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In this paper, we propose an end-to-end structured multimodal attention (SMA) neural network to mainly solve the first two issues above. SMA first uses a structural graph representation to encode the object-object, object-text and text-text relationships appearing in the image, and then designs a multimodal graph attention network to reason over it. Finally, the outputs from the above modules are processed by a global-local attentional answering module to produce an answer splicing together tokens from both OCR and general vocabulary iteratively by following M4C. Our proposed model outperforms the SoTA models on TextVQA dataset and two tasks of ST-VQA dataset among all models except pre-training based TAP. Demonstrating strong reasoning ability, it also won first place in TextVQA Challenge 2020. We extensively test different OCR methods on several reasoning models and investigate the impact of gradually increased OCR performance on TextVQA benchmark. With better OCR results, different models share dramatic improvement over the VQA accuracy, but our model benefits most blessed by strong textual-visual reasoning ability. To grant our method an upper bound and make a fair testing base available for further works, we also provide human-annotated ground-truth OCR annotations for the TextVQA dataset, which were not given in the original release. The code and ground-truth OCR annotations for the TextVQA dataset are available at https://github.com/ChenyuGAO-CS/SMA, winner of TextVQA Challenge 2020, Accepted by IEEE Transactions on Pattern Analysis and Machine Intelligence

Multi-modal imaging data fusion has attracted much attention in medical data analysis because it can provide complementary information for more accurate analysis. Integrating functional and structural multi-modal imaging data has been increasingly used in the diagnosis of brain diseases, such as epilepsy. Most of the existing methods focus on the feature space fusion of different modalities but ignore the valuable high-order relationships among samples and the discriminative fused features for classification. In this paper, we propose a novel framework by fusing data from two modalities of functional MRI (fMRI) and diffusion tensor imaging (DTI) for epilepsy diagnosis, which effectively captures the complementary information and discriminative features from different modalities by high-order feature extraction with the attention mechanism. Specifically, we propose a triple network to explore the discriminative information from the high-order representation feature space learned from multi-modal data. Meanwhile, self-attention is introduced to adaptively estimate the degree of importance between brain regions, and the cross-attention mechanism is utilized to extract complementary information from fMRI and DTI. Finally, we use the triple loss function to adjust the distance between samples in the common representation space. We evaluate the proposed method on the epilepsy dataset collected from Jinling Hospital, and the experiment results demonstrate that our method is significantly superior to several state-of-the-art diagnosis approaches.

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T-cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion, and cytotoxicity. In summary, we describe a potential mechanism of tumor-intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.

The aim of this Policy Review was to compare China's overall and synchronous participation in clinical trials for innovative anticancer drugs with that of the USA, the EU, Japan, and South Korea, and to assess changes in the participation rate trends in these five regions. Relevant data from the top 20 international pharmaceutical companies from 2011 to 2021 were systematically collected from the Trialtrove and Pharmaprojects databases. Among the 8260 trials for 954 new anticancer drugs identified, China was involved in 8·8% of the trials and with 20·4% of the drugs being trialled. These participation rates are significantly lower than those for South Korea (14·5% of trials and 36·3% of drugs), Japan (16·1% of trials and 38·7% of drugs), the EU (40·6% of trials and 67·7% of drugs), and the USA (65·7% of trials and 91·2% of drugs; plt;0·0001 for all). Similar results were found for the synchronous participation rate, defined as the proportion of drugs or trials at the highest development stage internationally, for the 803 tested drugs, which ranged from 9·0% in China to 87·7% in the USA. China's participation rate in early phase trials (4·4%) and in synchronous trials (5·4%) was even lower, in stark contrast to that of the USA (66·1% for early phase trials and 89·1% for synchronous trials). The fastest growing annual rate of participation in trials was observed in China (15·7%), followed by South Korea (8·2%) and Japan (6·8%); no change was detected in the USA or the EU. This Policy Review shows that Chinese participation in the clinical development of innovative cancer drugs by international pharmaceutical companies has increased over the past decade, but an obvious gap persists in comparison with the USA, the EU, Japan, and South Korea, especially in its synchronous participation and early participation rates.

Purpose. Natural orifice transluminal endoscopic surgery (NOTES) is a minimally invasive surgical procedure that reduces patient trauma, infection probability, and rehabilitation time. This paper reviews the progress made in the control-actuation robotic systems for gastrointestinal NOTES development. Material and Methods. A survey on both existing and state-of-the-art control-actuation robotic systems for gastrointestinal NOTES was conducted in December 2021. Results. Nine control-actuation robotic systems for gastrointestinal NOTES were identified. The structures and specifications of these robotic systems were reported. The technical parameters were also discussed. Special attention was directed to systems using a control-actuation structure and tendon-driven mechanism. The control-actuation robotic systems typically deploy a control-actuation structure and tendon-driven mechanism. Control-actuation robotic systems for gastrointestinal NOTES show great ability to improve operational accuracy and flexibility and flatten the learning curve of procedures. These characteristics suggest that the use of control-actuation robotic systems is worth exploring in future development.

Enterovirus A71 (EV71) vaccination program was introduced in 2016 in China. Based on a longitudinal surveillance dataset from 2012 to 2019 in Guangdong, China, we estimated the impact of the EV71 vaccination program on hand, foot, and mouth disease (HFMD) incidence, by using a counterfactual prediction made from synthetic control approach integrated with a Bayesian time-series model. We observed a relative reduction of 41.4% for EV71-associated HFMD cases during the post-vaccination period of 2017-2019, corresponding to 26,226 cases averted. The reduction of EV71-associated HFMD cases raised with the elevation of EV71 vaccine coverage by year. We found an indirect effect for the children aged 6-14 years who were less likely to be vaccinated. Whereas, the EV71 vaccine may not protect against non-EV71-associated HFMD. This study provides a template for ongoing public health surveillance of EV71 vaccine effectiveness with a counterfactual study design. Our results show strong evidence of the EV71 vaccination program working on reducing EV71-associated HFMD in real-world settings. The finding will benefit policy-making of EV71 vaccination and the prevention of HFMD.

Objective. This study focused on mood regulations and their association with sociodemographic status, exercise pattern, and physical conditions of adults and older adults in China who did not undergo interventions. Method. Data were based on the 2016 to 2018 Guangdong National Physique Monitoring data, in which 5242 participants aged 20-69 years were recruited. Multiple statistical analysis methods, such as descriptive and logistic regression analyses, were used to study each exercise motivation and its association with influencing factors, including sociodemographic characteristics, exercise measurements, and physical conditions. An exercise index for mental health was also used to investigate the number and types of people who were more likely to meet the index. Results. We observed that 44.9% (2355/5242) of participants did not engage in physical exercise in this study. Only older participants (40 to 69 years old) and those with an average level of education (high school/technical secondary school) showed a significant association with exercising for mood regulation. Few people met the index that is good for mental health (16.64% [872/5242] met index 1, and 2.84% (149/5242) met index 2), and higher education showed a significant association with a reduction in the mental health burden and the prevention of depression. Conclusion. This study found that motivating people to be more active and educating them on the potential mental health benefits of exercise could help them to exercise more.

Thoracolumbar metastases is a difficult disease to deal with in spinal surgery. The aim of this study is to investigate the clinical efficacy of bone-filled mesh vertebroplasty combined with posterior spinal internal fixation in the treatment of thoracolumbar metastases.The clinical data of 68 patients with thoracolumbar vertebral metastases from January 2018 to April 2020 were retrospectively analyzed. A total of 37 cases underwent bone filling mesh pocket vertebroplasty combined with posterior spinal internal fixation as the observation group, and 31 cases underwent routine vertebroplasty combined with posterior spinal internal fixation as the control group. The visual analogue scale (VAS) scores, Oswestry disability index (ODI) scores, Karnofsky performance status (KPS) scores, and the heights of the anterior margin and middle of the diseased vertebra were compared between the 2 groups before and 1 week, 3 months, 6 months, and 1 year after surgery.All cases successfully completed the operation, and there was no pulmonary embolism, paraplegia, or perioperative death in follow-up reported. Intraoperative bone cement leakage occurred in 4 cases with a total of 6 vertebrae in the observation group (leakage rate: 14.29%), and in 8 cases with a total of 11 vertebrae in control group (leakage rate: 31.43%). The differences in VAS scores, ODI scores, KPS scores, and the heights of the anterior margin and middle of the diseased vertebra between preoperative and postoperative periods at 1 week, 3 months, 6 months, and 1 year in both groups were statistically significant (P0.05), while the differences between the 2 groups were not statistically significant (P0.05).The application of bone-filled mesh vertebroplasty combined with posterior internal pedicle screws fixation for the treatment of thoracolumbar metastases can not only reduce the injury of the operation, but also achieve the purpose of relieving pain, controlling local tumor growth to a certain extent, restoring neural function, and rebuilding the stability of the spine, which has important clinical value.

Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.

Cancer stemness and immune evasion are closely associated and play critical roles in tumor development and resistance to immunotherapy. However, little is known about the underlying molecular mechanisms that coordinate this association.The expressions of heterogeneous nuclear ribonucleoprotein M (HNRNPM) in 240 hepatocellular carcinoma (HCC) samples, public databases, and liver development databases were analyzed. Chromatin immunoprecipitation assays were performed to explore the associations between stem-cell transcription factors and HNRNPM. HNRNPM-regulated alternative splicing (AS) and its binding motif were identified by RNA-seq and RIP-seq. HNRNPM-specific antisense oligonucleotides were developed to explore potential therapeutic targets in HCC. CD8+ T cells that were co-cultured with tumor cells were sorted by flow cytometry assays.We identified an elevated oncofetal splicing factor in HCC, HNRNPM, that unifies and regulates the positive association between cancer stemness and immune evasion. HNRNPM knockdown abolished HCC tumorigenesis and diminished cancer stem cell properties in vitro and in vivo. Mechanistically, HNRNPM regulated the AS of MBD2 by binding its flanking introns, whose isoforms played opposing roles. Although MBD2a and MBD2c competitively bound to CpG islands in the FZD3 promoter, MBD2a preferentially increased FZD3 expression and then activated the WNT/β-catenin pathway. Interestingly, FZD3 and β-catenin further provided additional regulation by targeting OCT4 and SOX2. We found that HNRNPM inhibition significantly promoted CD8+ T cell activation and that HNRNPM- antisense oligonucleotides effectively inhibited WNT/β-catenin to enhance anti-programmed cell death protein-1 immunotherapy by promoting CD8+ T cell infiltration.HNRNPM has a tumor-intrinsic function in generating an immunosuppressive HCC environment through an AS-dependent mechanism and demonstrates proof of the concept of targeting HNRNPM in tailoring HCC immunotherapeutic approaches.

The similar visual appearance of high-risk basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) may cause confusion for diagnosis. High-frequency ultrasound (HFUS) may provide additional intralesional information and thus help to distinguish them.In this retrospective study, we analyzed the clinical characteristics, HFUS grayscale, and color Doppler flow imaging (CDFI) features of pathologically confirmed high-risk BCC and cSCC lesions (n = 65 vs n = 68). Subsequently, discrimination models based on the significant HFUS features were established.Between high-risk BCC and cSCC lesions, the HFUS grayscale features of the lesion size (10.0 mm vs 17.4 mm), thickness (3.1 mm vs 5.9 mm), internal hyperechoic spots (80.0% vs 23.5%), and posterior acoustic shadowing (16.9% vs 66.2%) were statistically different (all p 0.001). As for the CDFI features, high-risk BCC lesions mainly appeared as pattern II (47.7%), while cSCC lesions mainly appeared as pattern III (66.2%). Based on the above five features, an optimal discrimination model was established with a sensitivity of 91.2%, a specificity of 87.7%, and an accuracy of 89.5%.HFUS features, including size, thickness, internal hyperechoic spots, posterior acoustic shadowing, and Doppler vascularity pattern, are useful for differential diagnosis between high-risk BCC and cSCC.

Introduction: The COVID-19 outbreak abruptly restricted gastrointestinal (GI) endoscopy services during the first wave of the pandemic. We aimed to assess the impact of COVID-19 on the practice of GI endoscopy in Asian countries. Methods: This was an International Questionnaire-based Internet Survey conducted at multiple facilities by the International Gastrointestinal Consensus Symposium. A total of 166 respondents in Japan, China, Hong Kong, South Korea, Philippines, Thailand, Indonesia, and Singapore participated in this study. Results: The volume of endoscopic screening or follow-up endoscopies and therapeutic endoscopies were markedly reduced during the first wave of the pandemic, which was mainly attributed to the decreased number of outpatients, cancellations by patients, and adherence to the guidelines of academic societies. The most common indications for GI endoscopy during the first wave were GI bleeding, cholangitis or obstructive jaundice, and a highly suspicious case of neoplasia. The most common GI symptoms of COVID-19 patients during the infected period included diarrhea, nausea, and vomiting. The pandemic exacerbated some GI diseases, such as functional dyspepsia and irritable bowel syndrome. There were cases with delayed diagnosis of cancers due to postponed endoscopic procedures, and the prescription of proton pump inhibitors/potassium-competitive acid blockers, steroids, immunosuppressive agents, and biologics was delayed or canceled. The personal protective equipment used during endoscopic procedures for high-risk patients were disposable gloves, disposable gowns, N95 or equivalent masks, and face shields. However, the devices on the patient side during endoscopic procedures included modified surgical masks, mouthpieces with filters, and disposable vinyl boxes or aerosol boxes covering the head. Furthermore, the time for education, basic research, clinical research, and daily clinical practice decreased during the first wave. Conclusion: This study demonstrated that the COVID-19 pandemic profoundly affected the method of performing GI endoscopy and medical treatment for patients with GI diseases in Asian countries.

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC., Here, we studied the value of circulating tumor DNA (ctDNA), in combination with germline and tissue DNA by whole‐exome sequencing in patients withhepatocellular carcinoma (HCC). Our analysis demonstrated that ctDNA may serve as a real‐time monitoring indicator by accurately reflecting tumor burden, and as a strong independent predictor of recurrence‐free survival in HCC.

Background: The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has gradually become a global public health crisis. Some patients who have recovered from COVID-19 subsequently tested positive again for SARS-CoV-2 after discharge (retesting-positive, RTP). However, the underlying mechanism is unknown. Methods: Here, 30 RTP patients, 20 convalescent patients, and 20 healthy controls were enrolled for analysis of the immunological characteristics of their peripheral blood mononuclear cells (PBMCs). Furthermore, we sought to comprehensively characterize the transcriptional changes in the three groups by transcriptome sequencing. Findings: It was found that the absolute numbers of CD4+ T cells, CD8+ T cells, and NK cells were not decreased remarkably, while the expression of activation markers on these cells was significantly decreased in RTP patients. Furthermore, the percentage of granzyme B-producing T cells was also decreased in RTP patients compared with that in convalescent patients. Moreover, the high expression of inhibitor of differentiation-1 (ID1) and the low expression of IFITM10 may be associated with the insufficient activation of immune cells and RTP occurrence. Interpretation: Our findings provide insights into the impaired immune function and pathogenesis of RTP occurrence in COVID-19, which may contribute to the development of immunotherapy for RTP patients. Funding Statement: This work was supported by China National Center for Biotechnology Development (2020YFC0843800 and 2020YFC0846800), Ministry of Science and Technology of China (2020TFC0844100), and China Postdoctoral Science Foundation (2020T130112ZX). Declaration of Interests: The authors declare no potential conflict of interest. Ethics Approval Statement: The studies were approved by the Ethics Committee of the First Affiliated Hospital of the University of Science & Technology of China (2020-XG(H)-005) and Peking University First Hospital (2020-Research-112) for Emerging Infectious Diseases. Experiments were conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, the Principles of Good Clinical Practice, and the guidelines of China’s regulatory requirements.

Background SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

Melatonin (MT) can improve the effect of cryopreservation on oocytes by suppressing oxidative stress and maintaining the permeability of the oolemma. In this study, MT was firstly applied to human oocytes’ cryopreservation to explore the effect of prolonged cryopreservation on developmental competence and its role. Collected in vitro-matured human oocytes were cryopreserved in MT-containing or MT-free medium for 0 and 6 months; after warming, viable oocytes were assessed for developmental viability, intracellular protein expression, mitochondrial function, and oxidation-antioxidant system. Meanwhile, fresh oocytes were set as the control. The results showed that with the extension of cryopreservation time, the developmental competence of oocytes gradually declined, accompanied by the down-regulation of most mitochondrial function-related proteins, the reduction in ATP and GSH production, the increase in ROS accumulation, and the aggravation of the imbalance of ROS/GSH in oocytes. However, the participation of MT seemed to effectively mitigate these negative effects. Therefore, we speculate that melatonin may maintain normal ATP production and ROS/GSH balance in cryopreserved oocytes by protecting mitochondrial function and inhibiting oxidative damage, thereby effectively maintaining the developmental competence of human oocytes in prolonged cryopreservation.

The main objective is to evaluate clinical efficacy and safety of using calcipotriol–betamethasone compounding agent for psoriasis treatment through a systematic review and meta-analysis. We searched MEDLINE, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), and WanFang Data from inception till July 31, 2020. Efficacy was evaluated based on primary outcome indicators including skin lesion improvement and overall adverse reaction rate. Secondary outcome indicators included degree of life quality improvement, clinical effectiveness rate, and specific adverse reaction rates. RevMan5.3 was used to perform the meta-analysis. 22 studies finally met our inclusion criteria for the meta-analysis. The results indicated that for short-term treatment, a sequential therapy that uses calcipotriol betamethasone compounding agent and calcipotriol improves PASI score (MD = −0.94, 95% CI − 1.38 ~ − 0.49, P

The sortilin-related receptor 1 (SORL1) gene has been the subject of many studies focusing on frequent polymorphisms, which is associated with increased risk for Alzheimer’s Disease (AD). By whole-exome sequencing (WES), we identified two pathogenic missense mutations c.579C > G (p.F193L) and c.1397A > G (p.N466S) in SORL1. The two mutations were located in the same protein domain, and the two unrelated probands both had an onset of memory problems at less than 65 years of age, but their clinical manifestations and cranial imaging are different. The protein structure and function affected by these mutations were predicted using bioinformatics analysis, which suggested they were pathogenic. 3D protein structural analysis revealed that these amino acid substitutions might result in instability of protein structure and adverse intramolecular interactions. These findings suggest that both F193L and N466S should be thought as potential causative mutations in early-onset Alzheimer’s disease (EOAD) patients. Further functional studies are warranted to evaluate their roles in the pathogenesis of AD.

Background Combination conversion therapies afforded curative surgery chance for initially unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the conversion rate and clinical outcomes of a first-line conversion regimen of lenvatinib combined with transarterial chemoembolization (TACE) plus immunotherapy for initial uHCC by interpreting real-world data. Methods Conversion therapy data of patients with uHCC from November 2018 to January 2021 were analysed. The regimens included triple combination therapy (t-CT: lenvatinib, TACE, plus toripalimab) and dual combination therapy (d-CT: lenvatinib plus TACE). Another study population diagnosed with hepatocellular carcinoma of macrovascular invasion disease were included as the upfront surgery cohort. Treatment responses and conversion rate were primary outcomes. Survival and adverse events were analysed. Results Fifty-one patients receiving t-CT (n = 30) and d-CT (n = 21) were enrolled. Higher overall response rates (76.7 per cent versus 47.6 per cent, P = 0.042) and disease control rates (90.0 per cent versus 57.1 per cent, P = 0.042) were observed via t-CT than d-CT. Both median overall survival and event-free survival were not reached in the t-CT cohort. A higher rate of curative conversion resection was achieved through t-CT than d-CT (50.0 per cent versus 19.0 per cent, P = 0.039). The disease-free survival of patients undergoing conversion resection in the t-CT cohort (n = 15) was higher than that in the upfront surgery cohort (n = 68, P = 0.039). Both t-CT and d-CT regimens were tolerable. Conclusions Better treatment responses and conversion rate for patients with uHCC were obtained with first-line t-CT. Neoadjuvant t-CT before surgery should be recommended for patients with macrovascular invasion.

Background: Ferroptosis is associated with cancer initiation and progression. However, the molecular mechanism and prognostic value of ferroptosis-related genes in lung squamous cell carcinoma (LUSC) are poorly understood. Methods: The mRNA expression profiles, methylation data, and clinical information of patients with LUSC were downloaded from TCGA and GEO database. Ferroptosis-related differentially expressed genes (DEGs) were identified between cancerous and non-cancerous tissues, and their prognostic value was systemically investigated by bioinformatic analyses. Results: A ferroptosis-related gene signature (ALOX5, TFRC, PHKG2, FADS2, NOX1) was constructed using multivariate Cox regression analysis and represented as a risk score. Overall survival (OS) probability was significantly lower in the high-risk group than in the low-risk group (P Conclusions: A ferroptosis-related gene signature was constructed to predict OS probability in LUSC. This could facilitate novel therapeutic methods and guide individualized therapy.

Objectives: Our objective was to analyze changes in lifestyle patterns of Chinese college students at home during the COVID-19 outbreak. Methods: According to a structured online questionnaire covering socio- demographic information, anthropometric data, and changes in food intake, physical activity, and sleep during the COVID-19 outbreak, the relationships between the above data before and during the outbreak were analyzed. Results: Among the 781 participants, 38.5% had significantly increased their total food intake and 29.1% had significantly decreased their physical activity. Overall, 44% of participants reported weight gain. The average weight gain was 0.7±2.5 kg. The main causes of weight gain were increased food intake (p < .001), decreased physical activity (p < .01), and an excessive increase or reduction in sleep duration (p < .024). Conclusion: During the COVID-19 outbreak, college students' food intake was found to be increased and physical activity decreased; sleep duration was irregular, and all these factors influenced weight gain.

With the continuous increase in transportation activities, the transportation sector has become an important source of global greenhouse gases. In 2019, road vehicles accounted for nearly three-quarters of the CO

Pain is an unpleasant sensory and emotional experience. Understanding the neural mechanisms of acute and chronic pain and the brain changes affecting pain factors is important for finding pain treatment methods. The emergence and progress of non-invasive neuroimaging technology can help us better understand pain at the neural level. Recent developments in identifying brain-based biomarkers of pain through advances in advanced imaging can provide some foundations for predicting and detecting pain. For example, a neurologic pain signature (involving brain regions that receive nociceptive afferents) and a stimulus intensity-independent pain signature (involving brain regions that do not show increased activity in proportion to noxious stimulus intensity) were developed based on multivariate modeling to identify processes related to the pain experience. However, an accurate and comprehensive review of common neuroimaging techniques for evaluating pain is lacking. This paper reviews the mechanism, clinical application, reliability, strengths, and limitations of common neuroimaging techniques for assessing pain to promote our further understanding of pain.

Sleep disturbances are common in preschoolers, and profoundly affected by parenting. Grandparents are increasingly involved in childcare and have attracted worldwide attention for their potential impacts on child well-being. However, no studies have explored child sleep health within the context of grandparental care. We aimed to explore the association between grandparents as primary caregivers and children's sleep disturbances.Participants included 20,324 preschoolers from the Shanghai Children's Health, Education and Lifestyle Evaluation-Preschool (SCHEDULE-P) in Shanghai, China. They were initially assessed in November 2016 and were reassessed in April 2018 and April 2019. Children's primary caregivers were collected at each survey. Sleep disturbances were assessed by the Children's Sleep Habits Questionnaire (CSHQ).At baseline, 84.4% of children had global sleep disturbances (CSHQ total score41). Compared with parents, random-effects model indicated that grandparents as primary caregivers increased the adjusted odds ratio (OR) for children's global sleep disturbances by 30% (OR [95%CI]: 1.30 [1.21, 1.40]). To the specific domains of CSHQ, two-way repeated-measures ANOVA showed significant "caregiver transition" group × wave interaction in the behavioral sleep disturbances, such as "Bedtime Resistance" (p 0.001). At each survey, children with grandparents as primary caregivers demonstrated significant higher behavioral sleep disturbances than their counterparts with parental care.Grandparental care is associated with increased sleep disturbances, particularly behavioral sleep disturbances, in preschoolers. Future studies should explore the underlying mechanisms and whether sleep programs targeting grandparents can decrease children's sleep disturbances.

Background Patients with osteoporosis have a high risk of implant loosening due to poor osteointegration, possibly leading to implant failure, implant revision, and refracture. RNA interference therapy is an emerging epigenetic treatment, and we found that miR-20a could enhance osteogenesis. Moreover, small extracellular vesicles (sEVs) derived from bone marrow mesenchymal stem cells (hBM-MSCs) were utilized as nanoscale carriers for the protection and transportation of miR-20a (sEV-20a). In this study, we intended to determine whether sEVs overexpressing miR-20a could exert a superior effect on osteoporotic bone defects and the underlying mechanism. Methods For evaluating the effect of sEV-20a on osteogenesis, in vitro and in vivo studies were performed. In vitro, we first showed that miR-20a was upregulated in the osteogenic process and overexpressed sEVs with miR-20a by the transfection method. Then, the proliferation, migration, and osteogenic differentiation abilities of hBM-MSCs treated with sEV-20a were detected by CCK-8 assays, alkaline phosphatase staining and alizarin red staining, qRT-PCR, and western blot. In vivo, we established an osteoporotic bone defect model and evaluated the effect of sEV-20a on bone formation by micro-CT, sequential fluorescent labeling, and histological analysis. To further explore the mechanism, we applied a bioinformatics method to identify the potential target of miR-20a. Results In vitro, sEV-20a was successfully established and proved to promote the migration and osteogenesis of hBM-MSCs. In vivo, sEV-20a promoted osteointegration in an osteoporotic rat model. To further elucidate the related mechanism, we proved that miR-20a could enhance osteogenesis by targeting BAMBI. Conclusions Collectively, the in vitro and in vivo results confirmed that MSC-derived sEV-20a therapy effectively promoted osteoporotic porous titanium alloy osteointegration via pro-osteogenic effects by targeting BAMBI.

Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

Dong Xie,1,2,* Chenhui Xu,1,* Cheng Ye,1,* Shiqi Mei,3 Longqing Wang,1 Qi Zhu,1 Qing Chen,1 Qi Zhao,1 Zhiyan Xu,3 Jie Wei,3 Lili Yang1 1Spine Center, Department of Orthopaedics, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 2Department of Orthopaedics, PLA Navy No.905 Hospital, Shanghai, 200052, People’s Republic of China; 3Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lili Yang Tel +86-021-81885793Email yangll@smmu.edu.cnPurpose: Polyetheretherketone (PEEK) exhibits high mechanical strengths and outstanding biocompatibility but biological inertness that does not excite the cell responses and stimulate bone formation. The objective of this study was to construct submicro-nano structures on PEEK by femtosecond laser (FSL) for exciting the responses of MC3T3-E1 cells and gingival epithelial (GE) cells, which induce regeneration of bone/gingival tissues for long-term stability of dental implants.Materials and Methods: In this study, submicro-nano structures were created on PEEK surface by FSL with power of 80 mW (80FPK) and 160 mW (160FPK).Results: Compared with PEEK, both 80FPK and 160FPK with submicro-nano structures exhibited elevated surface performances (hydrophilicity, surface energy, roughness and protein absorption). Furthermore, in comparison with 80FPK, 160FPK further enhanced the surface performances. In addition, compared with PEEK, both 80FPK and 160FPK significantly excited not only the responses (adhesion, proliferation, alkaline phosphatase [ALP] activity and osteogenic gene expression) of MC3T3-E1 cells but also responses (adhesion as well as proliferation) of GE cells of human in vitro. Moreover, in comparison with 80FPK, 160FPK further enhanced the responses of MC3T3-E1 cells/GE cells.Conclusion: FSL created submicro-nano structures on PEEK with elevated surface performances, which played crucial roles in exciting the responses of MC3T3-E1 cells/GE cells. Consequently, 160FPK with elevated surface performances and outstanding cytocompatibility would have enormous potential as an implant for dental replacement.Keywords: polyetheretherketone; PEEK, surface modification, submicro-nano structures, functional group, cell responses

Abnormal sleep duration has been identified as a risk factor for cognitive decline. However, most studies have measured sleep duration and cognitive function at a single time point, while both tend to decrease with age. This study aimed to investigate the association between changes in sleep duration patterns and cognitive trajectories in older adults. Using longitudinal data (2005–2014) from the Chinese Longitudinal Healthy Longevity Survey, a total of 4347 subjects were included in this study. Cognitive function was measured with the Chinese version of the Mini-Mental State Examination. Group-based trajectory models were used to identify the trajectories of sleep duration and cognitive decline within the study sample as the participants aged. Furthermore, the association between sleep duration patterns and cognitive trajectories was examined by multinomial logistic regression analysis. Using the medium-stable sleep duration pattern as a reference, the trajectory with a long and increased sleep duration pattern was more likely to be associated with the slight cognitive decline trajectory (OR = 1.80; 95% CI 1.31–2.44). Persistent short sleep was associated with a decreased likelihood of having a rapid cognitive decline trajectory (OR = 0.32; 95% CI 0.12–0.75). Changes in sleep duration over time were independently associated with cognitive decline and may be a marker of cognitive decline. Tracking of sleep duration over time in older adults may provide a useful insight for prevention of cognitive decline, and the increased sleep duration should be noticed with greater vigilance.

Zona pellucida (ZP) abnormalities are the cause of low fertility or infertility, agar-like ZP is more common in abnormal ZP. The purpose of this exploration is to systematically analyze the fertilization competence of agar-like ZP oocytes, the development characteristics of subsequent embryos as well as the results of embryo transfer, aiming to explore effective clinical treatment strategies. A total of 58 patients with agar-like ZP were set as the case group and the control group involved 3866 patients, in which the patients’ oocytes presented normal ZP. BMI, basal hormone levels, and hormone levels were similar in both groups. The case patients suffered significantly longer infertility years than control (p

Increased frequency of circulating double negative T (DNT, CD4A cross-sectional study was conducted to investigate the frequency and functional profiles of peripheral TCRαβSignificantly increased frequency of TCRαβReduced apoptosis may take part in the mechanism of increased frequency of peripheral TCRαβ

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time- and space-dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer, knocking down which attenuates metastatic phenotypes. However, due to the limited number of known substrates in the ovarian cancer context, the molecular basis for its pro-proliferation activity remains enigmatic. Here, we employed mass spectrometry and biochemical approaches to identify insulin receptor substrate 4 (IRS4) as a novel substrate of FER. FER engaged its kinase domain to associate with the PH and PTB domains of IRS4. Using a proximity-based tagging system in ovarian carcinoma-derived OVCAR-5 cells, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4 delayed ovarian tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

The present study aimed to explore the genomic profile in a cohort of Chinese patients with breast cancer (BC), as well as provide potential strategies for clinic treatment in specific subset of BC patients.Paired samples from 46 BC patients were subjected to DNA extraction and 537 gene targeted next-generation sequencing.In total, 742 somatic mutations were detected in these patients, which involved 303 genes. TP53 and PIK3CA were the most frequently mutated genes, with a mutation rate of 45.65% and 26.09%. CT, TC and CA comprised the main single nucleotide base variation for this Chinese cohort. Triple negative breast cancer (TNBC) group had more TP53-mutated patients than the Non-TNBC group (p = 0.0229). In addition, the cohort was also divided into 'Young' and 'Old' groups based on the age of onset. Compared with the 'Young' group, the 'Old' group had more frameshift mutations (p = 0.0190), less missense mutations (p = 0.0269) and more HOXA11-mutated patients (p = 0.0197). Additionally, the HOXA11The present study revealed the heterogeneity of gene mutation and clinical variables among BC subtypes and might provide guidance for developing a potential target for clinical treatment.

Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Graphical abstract Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP‐8, MMP‐9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP‐8); Matrix metalloproteinase 9 (MMP‐9).

Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic dysregulation and distinct immunological signatures. The interplay between metabolic and immune processes in the tumor microenvironment (TME) causes the complexity and heterogeneity of immunotherapy responses observed during ccRCC treatment. Herein, we initially identified two distinct metabolic subtypes (C1 and C2 subtypes) and immune subtypes (I1 and I2 subtypes) based on the occurrence of differentially expressed metabolism-related prognostic genes and immune-related components. Notably, we observed that immune regulators with upregulated expression actively participated in multiple metabolic pathways. Therefore, we further delineated four immunometabolism-based ccRCC subtypes (M1, M2, M3, and M4 subtypes) according to the results of the above classification. Generally, we found that high metabolic activity could suppress immune infiltration. Immunometabolism subtype classification was associated with immunotherapy response, with patients possessing the immune-inflamed, metabolic-desert subtype (M3 subtype) that benefits the most from immunotherapy. Moreover, differences in the shifts in the immunometabolism subtype after immunotherapy were observed in the responder and non-responder groups, with patients from the responder group transferring to subtypes with immune-inflamed characteristics and less active metabolic activity (M3 or M4 subtype). Immunometabolism subtypes could also serve as biomarkers for predicting immunotherapy response. To decipher the genomic and epigenomic features of the four subtypes, we analyzed multiomics data, including miRNA expression, DNA methylation status, copy number variations occurrence, and somatic mutation profiles. Patients with the M2 subtype possessed the highest VHL gene mutation rates and were more likely to be sensitive to sunitinib therapy. Moreover, we developed non-invasive radiomic models to reveal the status of immune activity and metabolism. In addition, we constructed a radiomic prognostic score (PRS) for predicting ccRCC survival based on the seven radiomic features. PRS was further demonstrated to be closely linked to immunometabolism subtype classification, immune score, and tumor mutation burden. The prognostic value of the PRS and the association of the PRS with immune activity and metabolism were validated in our cohort. Overall, our study established four immunometabolism subtypes, thereby revealing the crosstalk between immune and metabolic activities and providing new insights into personal therapy selection.

Objective To evaluate high-frequency ultrasound (HFUS) features for diagnosing cutaneous squamous cell carcinoma (cSCC) as a spectrum of progressively advanced malignancies, including precursor actinic keratosis (AK), Bowen's disease (BD), and invasive squamous cell carcinoma (iSCC). Method In this retrospective study, 160 skin lesions diagnosed histopathologically (54 AK, 54 BD, and 52 iSCC) in 160 patients were included. The HFUS features of AK, BD, and iSCC were analyzed. The obtained data were evaluated using univariate and forward multivariate logistic regression analyses. Results The most significant HFUS features in AK were regular surface (odds ratio [OR], 8.42) and irregular basal border (OR, 6.36). The most significant HFUS features in BD were crumpled surface (OR, 19.62) and layer involvement confined to the epidermis (OR, 3.96). The most significant HFUS features in iSCC were concave surface (OR, 27.06), stratum corneum (SC) detachment (OR, 14.41), irregular basal border (OR, 4.01), and convex surface (OR, 3.73). The characteristics of surface features, basal border, and layer involvement could be valuable HFUS clues in the discrimination of AK, BD, and iSCC. Conclusion High-frequency ultrasound is valuable for the differentiation of AK, BD, and iSCC, which may allow dynamic and noninvasive monitoring in the spectrum of cSCC.

Background: Stem cells play an important role in hepatocellular carcinoma (HCC). However, their precise effect on HCC tumorigenesis and progression remains unclear. The present study aimed to characterize stem cell-related gene expression in HCC.Methods: The mRNA expression-based stemness index (mRNAsi) was used to analyze the clinical characteristics and prognosis of HCC patients. The weighted gene co-expression network analysis (WGCNA) was used to construct a gene co-expression network of 374 HCC patients. Finally, six genes were used to construct the prognosis signature.Results: HCC patients had a higher mRNAsi score than healthy people, suggesting poor prognosis. Two gene modules highly related to mRNAsi were identified. Multivariate Cox analysis was carried out to establish a Cox proportional risk regression model. The risk score for each patient was the sum of the product of each gene expression and its coefficient. Survival analysis suggested that the low-risk group had a significantly better prognosis.Conclusions: The established six-gene signature was able to predict patient prognosis accurately. This new signature should be verified in prospective studies in order to determine patient prognosis in clinical decision-making.

Background Thrombus enhancement (TE) in large vessel occlusion in patients with acute ischemic stroke can be visualized with thin-slab maximum intensity projection (TS-MIP) image reconstruction of CT angiograms. Purpose To evaluate whether TE on TS-MIP reconstructed CT angiograms can be used to predict thrombus composition and stroke source. Materials and Methods This retrospective study included consecutive patients with acute ischemic stroke who underwent thrombectomy in the anterior circulation between August 2016 and July 2019. Stroke types were classified according to the Trial of ORG 10172 in Acute Stroke Treatment. TE on TS-MIP reconstructed CT angiograms was evaluated by two readers. Various clinical and interventional parameters and histopathologic thrombi examination results were compared between the TE-positive and TE-negative groups. The associations between TE and thrombus compositions and stroke sources were analyzed by using multivariable linear and logistic regression models. Results A total of 148 patients (mean age, 71 years ± 11 [standard deviation]; 94 men) were included. TE was confirmed in 80% (119 of 148) of the patients. TE-positive thrombi contained a higher fibrin and platelet proportion (mean, 46% ± 16 vs 34% ± 13; P = .02) and fewer erythrocytes (mean, 33% ± 14 vs 48% ± 20, P = .002) than the TE-negative thrombi. The proportion of cardioembolic and cryptogenic strokes in the TE-positive and TE-negative groups was 92% (110 of 119) and 24% (seven of 29), respectively (P < .001). In adjusted analysis, the presence of TE (odds ratio, 155; 95% CI: 17, 1438; P < .001) was associated with a combination of cardioembolic and cryptogenic strokes. A multiple logistic regression model showed that TE (odds ratio, 23; 95% CI: 1.8, 288; P = .02) was significantly associated with cardioembolic stroke. Conclusion Thrombus enhancement on thin-slab maximum intensity projection of CT angiography can be used to predict cardioembolic and cryptogenic strokes and identify thrombi with a higher fibrin-to-platelet fraction and a lower erythrocyte proportion. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kansagra and Goyal in this issue.

Background Diffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study. Methods The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model. Results A total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors. Conclusions This is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Cardiac endothelium communicates closely with adjacent cardiac cells by multiple cytokines and plays critical roles in regulating fibroblasts proliferation, activation, and collagen synthesis during cardiac fibrosis. E26 transformation-specific (ETS)-related gene (ERG) belongs to the ETS transcriptional factor family and is required for endothelial cells (ECs) homeostasis and cardiac development. This study aims at investigating the potential role and molecular basis of ERG in fibrotic remodeling within the adult heart. We observed that ERG was abundant in murine hearts, especially in cardiac ECs, but decreased during cardiac fibrosis. ERG knockdown within murine hearts caused spontaneously cardiac fibrosis and dysfunction, accompanied by the activation of multiple Smad-dependent and independent pathways. However, the direct silence of ERG in cardiac fibroblasts did not affect the expression of fibrotic markers. Intriguingly, ERG knockdown in human umbilical vein endothelial cells (HUVECs) promoted the secretion of endothelin-1 (ET-1), which subsequently accelerated the proliferation, phenotypic transition, and collagen synthesis of cardiac fibroblasts in a paracrine manner. Suppressing ET-1 with either a neutralizing antibody or a receptor blocker abolished ERG knockdown-mediated deleterious effect in vivo and in vitro. This pro-fibrotic effect was also negated by RGD (Arg-Gly-Asp)-peptide magnetic nanoparticles target delivery of ET-1 small interfering RNA to ECs in mice. More importantly, we proved that endothelial ERG overexpression notably prevented pressure overload-induced cardiac fibrosis. Collectively, endothelial ERG alleviates cardiac fibrosis via blocking ET-1-dependent paracrine mechanism and it functions as a candidate for treating cardiac fibrosis. • ERG is abundant in murine hearts, especially in cardiac ECs, but decreased during fibrotic remodeling. • ERG knockdown causes spontaneously cardiac fibrosis and dysfunction. • ERG silence in HUVECs promotes the secretion of endothelin-1, which in turn activates cardiac fibroblasts in a paracrine manner. • Endothelial ERG overexpression prevents pressure overload-induced cardiac fibrosis.

To study the impact of maternal sleep in late pregnancy on birth weight (BW) and leptin and lipid levels in umbilical cord blood.A total of 277 healthy and singleton pregnancy women were recruited for participation in the Shanghai Sleep Birth Cohort Study (SSBC) during their 36-38 weeks of pregnancy, from May 2012 to July 2013. Maternal night sleep time (NST), sleep efficiency (SE), sleep onset latency (SOL) and the percentage of wake after sleep onset (WASO) in NST and midpoint of sleep (MSF) were measured by actigraphy for seven consecutive days. The leptin and lipid levels were determined in cord blood samples collected from the umbilical vein immediately after delivery. Birth information (birth weight, gender, delivery type, etc.) was extracted from medical records. A multivariable linear regression model was applied to examine the effect of maternal sleep in late pregnancy on newborn leptin and lipid levels in umbilical cord blood.A total of 177 women and their infants were included in the analysis. Maternal mean NST was 7.03 ± 1.10 h in late pregnancy, and 48% had a shorter sleep time (NST 7 h). The average maternal SE was 72.54% ± 9.66%. The mean percentage WASO/NST was 21.62% ± 9.98%; the average MSF was about 3:34 (0:53); and the SOL was 46.78 ± 36.00 min. After adjustment for confounders, both maternal NST and SE were found to be significantly associated with triglyceride levels (β = -0.219, p = 0.006; β = -0.224, p = 0.006) in umbilical cord blood; and maternal NST was also observed to have positive association with newborn leptin levels (β = 0.146, p = 0.047). However, we did not find significant association between other maternal sleep parameters in late pregnancy and leptin and lipid levels and birth weight.Short sleep duration and poor sleep quality during late pregnancy were associated with newborn leptin and lipid levels, and efforts on improving maternal sleep during late pregnancy should be advocated for children's health.

Background Sleep disturbances in women occur frequently throughout pregnancy. Previous studies have demonstrated that the increasing incidence of physiological and psychological illness is concurrent with increasing sleep deprivation and poor sleep quality in adults and children. Objectives The Shanghai Sleep Birth Cohort Study (SSBCS) was established to examine the effect of sleep disturbances during the third trimester on emotional regulation of mothers; to assess the effect of maternal sleep during pregnancy on the growth and development of children; and to explore the influence of children's sleep characteristics on physical and social-emotional development. Population The study was conducted in the Renji Hospital in Pudong New District, Shanghai from May 2012 to July 2013. Women and their newborns who met the inclusion criteria and agreed to participate in this study were recruited to the SSBCS. Methods The follow-up visits for children were conducted at the age of 42 days, 3, 6, 9, 12, 18, and 24 months, and 3, 4, and 6 years. Data on demographic factors, physical examination, sleep assessment, developmental and psychiatric assessment, diet records, and biological samples were collected throughout the study. Preliminary results A total of 277 pregnant women were recruited to the study; the response rate was 64.3%. 37.9% of the pregnant women had poor sleep quality and 12.0% suffered from depression. Infant sleep patterns changed during the first year of life, but most sleep characteristics showed little variation from 6 to 12 months. Conclusions The SSBCS is an on-going prospective cohort study with follow-up to 6 years. The detailed data on demographic factors, sleep assessment, physical examinations, neurodevelopmental and psychiatric assessment, diet records, and biological samples make this research platform an important resource for examining the potential effects of sleep characteristics on both maternal and child health.

High-mobility group AT-hook2 (HMGA2), serving as an architectural transcription factor, participates in plenty of biological processes. Our study is aimed at illustrating the effect of HMGA2 on hypoxia-induced HUVEC injury and the underlying mechanism. To induce hypoxia-related cell injury, HUVECs were exposed to hypoxic condition for 12–24 h. Molecular expression was determined by Western blot analysis, real-time PCR and immunofluorescence staining. Cell migration was monitored by wound healing assay and Transwell chamber assay. Cell proliferation and apoptosis were measured by MTT assay kits and TUNEL staining. In this study, we discovered that HMGA2 was upregulated in hypoxia-induced HUVECs. Overexpression of HMGA2 promoted cell migration, decreased the apoptosis ratio in response to hypoxia stimulation, while HMGA2 knockdown inhibited cell migration and accelerated apoptosis in HUVECs under hypoxic condition. Mechanistically, we found that HMGA2 induced increased expression of HIF-1α,VEGF, eNOS and AKT. eNOS knockdown significantly reduced HMGA2-mediated pro-migration effects, and AKT knockdown strikingly counteracted HMGA2-mediated anti-apoptotic effect. Hence, our data indicated that HMGA2 promoted cell migration by regulating HIF-1α/VGEF/eNOS signaling and prevented cell apoptosis by activating HIF-1α/VGEF/AKT signaling in HUVECs.

The purpose of this study was to develop, validate and test a prediction model for discriminating malignant from benign breast lesions using conventional ultrasound (US), US elastography of strain elastography and contrast-enhanced ultrasound (CEUS). The study included 454 patients with breast imaging-reporting and data system (BI-RADS) category 4 breast lesions identified on histologic examinations. Firstly, 228 breast lesions (cohort 1) were analyzed by logistic regression analysis to identify the risk factors, and a breast malignancy prediction model was created. Secondly, the prediction model was validated in cohort 2 (84 patients) and tested in cohort 3 (142 patients) by using analysis of the area under the receiver operating characteristic curve (AUC). Univariate regression indicated that age ≥40 y, taller than wide shape on US, early hyperenhancement on CEUS and enlargement of enhancement area on CEUS were independent risk factors for breast malignancy (all p0.05). The logistic regression equation was established as follows: p = 1/1+Exp∑[-5.066 + 3.125 x (if age ≥40 y) + 1.943 x (if taller than wide shape) + 1.479 x (if early hyperenhancement) + 4.167 x (if enlargement of enhancement area). The prediction model showed good discrimination performance with an AUC of 0.967 in cohort 1, 0.948 in cohort 2 and 0.920 in cohort 3. By using the prediction model to selectively downgrade category 4a lesions, the re-rated BI-RADS yield an AUC of 0.880 (95% confidence interval [CI], 0.794-0.965) in cohort 2 and 0.870 (95% CI, 0.801-0.939) in cohort 3. The specificity increased from 0.0% (0/35) to 80.0% (28/35) without loss of sensitivity (from 100.0% to 95.9%, p = 0.153) in cohort 2. Similarly, the specificity increased from 0.0% (0/58) to 77.6% (45/58) without loss of sensitivity (from 100.0% to 96.4%, p = 0.081) in cohort 3. Multimodal US showed good diagnostic performance in predicting breast malignancy of BI-RADS category 4 lesions. Although the loss of sensitivity was existing, the addition of multimodal US to US BI-RADS could improve the specificity in BI-RADS category 4 lesions, which reduced unnecessary biopsies.

Atherosclerosis is a chronic disease of arteries, which constitutes the pathological basis of a series of cardiovascular diseases. The inflammatory response of vascular endothelial cells mediated by oxidized low density lipoprotein (ox-LDL) is the early behavior and main signal of atherosclerosis. In this study, the damage model of vascular endothelial cells treated with ox-LDL was used to reproduce the damage process of vascular endothelial cells in the process of atherosclerosis. Cell viability was detected by CCK-8. The release levels of reactive oxygen species, nitric oxide, and superoxide dismutase (SOD) were detected by commercial kits. EdU cell proliferation assay was used to detect cell proliferation, real-time fluorescent quantitative PCR and Western blot were used to detect the expression level of related genes. The results showed we successfully constructed a vascular endothelial injury model by incubating vascular endothelial cells with gradient concentrations of ox-LDL. The incubation of safflor yellow A (SYA) partially restored the loss of viability of vascular endothelial cells mediated by ox-LDL, and SYA could promote the proliferation of injured vascular endothelial cells. In addition, SYA may transmit related signals through the AMPK pathway to protect vascular endothelial cells from ox-LDL-mediated damage. All these results provide a further understanding of the occurrence and development of atherosclerosis, provide a theoretical basis for the use of SYA-related drugs in the treatment of cardiovascular diseases, and provide a reference paradigm for studying the pharmacology, toxicology, and mechanism of action of key active substances in TCM.

Background Chest computed tomography (CT) findings in children with coronavirus disease 2019 (COVID-19) have been rarely reported in a comprehensive and systematic manner. Objective We investigated the chest CT findings in children with COVID-19, and explored the differences in these findings between symptomatic patients and asymptomatic patients. Materials and methods Demographic findings, clinical characteristics, duration of hospital stay and viral shedding, and chest CT findings in 201 children infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were retrospectively analyzed from January 15 to March 20, 2020, and divided into two groups: symptomatic group (n=136) and asymptomatic group (n=65). Chi-square test and Student’s t-test were used for statistical analysis. Results Symptomatic patients were mainly young children ≤3 years old (54/63, 86%),while asymptomatic patients were mainly children ≥ 6 years old (51/111, 46%). Fever (41%) and cough (41%) were the most common symptoms. Overall, 119/201 (59%) patients had chest CT findings, and symptomatic patients accounted for 82% (98/119). The CT findings presented as bilateral multiple lesions (60/119, 50.4%), ground-glass opacities (83/119, 70%) and/or consolidation (44/119, 37%) with a peripheral and subpleural distribution (62/83, 75%). Fifteen of 87 (7.2%) patients with lung lesions showed complete lesion absorption, and 42/87 (48%) improved within a mean of 9.1 (standard deviation [SD] 3.2) days. The mean duration of viral shedding was 8.7 (SD 4.9) days. Pleural effusion was very rare. No lymphadenopathy was found in either group. Conclusion Symptoms associated with pulmonary involvement were most common in infants and young children. The lung lesions of most patients were absorbed and improved in about 9 days.

Tuberculosis (TB) is an important opportunistic infection in acquired immunodeficiency diseases (AIDS). Although the frequency of CD4The percentage and phenotypic and functional properties of peripheral blood DP T cells in patients with HT coinfection in comparison to uninfected controls and to patients with HIV or TB mono-infection were analyzed by direct intracellular cytokine staining (ICS).Total and CD4Our data suggested that HT coinfection resulted in a marked increase in DP T cells, especially the CD4

BackgroundBlastocyst biopsy has become the most mainstream biopsy method. Currently, there are two blastocyst biopsy strategies. Many studies have compared the advantages and disadvantages between blastomere and blastocyst biopsy, but fewer articles have compared the two blastocyst biopsy strategies. For the moment, no published studies have explored the entire set of information on embryo development, next-generation sequencing results, and clinical outcomes, including the baby’s health status with the two blastocyst biopsy strategies.MethodsA total of 323 preimplantation genetic testing cycles from April 2018 to May 2020, including 178 cycles with Strategy A and 145 cycles with Strategy B. Strategy A was to create a laser-assisted zona pellucid opening for cleavage embryo on the third day after insemination, but Strategy B was not. Strategy A performed a biopsy for artificially assisted hatching blastocysts, while Strategy B performed a biopsy for expanded blastocysts on day 5 or 6. In this study, embryo development, next-generation sequencing results, pregnancy outcomes, and offspring health of the two strategies were compared and analyzed.ResultsThere were no statistical differences between the two groups in the rate of fertilization, blastocyst and abortion. The rate of cleavage from Strategy A was slightly higher than Strategy B, and the rate of high-quality cleavage embryo was lower than Strategy B, while the rate of high-quality blastocyst was higher than Strategy B. The rate of no-results blastocyst was significantly lower than Strategy B. In particular, the rate of biochemical pregnancy, clinical pregnancy, and live birth of Strategy A were significantly lower than those of Strategy B. The average Apgar scores of newborns were ≥8 in both groups, and there was no significant difference in average height and weight. In Strategy A, a baby was born with thumb syndactyly, and Strategy B had no congenital disabilities.ConclusionsBlastocyst biopsy strategy without laser-assisted zona pellucid drilling on day 3 achieves better clinical treatment effects. Therefore, Strategy B is an optimal treatment regime for PGT.