with the progression of chronic kidney disease in the general population, we specifically investigated the influence of exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) on IgAN progression. Patients with biopsy-proven primary IgAN were recruited from seven Chinese kidney centers. PM2.5 exposure from 1998 to 2016 was derived from satellite aerosol optical depth data and a total of 1,979 patients with IgAN, including 994 males were enrolled. The PM2.5 exposure levels for patients from different provinces varied but, in general, the PM2.5 exposure levels among patients from the north were higher than those among patients from the south. The severity of PM2.5 exposure in different regions was correlated with regional kidney failure burden. In addition, each 10 μg/m

OBJECTIVE In this study, the authors aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome. METHODS A retrospective cohort of patients who underwent tumor resection from July 2013 to March 2021 for midline posterior fossa tumors was investigated. All patients were followed up at least once. Clinical data were extracted from medical records and follow-up databases. Two neuroradiologists independently reviewed preoperative and postoperative MRI. Univariable and multivariable analyses were performed to compare the postoperative cerebellar mutism syndrome (pCMS) and non-pCMS groups. Correlation analysis was performed using the Spearman correlation coefficient analysis. RESULTS Of 124 patients, 47 (37.9%) developed pCMS. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months. The median duration of mutism was 45 days. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm. In the univariable analysis, abnormal T2-weighted signal of the left dentate nucleus (DN) (74.5% in the pCMS group vs 36.4% in the non-pCMS group, p < 0.001), right DN (83.0% vs 40.3%, p < 0.001), left superior cerebellar peduncle (SCP) (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left middle cerebellar peduncle (MCP) (51.1% vs 26.0%, p = 0.008), and right MCP (61.7% vs 26.0%, p < 0.001); male sex (83.0% vs 45.5%, p < 0.001); vermis 3 impairment (49.4% vs 19.1%, p = 0.002); solid tumor (91.5% vs 72.7%, p = 0.022); and hydrocephalus (72.3% vs 45.5%, p = 0.006) were more frequent in the pCMS group than in the non-pCMS group. Multivariable logistic analysis showed that male sex (adjusted OR 4.08, p = 0.010) and the cerebro-cerebellar circuit score of T2-weighted images (adjusted OR 2.15, p < 0.001) were independent risk factors for pCMS. The cerebro-cerebellar circuit score positively correlated with the duration of mutism. In Cox regression analysis, the cerebro-cerebellar integrated circuit injury score of T2 (adjusted HR 0.790, 95% CI 0.637–0.980; p = 0.032) and injury of vermis 3 (adjusted HR 3.005, 95% CI 1.197–7.547; p = 0.019) were independently associated with the duration of mutism. CONCLUSIONS Male sex and cerebro-cerebellar circuit damage are independent risk factors for pCMS. The cerebro-cerebellar circuit score indicates the duration of mutism.

Monkeypox, caused by the monkeypox virus (MPXV), is a zoonotic disease endemic mainly in West and Central Africa. As of 27 September 2022, human monkeypox has occurred in more than 100 countries (mostly in non-endemic regions) and caused over 66,000 confirmed cases, which differs from previous epidemics that mainly affected African countries. Due to the increasing number of confirmed cases worldwide, the World Health Organization (WHO) has declared the monkeypox outbreak as a Public Health Emergency of International Concern on July 23, 2022. The international outbreak of human monkeypox represents a novel route of transmission for MPXV, with genital lesions as the primary infection, and the emergence of monkeypox in the current outbreak is also new, as novel variants emerge. Clinical physicians and scientists should be aware of this emerging situation, which presents a different scenario from previous outbreaks. In this review, we will discuss the molecular virology, evasion of antiviral immunity, epidemiology, evolution, and detection of MPXV, as well as prophylaxis and treatment strategies for monkeypox. This review also emphasizes the integration of relevant epidemiological data with genomic surveillance data to obtain real-time data, which could formulate prevention and control measures to curb this outbreak.

Deep learning models are increasingly being used to interpret whole-slide images (WSIs) in digital pathology and to predict genetic mutations. Currently, it is commonly assumed that tumor regions have most of the predictive power. However, it is reasonable to assume that other tissues from the tumor microenvironment may also provide important predictive information. In this paper, we propose an unsupervised clustering-based multiple-instance deep learning model for the prediction of genetic mutations using WSIs of three cancer types obtained from The Cancer Genome Atlas. Our proposed model facilitates the identification of spatial regions related to specific gene mutations and exclusion of patches that lack predictive information through the use of unsupervised clustering. This results in a more accurate prediction of gene mutations when compared with models using all image patches on WSIs and two recently published algorithms for all three different cancer types evaluated in this study. In addition, our study validates the hypothesis that the prediction of gene mutations solely based on tumor regions on WSI slides may not always provide the best performance. Other tissue types in the tumor microenvironment could provide a better prediction ability than tumor tissues alone. These results highlight the heterogeneity in the tumor microenvironment and the importance of identification of predictive image patches in digital pathology prediction tasks.

The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmaThis was a clinical trial of HSK3486 in subjects with normal hepatic function (In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS).Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment.The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

The purpose of this study is to investigate the chain mediating effects of networking behaviors and decision self-efficacy between work skills development and perceived employability. Structural equations modeling is used to analyze data collected from 813 Chinese students. The results show the following: first, the work skills development is positively correlated with perceived employability. Second, network behavior and decision self-efficacy each have a mediating effect between work skills development and perceived employability. Finally, this study found a chain mediating effect of network behavior and decision self-efficacy between work skills development and perceived employability. Therefore, this research shows that Work-Integrated Learning (WIL) needs to focus not only on skills development and employability outcomes but also on developing a strong network-based platform for stakeholders. In addition, higher education institutions and workplaces should also provide career guidance and counseling centers to help students build confidence in career decision-making and ensure students’ mental health care and healthy career development.

Although hydrogel-based patches have shown promising therapeutic efficacy in myocardial infarction (MI), synergistic mechanical, electrical, and biological cues are required to restore cardiac electrical conduction and diastolic-systolic function. Here, an injectable mechanical-electrical coupling hydrogel patch (MEHP) is developed via dynamic covalent/noncovalent cross-linking, appropriate for cell encapsulation and minimally invasive implantation into the pericardial cavity. Pericardial fixation and hydrogel self-adhesiveness properties enable the MEHP to highly compliant interfacial coupling with cyclically deformed myocardium. The self-adaptive MEHP inhibits ventricular dilation while assisting cardiac pulsatile function. The MEHP with the electrical conductivity and sensitivity to match myocardial tissue improves electrical connectivity between healthy and infarcted areas and increases electrical conduction velocity and synchronization. Overall, the MEHP combined with cell therapy effectively prevents ventricular fibrosis and remodeling, promotes neovascularization, and restores electrical propagation and synchronized pulsation, facilitating the clinical translation of cardiac tissue engineering.

Two new 22-membered macrolide metabolites, phthoramycins B (1) and C (2), were isolated from the fermentation broth of Streptomyces sp. HU210. Their structures were elucidated based on extensive spectroscopic techniques including 1D, 2D NMR and HRESIMS data. Compounds 1 and 2 showed moderate cytotoxic activity against human leukemia cell line K562 and lung carcinoma cell line A549.

PURPOSE Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)–positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)–positive populations. RESULTS At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference –0.33%; 95% CI, –9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1–positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference –8.26%; 95% CI, –20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

To systematically evaluate and integrate the qualitative research on physical activity (PA) experience of patients with chronic obstructive pulmonary disease (COPD).Web of Science, Cochrane Library, Embase, CINAHL and other databases were searched, and the qualitative research on PA experience of patients with COPD was collected. The systematic review was conducted in line with Joanna Briggs Institute (JBI) methodology for systematic reviews of qualitative evidence.12 studies were included and 3 themes were summarized, included: COPD patients experience more barriers while participating in physical activities than facilitators; COPD patients experience more positive effects post-physical activities than negative effects; Guaranteeing safety, goal setting, and establishing a professional support group improve compliance in COPD patients.Health care professionals should help patients overcome the obstacles of PA, pay attention to the PA experience of patients, adopt diversified PA methods, improve PA participation and compliance, and make patients develop good PA habits.

Thyroid cancer is not among the top cancers in terms of diagnosis or mortality but it still ranks fifth among the cancers diagnosed in women. Infact, women are more likely to be diagnosed with thyroid cancer than the males. The burden of thyroid cancer has dramatically increased in last two decades in China and, in the United States, it is the most diagnosed cancer in young adults under the age of twenty-nine. All these factors make it worthwhile to fully understand the pathogenesis of thyroid cancer. Towards this end, microRNAs (miRNAs) have constantly emerged as the non-coding RNAs of interest in various thyroid cancer subtypes on which there have been numerous investigations over the last decade and half. This comprehensive review takes a look at the current knowledge on the topic with cataloging of miRNAs known so far, particularly related to their utility as epigenetic signatures of thyroid cancer progression and metastasis. Such information could be of immense use for the eventual development of miRNAs as therapeutic targets or even therapeutic agents for thyroid cancer therapy.

Patients with chronic kidney disease (CKD) are at higher risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. However, a significant portion of CKD patients showed hesitation toward vaccination in telephone survey of our center. Yet no serial data available on humoral response in patients with CKD, especially those on immunosuppression. We conducted a pilot, prospective study to survey the safety and humoral response to inactivated SARS-CoV-2 vaccine in CKD patients receiving a 2-dose immunization of inactivated SARS-CoV-2 vaccine. We found the neutralizing antibody titers in CKD patients was significantly lower than that in healthy controls, hypertension patients, and diabetes patients. Notably, immunosuppressive medication rather than eGFR levels or disease types showed effect on the reduction of immunogenicity. Interestingly, a third dose significantly boosted neutralizing antibody in CKD patients while immunosuppressants impeded the boosting effects. In conclude, our data demonstrates that CKD patients, even for those on immunosuppression treatment, can benefit from a third vaccination boost by improving their humoral immunity.

Splicing factor poly(rC)-binding protein 1 (PCBP1) is a novel tumor suppressor that is downregulated in several cancers thereby regulating tumor formation and metastasis. However, the involvement of PCBP1 in apoptosis of cancer cells and the molecular mechanism remains elusive. On this basis, we sought to investigate the role of splicing factor PCBP1 in the apoptosis in human cervical cancer cells.To investigate PCBP1 functions in vitro, we overexpressed PCBP1 in human cervical cancer cells. A series of cytological function assays were employed to study to the role of PCBP1 in cell proliferation, cell cycle arrest and apoptosis.Overexpression of PCBP1 was found to greatly repress proliferation of HeLa cells in a time-dependent manner. It also induced a significant increase in G2/M phase arrest and apoptosis. Furthermore, overexpressed PCBP1 favored the production of long isoforms of p73, thereby inducing upregulated ratio of Bax/Bcl-2, the release of cytochrome c and the expression of caspase-3.Our results revealed that PCBP1 played a vital role in p73 splicing, cycle arrest and apoptosis induction in human cervical carcinoma cells. Targeting PCBP1 may be a potential therapeutic strategy for cervical cancer therapy.

Increasing evidence has shown that long non-coding RNAs (lncRNAs), which are non-coding endogenous single-stranded RNAs, play an essential role in various physiological and pathological processes through transcriptional interference, post-transcriptional regulation, and epigenetic modification. Moreover, lncRNAs, as oncogenes or tumor suppressor genes, play an important role in the occurrence and development of human cancers. Prostate androgen-regulated transcript 1 (PART1) was initially identified as a carcinogenic lncRNA in prostate adenomas. The upregulated expression of PART1 plays a tumor-promoting role in liver, prostate, lung cancers, and other tumors. In contrast, the expression of PART1 is downregulated in esophageal squamous cell carcinoma, glioma, and other tumors, which may inhibit the tumor. PART1 plays a dual role in cancer and regulates cell proliferation, apoptosis, invasion, and metastasis through a variety of potential mechanisms. These findings suggest that PART1 is a promising tumor biomarker and therapeutic target. This article reviews the biological functions, related mechanisms, and potential clinical significance of PART1 in a variety of human cancers.

Flexible ureteroscopy (FURS) plays an important role in the diagnosis and treatment of urological diseases. However, manipulating a flexible ureteroscope to the target quickly and safely may be challenging because of the tortuous lumen or poor visibility. Thus, information on the shape of the anterior part of a flexible ureteroscope in addition to the real-time pose is needed to perform accurate maneuvering in the lumen with minimal impingement on the inner renal wall and resulting tissue damage in FURS.An adaptive mixed-order Bézier curve fitting algorithm and electromagnetic tracking (EMT) technique were developed for shape estimation utilizing the length of the anterior part, kinematic constraints and the pose information provided by two electromagnetic (EM) sensors mounted at the tip and base of the anterior part. A series of experiments were performed to qualitatively and quantitatively verify the validity of our method. Moreover, algorithm threshold conditions with reference significance under various shape cases were studied.The performance of our method was evaluated based on 19 representative planar bending shapes that often appear in FURS and eight non-planar shapes, yielding an average error (AE) of 1.0 mm. Moreover, the experiments proved the feasibility of applying our method in cases in which large bending angles (near 270 degrees) occur.Based on data from two EM sensors mounted at the tip and base of the anterior part of a flexible ureteroscope, the proposed algorithm adaptively selects a cubic or quartic Bézier curve to fit the shape of the anterior part. Experimental results prove the feasibility of our shape estimation method over a broad bending range. The proposed method demonstrates significant potential for use in ureteroscopic navigation systems and robot-assisted surgery.

Cancer is a malignant tumor with the highest mortality of human diseases. The early diagnosis of cancer can greatly reduce its mortality. Ultracentrifugation is the most commonly employed technique to separate small extracellular vesicles (sEVs) due to their small size and rare abundance, but the low separation efficiency is a major concern. Herein, we proposed a DNAzyme-triggered assembly and disassembly system that converted single nano-sized sEVs into clusters that could be conveniently enriched by ordinary centrifugation and then be broken into single sEVs in the presence of magnesium ions. The simultaneous quantification of sEVs was realized by recording the increase in fluorescence upon nucleic acid cleavage, and a detection limit as low as 54 particles/μL was achieved. The whole analytical procedure could be completed in 1.5 h without the assistance of ultracentrifugation. Efficient enrichment and accurate quantification of sEVs are enabled through the proposed approach, broadening the potentials of sEVs in biological science, biomedical engineering, and personalized medicine.

Objective The ataxia telangiectasia mutated (ATM) gene is a master regulator in cellular DNA damage response. The dysregulation of ATM expression is frequent in breast cancer, and is known to be involved in the carcinogenesis and prognosis of cancer. However, the underlying mechanism remains unclear. The bioinformatic analysis predicted a potential antisense transcript ATM-antisense (AS) from the opposite strand of the ATM gene. The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the ATM gene regulation. Methods Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the ATM gene locus. qRT-PCR and Western blotting were used to detect the expression levels of ATM-AS and ATM in normal and breast cancer cell lines as well as in tissue samples. Luciferase reporter gene assays, biological mass spectrometry, ChIP-qPCR and RIP were used to explore the function of ATM-AS in regulating the ATM expression. Immunofluorescence and host-cell reactivation (HCR) assay were performed to evaluate the biological significance of ATM-AS in ATM-mediated DNA damage repair. Breast cancer tissue samples were used for evaluating the correlation of the ATM-AS level with the ATM expression as well as prognosis of the patients. Results The ATM-AS significantly upregulated the ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter. The reduced ATM-AS level led to the abnormal downregulation of ATM expression, and impaired the ATM-mediated DNA damage repair in normal breast cells in vitro. The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples, and the patient prognosis. Conclusion The present study demonstrated that ATM-AS, an antisense transcript located within the ATM gene body, is an essential positive regulator of ATM expression, and functions by mediating the binding of KAT5 to the ATM promoter. These findings uncover the novel mechanism underlying the dysregulation of the ATM gene in breast cancer, and enrich our understanding of how an antisense transcript regulates its host gene.

The aim is to explore the impact of violence and psychological resilience on psychiatric nurses as second victims.Workplace violence is a public health concern, seriously influencing medical staff's physical and mental health. However, few pieces of research have concentrated on psychiatric nurses as second victims.The socio-demographic data, violence-related data, psychological resilience scale, the Chinese version of the Second Victim Experience and Support Tool were applied to conduct a cross-sectional survey on nurses from psychiatric hospitals. The multiple linear regression model identified significant variables associated with violence-related injury and resilience.A total of 683 nurses completed the survey, of whom 88.3% were women. The average scores of the second victims' experience and support, support and distress were 3.45 ± 0.43, 3.71 ± 0.57 and 3.19 ± 0.67, respectively. Physical violence, psychological violence, psychological influence and nursing work environment were positively correlated with the experience and support of the second victims, and innocuous violence was a negative factor, which explains 20.6% of the variation. Moreover, physical injury, nursing work environment, resilience restructuring, physical violence, psychological violence, psychological impact and disagreement about the existence of violence explained 14.8% of the distress. The innocuous violence, psychological violence and nursing work environment explained 46.2% of the support.Our findings suggest that nurses who are second victims after the violence mainly suffer from severe psychological distress and receive the least support for the same.The study provides clues to help nursing managers' emphasis on the distress and support of second victims and provides targeted intervention based on the relevant factors and these results. The article is a cross-sectional study of psychiatric nurses, which has been approved by the ethics committee of the hospital before the survey. All the nurses who participated in the survey have been informed and agreed.

Degloving injury is a common and intractable injury with the bone and tendon exposed and contamination, the stripped skin cannot be replanted immediately and will be discarded, although auto-graft is needed for subsequent wound repair. In this study, autologous skin cryopreservation technique was applied to the treatment of severe limb degloving injuries. The clinical data of 9 patients from January 2016 to December 2018 were analyzed retrospectively. Among the 9 cases, 1 case developed necrosis due to wound infection, and the rest survived 60-100%. The replanted cryopreserved skin were soft and resilient, with poor sensory recovery, varying degrees of discoloration and no hair growth. Cryopreservation provides more time for improving the wound and whole-body condition. The frozen skin had good quality and high survival rate. Our study can effectively use the degloving skin, reduce the damage of the donor area.

Adoptive cellular therapies are making major strides in the treatment of cancer, both for hematologic and solid tumors. These cellular products include chimeric antigen receptor T cells and T-cell receptor-modified T cells, tumor-infiltrating lymphocytes, marrow-infiltrating T cells, natural killer cells as well as macrophage-based therapeutics. Advancement in genomics, computational biology, immunology, and cell therapy manufacturing has facilitated advancement of adoptive T cell therapies into the clinic, whereas clinical efficacy has driven Food and Drug Administration approvals. The growth of adoptive cellular therapy has, in turn, led to innovation in the preclinical models available, from ex vivo cell-based models to in vivo xenograft models of treatment. This review focuses on the development and application of in vitro models and in vivo models (cell line xenograft, humanized mice, and patient-derived xenograft models) that directly evaluate these human cellular products.

Introduction Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury. Objectives In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs). Methods Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155−/− and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart. Results When both miR-155−/− and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart. Conclusion In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.

Chronic occupational manganese (Mn) exposure is characterized by motor and cognitive dysfunction. This study aimed to investigate structural abnormalities in Mn-exposed welders compared to healthy controls (HCs).Thirty-five HCs and forty Mn-exposed welders underwent magnetic resonance imaging (MRI) scans in this study. Based on T1-weighted MRI, the voxel-based morphometry (VBM), structural covariance, and receiver operating characteristic (ROC) curve were applied to examine whole-brain structural changes in Mn-exposed welders.Compared to HCs, Mn-exposed welders had altered gray matter volume (GMV) mainly in the medial prefrontal cortex, lentiform nucleus, hippocampus, and parahippocampus. ROC analysis indicated the potential highest classification power of the hippocampus/parahippocampus. Moreover, distinct structural covariance patterns in the two groups were associated with regions, mainly including the thalamus, insula, amygdala, sensorimotor area, and middle temporal gyrus. No significant relationships were found between the findings and clinical characteristics.Our findings showed Mn-exposed welders had changed GMV and structural covariance patterns in some regions, which implicated in motivative response, cognitive control, and emotional regulation. These results might provide preliminary evidence for understanding the pathophysiology of Mn overexposure.• Chronic Mn exposure might be related to abnormal brain structural neural mechanisms. • Mn-exposed welders had morphological changes in brain regions implicated in emotional modulation, cognitive control, and motor-related response. • Altered gray matter volume in the hippocampus/parahippocampus and putamen might serve as potential biomarkers for Mn overexposure.

This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent hemophilia. PubMed, Medline, Web of Science, and other computers were used to search the database, and the statistical randomized controlled trials of coagulation factor vWF in the risk analysis of unknown recurrent hemophilia were collected. The Cochrane systematic evaluation method was used to evaluate the quality of the included kinds of literature, and Revman5 software was used to sort out and analyze the kinds of literature. Meta-analysis showed that there was a statistical difference between the experimental group and the control group in case fatality rate (OR = 1.76, 95% CI (1.29, 2.39), P = 0.0003 , I2 = 0%, Z = 3.58), adverse events (OR = 2.38, 95% CI (1.65, 3.45), P < 0.00001 , I2 = 0%, Z = 4.60), incidence of joint hemorrhage (OR = 2.52, 95% CI (1.62, 3.91), P < 0.00001 , I2 = 0%, Z = 4.12), incidence of subcutaneous stasis (OR = 1.76, 95% CI (1.26, 2.45), P = 0.0009 , I2 = 5%, Z = 3.33), and hematoma volume (OR = 1.78, 95% CI (1.32, 2.40), P = 0.0001 , I2 = 23%, Z = 3.80). DNA methylation in the promoter region of the coagulation factor vWF gene was significantly associated with the risk of unexplained recurrent hemophilia. Whether demethylation can improve the bleeding index of patients with recurrent hemophilia remains to be further explored.

Quantification approaches of positron emission tomography (PET) imaging provide user-independent evaluation of pathophysiological processes in living brains, which have been strongly recommended in clinical diagnosis of neurological disorders. Most PET quantification approaches depend on spatial normalization of PET images to brain template; however, the spatial normalization and quantification approaches have not been comprehensively reviewed. In this review, we introduced and compared PET template-based and magnetic resonance imaging (MRI)-aided spatial normalization approaches. Tracer-specific and age-specific PET brain templates were surveyed between 1999 and 2021 for

Next-generation sequencing (NGS) is rapidly becoming routine in clinical oncology practice to identify therapeutic biomarkers, including gene rearrangements in anaplastic lymphoma kinase (ALK). Our study investigated the concordance of ALK positivity evaluated by DNA-based NGS with orthogonal ALK testing methods such as fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and RNA-based NGS (RNA-NGS). Thirty-eight patients with lung adenocarcinoma who were detected with ALK rearrangements using DNA-NGS and also had adequate tissue samples submitted for FISH, IHC, and RNA-NGS, were included in this study. Of the 38 patients, RNA samples from 3 patients failed quality control for RNA-NGS. The concordance of ALK positivity was calculated relative to DNA-NGS results. The concordance rates were 97.1% (34/35) for RNA-NGS, 94.7% (36/38) for IHC, and 97.4% (37/38) for FISH. DNA-NGS detected single ALK rearrangements in 14 (35.0%) patients and complex ALK rearrangements in 26 (65.0%). RNA-NGS detected only single transcripts of the primary ALK fusions. A novel LANCL1-ALK (L7:A20) detected using DNA-NGS was detected as EML4-ALK (E13:A20) transcripts using RNA-NGS. Interestingly, patients with single ALK rearrangements were more likely to be detected with atypical isolated red signals (p 0.001), while patients with complex ALK rearrangements were more likely to be detected with atypical split red and green signals less than 2 signal diameters apart (p 0.001). Our study highlights the reliability of NGS in the accurate detection of specific ALK fusion variants and concomitant mutations that are crucial for individualized treatment decisions in patients with lung cancer.

Computer tomography texture analysis (CTTA) based on the V-Net convolutional neural network (CNN) algorithm was used to analyze the recurrence of advanced gastric cancer after radical treatment. Meanwhile, the clinical characteristics of patients were analyzed to explore the recurrence factors. 86 patients who underwent the advanced radical gastrectomy for gastric cancer were retrospectively selected as the research objects. Patients were divided into the no-recurrence group (30 cases) and the recurrence group (56 cases) according to whether there was recurrence after radical treatment. CTTA was performed before and after surgery in both groups to analyze the risk factors for recurrence. The results showed that the dice coefficient (0.9209) and the intersection over union (IOU) value (0.8392) of the V–CNN segmentation effect were signally higher than those of CNN, V-Net, and context encoder network (CE-Net) ( P P P

This is the first-in-human study to evaluate the pharmacokinetics, safety, and tolerability of TQC3564 (a novel CRTh2 receptor antagonist) in healthy Chinese subjects.This project was a phase Ia clinical study of TQC3564 as a single-ascending dose (SAD) (25 to 1200 mg) and a multiple-ascending dose (MAD) (100 or 500 mg, QD) as well as a two-period crossover food-effect study (300 mg). In the SAD and MAD study, TQC3564 were found to be safe and well tolerated, without dose-dependent adverse events (AEs), and all AEs were mild or moderate in severity. In the SAD study, the median tIn healthy subjects, TQC3564 at a single dose of 25-1200 mg or 100-500 mg at multiple doses (QD) was safe and tolerable with acceptable PK profiles, indicating that TQC3564 has potential as a therapeutic option for asthma. (This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20192397.).

BACKGROUND: Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC). OBJECTIVE: To understand the mechanisms by which subclones within early PCa develop into CRPC. DESIGN, SETTING, AND PARTICIPANTS: We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We revealed dynamic transcriptional reprogramming that promotes disease progression among 23 226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data. RESULTS AND LIMITATIONS: We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa. CONCLUSIONS: CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa. PATIENT SUMMARY: Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.

Background: The new coronavirus disease 2019 (COVID-19) is spreading rapidly around the world. Artificial Intelligence (AI) assisted identification and detection of diseases is an effective method of medical diagnosis. Objectives: To present recent advances in AI-assisted diagnosis of COVID-19, we introduce major aspects of AI in the process of diagnosing COVID-19. Methods: In this paper, we firstly cover the latest collection and processing methods of datasets of COVID-19. The processing methods mainly include building public datasets, transfer learning, unsupervised learning and weakly supervised learning, semi-supervised learning methods and so on. Secondly, we introduce the algorithm application and evaluation metrics of AI in medical imaging segmentation and automatic screening. Then, we introduce the quantification and severity assessment of infection in COVID-19 patients based on image segmentation and automatic screening. Finally, we analyze and point out the current AI-assisted diagnosis of COVID-19 problems, which may provide useful clues for future work. Conclusion: AI is critical for COVID-19 diagnosis. Combining chest imaging with AI can not only save time and effort, but also provide more accurate and efficient medical diagnosis results.

Ying-Ying Zhang,1 Wen-Tao Tang,2 Hong Zhang,3 Jing Wang,3 Xiao-Xu Bai,3 Yan-Hui Liao,4 Nicola Robinson,1,5 Jian-Ping Liu1 1Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Pingyi Hospital of Traditional Chinese Medicine, Linyi, Shandong, People’s Republic of China; 3Fangshan Hospital of Traditional Chinese Medicine Affiliated to Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, People’s Republic of China; 5Institute of Health and Social Care, London South Bank University, London, UKCorrespondence: Jian-Ping Liu, Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email liujp@bucm.edu.cn; jianping_l@hotmail.comBackground: Smoking cessation is recommended as a key intervention for chronic obstructive pulmonary disease (COPD) smokers. However, in China, few COPD smokers quit successfully. The aim of this study was to explore in depth the barriers and facilitators for smoking cessation among smokers with COPD in China.Methods: A purposive sample of 32 hospitalized smokers with COPD were included, 17 ex-smokers and 15 current smokers, participated in the semi-structured interviews. Interviews were analyzed thematically and using a deductive approach guided by Capability, Opportunity, Motivation-Behavior (COM-B) framework.Results: Three inter-related themes were generated: smokers’ motivation was a prerequisite for quitting, maintaining capability to quit smoking, and opportunities that facilitated smokers to quit. Motivation to quit for most participants was activated by COPD-related symptoms, although they had a limited knowledge of COPD. Physical benefits from quitting and strong willpower were facilitators for maintaining quitting, while exposure to smoking environment and strong addiction to nicotine were frequent reasons for relapse. Most ex-smokers quit smoking by their own willpower rather than professionally delivered smoking cessation interventions. Smokers’ attitudes toward these interventions depended on their effectiveness and convenience. Very few participants had experienced pharmacotherapy or behavioral support from physicians. However, interviewees preferred auricular acupressure to pharmacotherapy.Conclusion: Motivation to quit among smokers with COPD was usually initiated by COPD-related symptoms. Physical benefits observed by quitting and strong willpower facilitated smoking cessation, while exposure to smoking environment and strong addiction to nicotine led to relapse. COPD smokers in China preferred auricular acupressure to pharmacotherapy.Keywords: chronic obstructive pulmonary disease, smoking cessation, tobacco, qualitative research, acupuncture

Mucosal immune regulation is considered a key aspect of immunopathogenesis of IgA nephropathy (IgAN). Direct experimental evidence clarifying the role of intestinal mucosa attributes in IgAN is lacking. In this study, a mouse model was established via multiple low-dose intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE) emulsified with Complete Freund's Adjuvant (CFA). We found continuous and stable deposition of IgA in glomerular mesangial areas, accompanying high circulating levels of IgA and IgA-IgG complexes. Expression of the key extracellular matrix components collagen IV and fibronectin also increased in the mesangial areas of LCWE-induced mice. IgA

Sepsis is a severe and acute disease associated with high mortality, for those who survive, long-term morbidity. In-time detection of pathogen for proper and optimized treatment in the early stage of sepsis is crucial.We performed droplet digital PCR (ddPCR) on two cases of sepsis. The clinical information, laboratory test results, and the therapeutic regimen was detailed recorded.ddPCR showed its clinical value of sepsis ultra-early diagnosis and the guidance of medication in both cases we provided.ddPCR has potential for rapid and precise diagnose in ultra-early stage of sepsis for its high sensitivity and short turn-around-time, thus benefiting in optimal and timely treatment of sepsis.

Background: Studies have shown that pharmacological and psychological treatments are effective for children and adolescents with obsessive-compulsive disorder (OCD). However, few network meta-analyses have examined whether pharmacological or psychological treatments on their own, or combined, are most effective. Methods: We conducted a database search and selected randomized controlled trials of pharmacological or psychological treatments, alone or in combination, for children and adolescents with OCD. The primary outcome was change in symptom severity as a result of treatment, as assessed using the Yale-Brown Obsessive Compulsive Scale (BOCS) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) . Findings: We included 18 studies with 1353 participants and 12 kinds of treatments. In terms of efficacy, all pharmacological and psychotherapy treatments were more effective than placebo. Among the 12 treatments, the efficacy of pharmacological treatment combined with cognitive behavioral therapy (CBT) was better than pharmacological treatment alone. When pharmacological treatment was used alone, escitalopram was significantly better than clomipramine(CY-BOCS average change 3.42; 95% CI 2.11, 4.65), fluvoxamine(CY-BOCS average change 3.59; 95% CI 1.09, 6.20), paroxetine(CY-BOCS average change 2 .80; 95% CI 0.01, 5.64) and sertraline(CY-BOCS average change 3.49; 95% CI 1.53, 5.64). Interpretation: The available evidence suggests that the combination of pharmacological and psychological treatment is likely to be most effective for children and adolescents with OCD. Funding: The National Nature Science Foundation of China (81801357, 81801350), the Science and Technology Education Program of the Sichuan Province (2020JDKP0013), the Key R&D Projects of the Science and Technology Department of Sichuan Province(2020YFS0259 ), and the Chengdu Key Technology R&D Program (2019-YF05– 00284-SN). Declaration of Interest: None to declare.

Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations.In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns.As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs.We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. The processing of pain involves complicated modulation at the levels of the periphery, spinal cord, and brain. The pathogenesis of chronic pain is still not fully understood, which makes the clinical treatment challenging. Optogenetics, which combines optical and genetic technologies, can precisely intervene in the activity of specific groups of neurons and elements of the related circuits. Taking advantage of optogenetics, researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission, pain modulation, and chronic pain both in the periphery and the central nervous system. In this review, we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.

Long non-coding RNA (lncRNA) FAM230B has been reported to participate in gastric cancer and papillary thyroid cancer, while its role in other cancers has not been reported. We then explored the role of FAM230B in lung adenocarcinoma (LA). This study enrolled a total of 60 LA patients, 60 patients with gastric reflux disease (GRD), 60 cases of chronic obstructive pulmonary disease (COPD), 60 cases of asthma and 60 cases of healthy controls. LA and paired non-tumor tissues were donated by all LA patients. Plasma samples were donated by all participants. Expression of FAM230B in these samples was determined by RT-qPCR. The 60 LA patients were followed up for 5 years to evaluate the prognostic value of plasma FAM230B for LA. Diagnostic value of FAM230B for LA was analyzed with ROC curve analysis. FAM230B was highly expressed in LA tissues compared to that in non-tumor samples. In addition, plasma FAM230B was specifically upregulated in LA patients, but not in GRD, COPD and asthma patients. High expression levels of FAM230B in plasma samples were closely correlated with poor survival. Plasma FAM230B effectively separated LA patients from GRD, COPD, asthma and control groups. Plasma FAM230B was closely correlated with tumor size, but not other clinical factors of LA patients. Therefore, FAM230B is highly upregulated in LA and may serve as a potential diagnostic and prognostic biomarker for LA.

Ischemic stroke (IS) is a major cause of permanent morbidity and lifelong disability worldwide. Circular RNA (circRNA) circ_0007865 has been reported to be upregulated in acute ischemic stroke (AIS) patients. Also, AIS patients exhibited increased death of human brain microvascular endothelial cells (HBMECs). This study is designed to explore the role and mechanism of circ_0007865 in the oxygen-glucose deprivation (OGD)-induced cell damage in AIS.Circ_0007865, microRNA-214-3p (miR-214-3p), and FK506-binding protein 5 (FKBP5) levels were detected by real-time quantitative PCR. Cell proliferative angiogenesis, migration, and apoptosis were assessed by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, tube formation, wound healing, transwell, and flow cytometry assays. B-cell lymphoma-2 (Bcl-2), Bcl-2-related X protein (Bax), cleaved caspase-3, and FKBP5 protein levels were determined by western blot assay. The binding relationship between miR-214-3p and circ_0007865 or FKBP5 was predicted by StarBase, and verified by a dual-luciferase reporter, RNA pull-down assay.Circ_0007865 and FKBP5 were increased, and miR-214-3p was decreased in OGD-treated HBMECs. Furthermore, the silencing of circ_0007865 could promote cell proliferative angiogenesis, migration, and inhibit apoptosis in OGD-triggered HBMECs in vitro. Mechanically, circ_0007865 acted as a sponge of miR-214-3p to regulate FKBP5.According to these results, circ_0007865 deficiency could attenuate OGD-induced HBMEC damage by modulating the miR-214-3p/FKBP5 axis, hinting at a promising therapeutic target for future acute IS therapy.

The aim of this study was to evaluate the pharmacokinetics, safety, and tolerability of aclidinium bromide/formoterol fumarate in patients from China with moderate-to-severe chronic obstructive pulmonary disease (COPD).In this open-label, repeat-dose, 5-day pharmacokinetic study (NCT03276078) of inhaled aclidinium bromide/formoterol fumarate 400/12 µg twice daily, plasma concentrations of aclidinium, formoterol, and two aclidinium metabolites (LAS34823, LAS34850) were assessed (days 1 and 5). Adverse event (AE) data were collected.Twenty patients (15 [75%] males) with a mean age of 59.2 years were included. Median (range) time to maximum concentration on days 1 and 5 was 0.08 (0.08-0.50) and 0.08 (0.08-0.50) h, respectively, for aclidinium; and 1.00 (0.08-3.00) and 0.08 (0.08-1.50) h, respectively, for formoterol. Mean elimination half-life and accumulation ratio for area under the concentration-time curve during a dosage interval (AUCAclidinium/formoterol 400/12 µg twice daily was well-tolerated in patients from China with moderate-to-severe COPD. Safety findings were consistent with the known safety profile.ClinicalTrials.gov, NCT03276078.

The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). Whereas male CF-patients are infertile due to bilateral agenesis of the efferent ducts, the fertility status of male heterozygous carriers is uncertain. We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Using FC and sorting, single cell polymerase chain reaction, immuno-fluorescent staining an experimental study was performed on nine fertile semen donors and three heterozygous infertile men carrying the Phe508del gene variant. Chemical inhibition of CFTR interfered with sperm capacitation. Most viable spermatozoa of heterozygous carriers of the Phe508del variant of the CFTR-gene show immune-fluorescent CFTR. Sperm capacitation in Phe508del carriers was similar to that in healthy semen donors. Distribution of the Phe508del allele in trio data of CF-affected families corresponded to the expected recessive inheritance pattern. Infertility in Phe508del heterozygous men is unlikely to be caused by the pathogenic variant although some contribution cannot be excluded. Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder.

Background Positive glomerular C4d staining, representative of lectin pathway activation, has been proven to be associated with unfavorable outcomes in immunoglobulin A nephropathy (IgAN). Our previous study suggested that urinary C4d correlated positively with an increase in crescents while the relationship between urinary C4d and disease severity and progression remains unelucidated. Methods In this study we enrolled 168 patients diagnosed with IgAN with varying proportions of crescent formation at the time of biopsy. An independent cohort of 107 IgAN patients was enrolled for validation. Kidney biopsy specimens were stained using immunohistochemistry. Urinary C4d levels at renal biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was end-stage kidney disease (ESKD). Results Higher urinary C4d/creatinine levels were associated with a lower estimated glomerular filtration rate (eGFR); massive proteinuria; hypertension and severe Oxford M, E, T and C scores. After a median follow-up of 19 months (interquartile range 9–27), 53 (31.5%) participants reached ESKD. High urinary C4d/creatinine levels were independently and significantly associated with a risk of developing ESKD [hazard ratio per standard deviation increment of log-transformed C4d/creatinine 7.623 (95% confidence interval 4.117–14.113)]. Conclusions The urinary C4d/creatinine level is a potential useful biomarker that was associated with disease severity and progression in patients with IgAN and crescents.

Introduction: Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology. However, these biological subgroups overlap clinically. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for treating patients with DLBCL, predicting which patients will not benefit from such therapy is important so that alternative therapy or clinical trials can be considered. Most of the studies stratifying patients select biomarkers first, then explore how these biomarkers can stratify patients based on outcome. We explored the potential of using machine learning to first group patients with DLBCL based on survival, then isolating the biomarkers necessary for predicting these survival subgroups. Methods: RNA was extracted from tissue paraffin blocks from 379 R-CHOP treated patients with de novo DLBCL, and from 247 patients with extranodal DLBCL. A targeted hybrid capture RNA panel of 1408 genes was used for next generation sequencing (NGS). Sequencing was performed using an Illumina NextSeq 550 System platform. Ten million reads per sample in a single run were required, and the read length was 2 × 150 bp. An expression profile was generated from the sequencing coverage profile of each individual sample using Cufflinks. A machine learning system was developed to classify patients into four groups based on their overall survival. This machine learning approach based on Naïve Bayesian algorithm was also used to discover the relevant subset of genes with which to classify patients into each of the four survival groups. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict the survival group for each patient. Results: Using machine learning, patients were first divided into two groups: short survival (S) and long survival (L). To refine this model, we used the same approach and divided the patients in each group into two subgroups, generating four groups: long survival in the long group (LL), short survival in the long group (LS), long survival in the short group (SL), and short survival in the short group (SS). The hazard ratio for this model was 0.174 (confidence interval: 0.120-0.251), and P-value Conclusions: Using a novel machine learning approach with the expression levels of 180 genes, we developed a model that can reliably stratify patients with DLBCL treated with R-CHOP into four survival subgroups. This model can be used to identify patients who may not respond well to R-CHOP to be considered for alternative therapy and clinical trials. Figure 1 Figure 1. Disclosures Hsi: AbbVie Inc, Eli Lilly: Research Funding. Ferreri: Ospedale San Raffaele srl: Patents & Royalties; BMS: Research Funding; Pfizer: Research Funding; Beigene: Research Funding; Hutchison Medipharma: Research Funding; Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees. Piris: Millenium/Takeda, EUSA, Jansen, NanoString, Kyowa Kirin, Gilead and Celgene.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria.

BackgroundThe purpose of this study was to investigate the diagnosis and treatment experience of traumatic duodenal ruptures in children.MethodsClinical data were collected from four children suffering from a traumatic duodenal rupture who were admitted to and treated by our hospital from January 2012 to December 2020. The early diagnosis and treatment, surgical plan, postoperative management, complications, and prognosis of each child were analyzed. The key points and difficulties of the diagnosis and treatment for this type of injury are summarized.ResultsOne child had an extreme infection caused by drug-resistant bacteria, which resulted in severe complications, including wound infection, dehiscence, and an intestinal fistula. One child developed an anastomotic stenosis after the duodenostomy, which improved following an endoscopic balloon dilatation. The other two children had no relevant complications after their operations. All four patients were cured and discharged from hospital. The average hospital stay was 48.25 ± 26.89 days. The follow-up period was 0.5 to 1 year. No other complications occurred, and all children had a positive prognosis.ConclusionsThe early identification of a duodenal rupture is essential, and surgical exploration should be carried out proactively. The principles of damage-control surgery should be followed as much as possible during the operation. Multidisciplinary cooperation and management are both important to reduce the occurrence of postoperative complications and improve cure rates.

Background Albumin (ALB) levels are negatively associated with mortality in patients with sepsis. However, among sepsis patients with acute kidney injury (AKI) undergoing continuous renal replacement therapy (CRRT), there has been no similar study on the correlation between ALB levels and mortality alone. This study tested the hypothesis that ALB levels are negatively associated with mortality among such patients. Methods We conducted a secondary analysis of 794 septic patients who were diagnosed with AKI and underwent CRRT in South Korea. For the Kaplan–Meier survival analysis, Cox proportional hazards models were used to study the hypotheses, with adjustments for the pertinent covariables. We also explore the possible nonlinear relationship and conducted sensitivity analyses including subgroup analyses and tests for interactions to investigate the association further. Additionally, ALB was used to construct model and we then compared the performance of ALB with that of APACHE II and SOFA in predicting mortality. Results The ALB level was an independent prognostic factor for death at 28 and 90 days after CRRT initiation (HR = 0.75, 95% CI: 0.62–0.90, P = 0.0024 for death at 28 days and HR = 0.73, 95% CI: 0.63–0.86, P 3 and CRP played an interactive role in the association. ROC analysis indicated ALB, SOFA and APACHE-II were separately inadequate for clinical applications. Conclusion A 1 g/dL increase in ALB levels was independently associated with a 25 and 27% decrease in the risk of death at 28 and 90 days, respectively. However, this conclusion needs to be taken with caution as this study has several limitations.

Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients.This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS.A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P0.0001) and PM (P = 0.004) groups.Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.