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The PA28 family proteasome activators play important roles in regulating proteasome activities. Though the three paralogs (PA28α, PA28β, and PA28γ) are similar in terms of primary sequence, they show significant differences in expression pattern, cellular localization and most importantly, biological functions. While PA28αβ is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28γ is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. However, why this paralog has the unique function remains elusive. Previous structural studies have mainly focused on mammalian PA28α, PA28β and PA28αβ heptamers, while structural studies on mammalian PA28γ of atomic resolution are still absent to date. In the present work, we determined the Cryo-EM structure of the human PA28γ heptamer at atomic resolution, revealing interesting unique structural features that may hint our understanding the functional mechanisms of this proteasome activator.

Epigenetic influence plays a role in the association between exposure to air pollution and attention deficit hyperactivity disorder (ADHD); however, research regarding sulfur dioxide (SO2) is scarce. Herein, we investigate the associations between prenatal SO2 exposure and ADHD rating scale (ARS) at ages 4, 6 and 8 years repeatedly in a mother–child cohort (n = 329). Whole blood samples were obtained at ages 2 and 6 years, and genome-wide DNA methylation (DNAm) was analyzed for 51 children using the Illumina Infinium HumanMethylation BeadChip. We analyzed the associations between prenatal SO2 exposure and DNAm levels at ages 2 and 6, and further investigated the association between the DNAm and ARS at ages 4, 6 and 8. Prenatal SO2 exposure was associated with ADHD symptoms. From candidate gene analysis, DNAm levels at the 6 CpGs at age 2 were associated with prenatal SO2 exposure levels. Of the 6 CpGs, cg07583420 (INS-IGF2) was persistently linked with ARS at ages 4, 6 and 8. Epigenome-wide analysis showed that DNAm at 6733 CpG sites were associated with prenatal SO2 exposure, of which 58 CpGs involved in Notch signalling pathway were further associated with ARS at age 4, 6 and 8 years, persistently. DNAm at age 6 was not associated with prenatal SO2 exposure. Changes in DNAm levels associated with prenatal SO2 exposure during early childhood are associated with increases in ARS in later childhood.

Background Lucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/β. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC). Methods Patients with pretreated RM-NPC were randomly divided into two treatment arms: continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results One hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years. Conclusion Lucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies. ClinicalTrials.gov identifier NCT03260179

The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1α inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1α inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1α and LOXL2 as well as EMT-associated markers and CD8

Background The long-term prognostic value of coronary CT angiography (CCTA) in asymptomatic adults with hepatic steatosis (HS) remains unknown. Purpose To evaluate the long-term prognostic value of CCTA in asymptomatic adults with HS. Materials and Methods Between January 2009 and December 2013, consecutive asymptomatic adults who underwent CCTA evaluation and unenhanced abdominal CT were prospectively enrolled. All participants were divided into two groups-with HS and without HS according to abdominal CT results. The primary end point was major adverse cardiovascular events (MACEs), defined as cardiac death, stroke, myocardial infarction, and angina requiring hospitalization. Multivariable Cox regression analysis and Kaplan-Meier analysis were used to compare survival rates. Results One thousand thirteen participants with HS and 1940 participants without HS who completed the follow-up were included (mean age, 66 years ± 10 [standard deviation] [range, 29-90 years]; 1940 men). During a median of 7.2 years of follow-up (interquartile range, 6.3-8.1), MACEs were observed in 96 of 1013 participants with HS (10%), whereas 80 of 1940 participants without HS (4%) had MACEs. In participants with a Coronary Artery Disease Reporting and Data System (CAD-RADS) category of 0, both participants with and without HS had a similar 8.8-year event-free survival rate (99.2% event-free survival rate in participants with HS vs 99.0% event-free survival rate in participants without HS, P = .77). As for participants with CAD-RADS categories 1 or 2 or 3-5, the 8.8-year event-free survival rate was lower in participants with HS than in those without HS (70.6% vs 85.2%, P < .001; 51.4% vs 71.7%, P = .03, respectively). The risk of MACEs was higher for participants with HS than for those without HS in CAD-RADS categories 1 and 2 (adjusted hazard ratio = 2.3; 95% CI: 1.4, 3.9; P < .001) and CAD-RADS categories 3-5 (adjusted HR = 2.1; 95% CI: 1.2, 3.6; P = .006) but not in the setting of CAD-RADS category 0 (adjusted HR = 5.1; 95% CI: 0.1, 398; P = .47). Conclusion Asymptomatic participants with hepatic steatosis (HS) had a worse prognosis than those without HS in the presence of coronary artery disease (CAD) at coronary CT angiography, whereas participants with HS and without CAD might have excellent clinical outcomes during a median follow-up of 7.2 years. © RSNA, 2021 Online supplemental material is available for this article.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders and the main symptoms of ASD are impairments in social communication and abnormal behavioral patterns. Studies have shown that immune dysfunction and neuroinflammation play a key role in ASD patients and experimental models. Chemokines are groups of small proteins that regulate cell migration and mediate inflammation responses via binding to chemokine receptors. Thus, chemokines/chemokine receptors may be involved in neurodevelopmental disorders and associated with ASD. In this review, we summarize the research progress of chemokine aberrations in ASD and also review the recent progress of clinical treatment of ASD and pharmacological research related to chemokines/chemokine receptors. This review highlights the possible connection between chemokines/chemokine receptors and ASD, and provides novel potential targets for drug discovery of ASD.

Machine learning methods are a novel way to predict and rank donors' willingness to donate blood and to achieve precision recruitment, which can improve the recruitment efficiency and meet the challenge of blood shortage. We collected information about experienced blood donors via short message service (SMS) recruitment and developed 7 machine learning-based recruitment models using PyCharm-Python Environment and 13 features which were described as a method for ranking and predicting donors’ intentions to donate blood with a floating number between 0 and 1. Performance of the prediction models was assessed by the Area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1 score in the full dataset, and by the accuracy in the four sub-datasets. The developed models were applied to prospective validations of recruiting experienced blood donors during two COVID-19 pandemics, while the routine method was used as a control. Overall, a total of 95,476 recruitments via SMS and their donation results were enrolled in our modelling study. The strongest predictor features for the donation of experienced donors were blood donation interval, age, and donation frequency. Among the seven baseline models, the eXtreme Gradient Boosting (XGBoost) and Support vector machine models (SVM) achieved the best performance: mean (95%CI) with the highest AUC: 0.809 (0.806–0.811), accuracy: 0.815 (0.812–0.818), precision: 0.840 (0.835–0.845), and F1 score of XGBoost: 0.843 (0.840–0.845) and recall of SVM: 0.991 (0.988–0.994). The hit rate of the XGBoost model alone and the combined XGBoost and SVM models were 1.25 and 1.80 times higher than that of the conventional method as a control in 2 recruitments respectively, and the hit rate of the high willingness to donate group was 1.96 times higher than that of the low willingness to donate group. Our results suggested that the machine learning models could predict and determine the experienced donors with a strong willingness to donate blood by a ranking score based on personalized donation data and demographical details, significantly improve the recruitment rate of blood donors and help blood agencies to maintain the blood supply in emergencies.

BackgroundCT053PTSA is a novel tyrosine kinase inhibitor that targets MET, AXL, VEGFR2, FLT3 and MERTK. Here, we present preclinical data about CT053PTSA, and we conducted the first-in-human (FIH) study to evaluate the use of CT053PTSA in adult patients with pretreated advanced solid tumors.MethodsThe selectivity and antitumor activity of CT053PTSA were assessed in cell lines in vitro through kinase and cellular screening panels and in cell line-derived tumor xenograft (CDX) and patient-derived xenograft (PDX) models in vivo. The FIH, phase I, single-center, single-arm, dose escalation (3 + 3 design) study was conducted, patients received at least one dose of CT053PTSA (15 mg QD, 30 mg QD, 60 mg QD, 100 mg QD, and 150 mg QD). The primary objectives were to assess safety and tolerability, to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended dose of CT053PTSA for further study. Secondary objectives included pharmacokinetics, antitumor activity.ResultsCT053 (free-base form of CT053PTSA) inhibited MET, AXL, VEGFR2, FLT3 and MERTK phosphorylation and suppressed tumor cell angiogenesis by blocking VEGF and HGF, respectively, in vitro. Moreover, cell lines with high MET expression exhibited strong sensitivity to CT053, and CT053 blocked the MET and AXL signaling pathways. In an in vivo study, CT053 significantly inhibited tumor growth in CDX and PDX models. Twenty eligible patients were enrolled in the FIH phase I trial. The most common treatment-related adverse events were transaminase elevation (65%), leukopenia (45%) and neutropenia (35%). DLTs occurred in 3 patients, 1/6 in the 100 mg group and 2/4 in the 150 mg group, so the MTD was set to 100 mg. CT053PTSA was rapidly absorbed after the oral administration of a single dose, and the Cmax and AUC increased proportionally as the dose increased. A total of 17 patients in this trial underwent tumor imaging evaluation, and 29.4% had stable disease.ConclusionsCT053PTSA has potent antitumor and antiangiogenic activity in preclinical models. In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing.

We performed an up-to-date meta-analysis to quantify the overall incidence and risk of severe adverse events (AEs) associated with T-DM1 in patients with breast cancer. Pubmed, Embase, and oncology conference proceedings were searched for relevant studies. Data were extracted to calculate the summary incidence rate and relative risk (RR) of grade ≥3 AEs. A total of 5,045 patients from 7 RCTs were included in the meta-analysis. The use of T-DM1 was associated with an increased risk of severe thrombocytopenia (RR 10.66, 95% CI 3.23–35.18, P < 0.001), anemia (RR 1.68, 95% CI 1.15–2.44, P = 0.007), elevated ALT (RR 2.67, 95% CI 1.60–4.47, P < 0.001), and AST (RR 3.76, 95% CI 1.45–9.78, P = 0.007). In addition, the use of T-DM1 can increase the risk of severe hypertension (RR 1.59, 95% CI 1.03–2.45, P = 0.037) and peripheral sensory neuropathy (RR 8.13, 95% CI 1.89–35.03, P = 0.005). Treatment with T-DM1 increases the risk of severe hematologic toxicities, hepatotoxicity, hypertension, and peripheral sensory neuropathy in patients with breast cancer, while the overall incidence of these AEs is low.

Autophagy was prominently activated by cerebral ischaemia. This study was to investigate the exact role of autophagy in ischaemic stroke. Two rat models of transient middle cerebral artery occlusion (tMCAO) and permanent MCAO (pMCAO) were prepared. The brain tissues in the penumbra were obtained to observe the dynamic variations of autophagy activity with Beclin1 and LC3 antibodies by Western blotting. At the characteristic time points, when autophagy activity was markedly elevated or reduced, the autophagy activation signaling was intervened with rapamycin and 3-methyladenine, respectively. Thereafter, key proteins in the autopahgic/lysosomal pathway were detected with the antibodies of LC3, p62, ubiquitin, LAMP-1 and cathepsin B. Meanwhile, TTC staining, neurological score and immunofluorescence were performed to evaluate brain infarct volume, neurological deficit and neuron survival, respectively. Both Beclin1 and LC3 expression levels were remarkably altered at 6 h, 12 h, 2 days and 7 days after tMCAO. Interestingly, the dynamic changes of autophagy activity following pMCAO were identical to those after tMCAO. Neither autophagy induction nor autophagy inhibition was able to ameliorate the pMCAO-induced neurological injury due to lysosomal dysfunction, as indicated by low levels of LAMP-1 and cathepsin B, accompanied with the accumulation of LC3-II, ubiquitin and insoluble p62. Comparatively, autophagy induction elicited overt neuroprotection at 2 and 7 days after tMCAO, and this neuroprotection might be elicited by the enhancement of autophagy flux. Our study suggests that autophagy confers neuroprotection at the subacute phase of tMCAO but has few effects on neurological outcomes after pMCAO.

Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.

ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15

Commensal bacteria and other microorganisms that reside in the human body are closely associated with the development and treatment of cancers. Recently, tumor microbiome (TM) has been identified in a variety of cancers such as pancreatic, lung, and breast cancers. TM has different compositions in different tumors and has different effects on tumors. TM plays an important role in the formation of the tumor microenvironment, regulation of local immunity, and modification of tumor cell biology, and directly affects the efficacy of drug treatment for tumors. TM is expected to be a biomarker for tumors, and engineered tumor-targeting bacteria and anti-cancer microbial agents (GEN-001) have an important role in the treatment of tumors. This paper reviews the relevant studies on TM in recent years and describes its distribution in different tumors, its correlation with clinical features, its effect on local immunity, and the research directions of TM in tumor treatment.

Dysphagia is a common and serious complication in patients with oral cancer after free flap transplantation (OC-FFT), which seriously affects their quality of life. Studies have found swallowing rehabilitation can improve the swallowing ability of these patients, but the studies have design deficiencies. This study's purpose was to test the effectiveness of personalized swallowing rehabilitation for this patient population.This is a cluster randomized, non-blind, controlled clinical trial. Participants were 68 OC-FFT patients randomly assigned to intervention (n = 34) or control (n = 34) groups. The control group received routine nursing and health education, while the intervention group received personalized swallowing rehabilitation twice a day for 10 days, based on the results of the Mann Assessment of Swallowing Ability-Oral Cancer (MASA-OC). On the 6th and 15th days and 1 month after the operation, MASA-OC scores and percentage weight loss were measured, and the removal time to nasogastric tube was also recorded. The quality of life was evaluated 1 month after the operation.On day 15 and 1 month after the operation, MASA-OC scores were higher and the percentage weight loss was lower in the intervention group than the control group (P lt; 0.05). The removal time of the nasogastric tube was shorter (P lt; 0.05), and the quality of life at 1 month was better in the intervention group (P lt; 0.05).Personalized swallowing rehabilitation can improve patients' swallowing after OC-FFT, promote the early removal of the nasogastric tube, and improve nutritional status and quality of life.

Recent evidence shows that when ischemic stroke (IS) occurs, the BBB would be destructed, thereby promoting the immune cells to migrate into the brain, suggesting that the immune responses can play a vital role in the pathology of IS. As an essential subpopulation of immunosuppressive T cells, regulatory T (Treg) cells are involved in maintaining immune homeostasis and suppressing immune responses in the pathophysiological conditions of IS. During the past decades, the regulatory role of Treg cells has attracted the interest of numerous researchers. However, whether they are beneficial or detrimental to the outcomes of IS remains controversial. Moreover, Treg cells exert distinctive effects in the different stages of IS. Therefore, it is urgent to elucidate how Treg cells modulate the immune responses induced by IS. In this review, we describe how Treg cells fluctuate and play a role in the regulation of immune responses after IS in both experimental animals and humans, and summarize their biological functions and mechanisms in both CNS and periphery. We also discuss how Treg cells participate in poststroke inflammation and immunodepression and the potential of Treg cells as a novel therapeutic approach.文章介绍: 免疫细胞浸润是调控卒中后神经损伤与修复的核心机制。调节性T (Treg) 细胞作为免疫抑制T细胞的重要亚群, 在缺血性脑卒中的病理进程中, 参与维持免疫稳态, 调控免疫反应等作用。既往研究表明, Treg细胞因缺血性脑卒中病理阶段不同而功能各异, 例如, Liesz等人证实, 脑卒中发生7天后, Treg细胞具有神经保护作用; 而Kleinschnitz等人发现, Treg 细胞缺失的DEREG小鼠在脑卒中1天后的梗死体积小于对照组, 证明Treg细胞在其中扮演有害角色。因此, 阐明Treg细胞如何调节缺血性脑卒中后免疫反应十分重要。在本篇综述中, 我们描述了Treg细胞在实验动物和人类发生缺血性脑卒中后的变化特征, 以及该细胞在调节免疫应答中的作用, 并讨论了Treg细胞如何参与缺血性脑卒中后炎症和免疫抑制的分子机制, 提出了Treg细胞作为一种新型细胞治疗方法的潜力及未来的研究方向。.

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1., Once DNA breaks occur, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other DNA repair factors to initiate the repair process. Here, the authors resolve the crystal structures of mouse and human HPF1, and human HPF1/PARP1 complex proving insights into PARP1 regulation.

The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy.To evaluate the safety and maximum tolerated dose of MRG003 in a phase 1a study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study.This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase 1a dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase 1a without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021.An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase 1a. During phase 1b, patients were administered the recommended dose identified in phase 1a.The primary end points were dose-limiting toxic effects in phase 1a and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1.Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase 1a and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase 1a, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively.The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN.Clinicaltrials.gov Identifier: NCT04868344.

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1–60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

Background Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients. Results LCH patients with MAS-HLH were aged P = 0.034). Conclusions LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.

Professor总结张善忱先生在针灸领域主要临床经验与治学思想。先生注重理论探究，著有《针灸甲乙经腧穴重辑》一书，并发表系列文章考证和阐释腧穴之命名；认为临床之参悟须以理论为指导，强调整体综合辨证，树立人体为一有机整体以及与自然相适应等整体观念，加以综合诊断方能有效施治；主张从简取穴，辨虚实而定补泻，针法精炼而合法度，注重加强针下辨气以应之；同时，亦特别重视灸法在临床中的研究与应用，使之与针法相辅相成，两者相宜以成佳效。.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a potentially fatal complication. Sparse published researches evaluated the prognostic value of cardiovascular magnetic resonance feature tracking (CMR-FT) for ICI-associated myocarditis.In the single-center retrospective study, 52 patients with ICI-associated myocarditis and CMR were included from August 2018 to July 2021. The ICI-associated myocarditis was diagnosed by using the clinical criteria of the European Society of Cardiology guidelines. Major adverse cardiovascular events (MACE) were comprised of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.During a median follow-up of 171 days, 14 (27%) patients developed MACE. For patients with MACE, the global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) were significantly worse and native T1 values and late gadolinium enhancement (LGE) extent were significantly increased, compared with patients without MACE (p0.05). The GLS remained the independent factor associated with a higher risk of MACE (hazard ratio (HR): 2.115; 95% confidence interval (CI): 1.379-3.246; p = 0.001) when adjusting for LVEF, LGE extent, age, sex, body mass index, steroid treatment, and prior cardiotoxic chemotherapy or radiation. After adjustment for LVEF, the GLS remained the independent risk factor associated with a higher rate of MACE among patients with a preserved LVEF (HR: 1.358; 95% CI: 1.007-1.830; p = 0.045).GLS could provide independent prognostic value over GCS, GRS, traditional CMR features, and clinical features in patients with ICI-associated myocarditis.• The global circumferential strain (GCS), global radial strain (GRS), and global longitudinal strain (GLS) by cardiovascular magnetic resonance feature tracking were significantly impaired in patients with an immune checkpoint inhibitor (ICI)-associated myocarditis. • GLS was still significantly impaired in patients with preserved left ventricular ejection fraction. • The worse GLS was an independent risk factor over GCS, GRS, traditional CMR features, and clinical features for predicting major adverse cardiovascular events in patients with ICI-associated myocarditis.

China lacks data demonstrating associations of cervical neoplastic lesions with CD4 T‐lymphocyte (CD4 cell) counts and antiretroviral therapy (ART) among HIV‐infected women, suggesting relevant investigations are needed. A total of 545 HIV‐infected women were enrolled in Yunnan, China, between 2011 and 2013. CD4 cell counts and ART were measured via medical records and cervical neoplastic lesions were measured by professional pathologists. Multivariable logistic models, which treated cervical intraepithelial neoplasia (CIN) 1+ and CIN2+ as outcomes, calculated adjusted odds ratio (aOR) of CD4 cell counts and ART. Subgroup analysis treating CIN1+ as the outcome was conducted by HIV infection duration (

Objective There is lack of standardized management and mobilization strategies after oral and maxillofacial reconstruction surgery. We used prospective randomized controlled trials to explore improvements in postoperative mobilization protocol in such patients. Methods A total of 149 patients were randomly divided into tracheotomy control group A (38 cases) and test group A (37 cases), nontracheotomy control group B (38 cases) and test group B (36 cases). Test group patients sat up in bed on the 2nd day after surgery and performed off-bed activity on the 3rd day, whereas control group patients sat up in bed on the 4th day postoperatively and performed off-bed activity on the 6th day. Objective evaluation included free flap success rate, postoperative complications, sleep time, and catheter removal time, among other parameters. Subjective evaluation included postoperative pain and comfort evaluation. Results The success rate of free flaps was 97.3% in test group A and 100% in the other groups. In terms of mean sleep time, 4.6 ± 1.0 h in test group A, which was longer than 4.1 ± 1.0 h in control group A (P = 0.034); 5.7 ± 1.4 h in test group B, which was longer than 4.9 ± 1.7 h in control group B (P = 0.026). Early activity makes catheter removal time (tracheal incision, nasogastric tube, urethral catheter) shorter and gets higher comfort evaluation scores in both test groups versus control groups (P Conclusions The early mobilization protocol for patients undergoing free flap reconstruction was safe, and can effectively improve sleep, shorten the catheter indwelling time, and increase the patient's comfort level.

BACKGROUND This study aimed to investigate frontoparietal network (FPN) dysfunction in participants with migraine without aura (MwoA). MATERIAL AND METHODS We selected 48 age-, sex-, and education level-matched graduate students (24 participants with MwoA [MwoA group] and 24 healthy controls). RS-fMRI and independent component analysis were used to examine the FPN and to compare abnormal encephalic regional homogeneity values. The Mindful Attention Awareness Scale (MAAS), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Self-Rating Scale of Sleep (SRSS) were used to evaluate attention, anxiety, depression, and sleep, respectively. Pearson's correlation was applied to evaluate the association between abnormal brain areas and the scores for each scale. RESULTS Neural function activity in encephalic regions of FPN showed abnormal changes in the MwoA group. The MwoA group had significantly lower MAAS scores (P0.001), higher SAS scores (P0.001), and higher SDS (P=0.06) and SRSS scores (P=0.26). In the MwoA group, functional activity of the right parietal lobule in the left FPN was positively correlated with MAAS scores (P=0.01) and negatively correlated with SAS (P=0.02). The orbital part of left inferior frontal gyrus activity in the right FPN was positively correlated with SDS (P=0.04) and SRSS (P0.001). Right superior marginal gyrus activity in the right FPN was positively correlated with SDS (P=0.02). CONCLUSIONS Abnormal FPN function was correlated with attention, anxiety, depression, and sleep status in the MwoA group. These results offer further insights into the evaluation and treatment of MwoA.

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations., Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.

R0 resection with a wide surgical margin is the gold standard for hepatocellular carcinoma (HCC), yet R0 resection with narrow margins and even R1 resection is not uncommon in real-world clinical practice. We sought to use a propensity-matched analysis to characterize the efficacy of adjuvant radiation therapy on long-term oncological survival after hepatectomy for HCC with narrow or positive margins.Using a multi-institutional database, patients with HCC who underwent hepatectomy with negative margins of 0.1 to 1.0 cm or pathologically positive margins were analyzed. Using propensity score matching (PSM) and multivariate Cox-regression analysis, the effect of adjuvant radiation therapy on long-term overall survival (OS) and recurrence-free survival (RFS) was evaluated.Among 683 patients who met inclusion criteria, 82 patients received adjuvant radiation therapy within 10 weeks after surgery. Radiation therapy-related major toxic effects were minimal among patients receiving adjuvant radiation therapy. PSM analysis created 78 matched pairs of patients. In the PSM cohort, median OS and RFS among patients treated with adjuvant radiation therapy were more favorable than individuals who were not treated (72.5 and 37.3 months versus 52.5 and 24.0 months, both P.05). After adjustment for other confounding factors on multivariate analyses, adjuvant radiation therapy remained independently associated with favorable OS and RFS after hepatectomy with close/positive surgical margins for HCC (hazard ratios, 0.821 and 0.827, respectively).Despite the lack of consensus on the role of adjuvant radiation therapy after HCC resection, this PSM analysis suggested improved OS and RFS with adjuvant radiation therapy after hepatectomy with close/positive surgical margins for HCC. Future randomized controlled trials are needed to further define the survival benefit of adjuvant radiation therapy for patients with HCC.

There is a paucity of data regarding the border zone parameters in patients with chronic coronary total occlusion (CTO). We investigated the border zone extent and contractile function and their associations with collateral flow.CTO patients (n = 47) and sex- and age-matched volunteers (n = 15) were prospectively enrolled and underwent cardiac MRI examinations to acquire cine and late-gadolinium enhancement (LGE) images. Myocardial peak strain (PS) and the time to PS were determined at the segmental level and global level. Infarct, border zone, adjacent, and remote regions were defined according to the transmural extent of infarction (TEI) by LGE at each segment. Angiographic collateral flow was evaluated using the Rentrop grading system.CTO patients with well-developed collateral flow had a higher TEI in border zone regions compared to patients with poorly developed collateral flow (p = 0.02). Conversely, CTO patients with poorly developed collaterals showed a higher TEI in infarct regions (p 0.01). Enhanced border function, characterized by greater PS and earlier time to PS, was noted in well-developed collaterals (all p 0.05). In the multivariate linear analyses, the level of collateral flow was an independent predictor of the border zone extent (β = 0.40, p = 0.02) and contractile function (radial: β = -0.42, p = 0.02; circumferential: β = 0.39, p = 0.02; and longitudinal: β = 0.47, p 0.01).In CTO patients, the presence of well-developed collateral flow was closely linked to a greater extent of LGE and contractile function in border zone regions. Our findings shed light on the cardiac MRI-based pathophysiological underpinning in border zone regions, which could offer complementary and prognostic information in clinical practice.

OBJECTIVE: To explore the characteristics of immune function of healthy full-term infants at the age of 3 months, and to analyze the relationship of immune function with feeding pattern and sex. METHODS: A total of 84 healthy full-term infants born in four hospitals in Beijing and Hohhot, China were prospectively recruited. Their feeding patterns remained unchanged within 4 months after birth. They were divided into a breast-feeding group and a milk powder feeding group according to their feeding patterns. At the age of 3 months after birth, peripheral venous blood samples of the two groups were collected to evaluate cellular immunity and humoral immunity and perform routine blood test. The laboratory indices were compared between infants with different feeding patterns and sexes. RESULTS: Compared with the milk powder feeding group, the breast-feeding group had significantly lower proportion of T cell second signal receptor CD28, immunoglobulin M, and proportion and absolute count of neutrophils (P

The main purpose of the National Nutrition and Health Systematic Survey for children 0-17 years of age in China (CNHSC) was to collect basic data on the nutrition, development, and health status for children in different regions across China using evidence-based, reliable, and cost-effective approaches. Children and their parents or guardians from seven regions (south, southwest, north, northwest, eastern, central, and northeast China) in China were recruited. A multi-stage stratified randomized sampling method was used. Two provinces were randomly sampled from each of the seven regions, from which one urban district and one rural country were also randomly sampled, resulting in a total of 28 survey counties/districts. Dietary surveys, health examinations, laboratory testing, and questionnaires were used to collect dietary intake, nutritional status, child development, and health status information. Nutrition, health, and lifestyle assessment of children and their parents was determined using the Knowledge Attitude Practice (KAP) survey. Greater than 100,000 children (38,000 children6 years of age and 66,000 children 6-17 years of age) completed the survey. The survey provided comprehensive data on child nutrition and health status for future studies and will serve as the basis for an integrated nutrition and health improvement strategies proposal for children in China.

To investigate the effect of high mobility group protein 1(HMGB1) on the proliferation and cytokine expression of human bone marrow mesenchymal stem cells (MSC).Different concentrations of recombinant human HMGB1 protein (100, 200, 400, 800 and 1000 ng/ml) were incubated with MSC for 24, 48, 72 h and the proliferation of MSC were detected respectively by using the CCK-8 method and flow cytometry. The best concentrations of HMGB1 incubated with MSC was determined (200 ng/ml, 1000 ng/ml), and the flow cytomerty was used to determine the effect of HMGB1 on the proliferation of MSC. The mRNA expression levels of IL-10, TGF- β1, TSG-6 and IFN-γ in MSC incubated with HMGB1 protein were detected by real-time quantitative PCR and ELISA.The result of MSC identification and flow cytometry showed that the CD105, CD73 and CD90 were expressed, but did not expression CD45, CD34, CD11b, CD19 and HLA-DR; CCK-8 showed that HMGB1 at the concentrations of 100 ng/ml, 200 ng/ml and 400 ng/ml could promote the proliferation of MSC incubated for 24, 48 and 72 h as compared with the control group (P0.05), and the most effective concentration was 200 ng/ml; flow cytometry showed that the compared with the control group, HMGB1 200 ng/ml could induce MSC from G1 phase to S phase to promote the proliferation of MSC; QPCR showed that the mRNA expression of MSC cytokines IL-10, TGF-β1, TSG-6 increased while IFN-γ decreased at the concentration of 200 ng/ml HMGB1 as compared with the control group. ELISA experiments showed that the HMGB1 200 ng/ml acting on MSC for 48 h could significantly promoted the secretion of IL-10, TGF-β 1 and TSG-6(P0．05), while IFN-γ showed no significant difference as compared with control group.Recombinant human HMGB1 can promote the proliferation and secretion of MSC in healthy people.HMGB1对健康人骨髓间充质干细胞增殖和细胞因子分泌的影响.探讨高迁移率族蛋白1（HMGB1）对健康人骨髓间充质干细胞（MSC）增殖及相关细胞因子分泌的影响.分别用CCK-8法和流式细胞术检测HMGB1对MSC增殖的影响，以不同浓度重组人HMGB1（100、200、400、800和1 000 ng/ml）分别作用MSC 24、48、72 h后，CCK-8法检测不同浓度的HMGB1对MSC增殖的影响。确定HMGB1对MSC作用的最佳实验药物浓度（200和1 000 ng/ml），进一步用流式细胞术明确HMGB1对MSC增殖的影响。采用ELISA与qPCR法检测HMGB1作用前后MSC中IL-10、TGF-β1、TSG-6、IFN-γ的表达水平.MSC的鉴定，流式细胞术检测结果显示，培养细胞表面表达CD105、CD73、CD90，不表达CD45、CD34、CD11b、CD19和HLA-DR。CCK-8法检测HMGB1对MSC增殖的影响发现，与对照组比较，HMGB1 100、200和400 ng/mL作用于MSC 24、48和72 h可明显促进MSC增殖（P0.05），以200 ng/ml浓度作用的增殖效果最明显。流式细胞术检测结果显示，HMGB1于200 ng/ml时可诱导MSC由G1期进入S期，促进MSC增殖。qPCR法检测结果显示，在HMGB1 200 ng/ml作用下，MSC中IL-10、TGF-β1、TSG-6 mRNA较作用前表达增高，IFN-γ表达降低。ELISA实验表明，与对照组比较，HMGB1 200 ng/ml 作用48 h后，MSC分泌的细胞因子IL-10、TGF-β1、TSG-6蛋白水平显著升高（P0.05），IFN-γ蛋白水平无明显变化（P0.05）.重组人HMGB1可促进健康人MSC增殖和影响其细胞因子分泌.

Swallowing disorder is one of the most common postoperative complications for oral cancer patients and seriously influences quality of life. Limited attention has been paid to evaluating swallowing training measures in postoperative oral cancer patients. This study systematically reviewed swallowing training measures for these patients. A comprehensive search strategy was undertaken across various databases for studies published between database inception and 15 June 2021. Raters independently judged titles, abstracts and full articles for selection according to inclusion and exclusion criteria. The included literature was evaluated for quality and data were extracted. Meta-analyses were conducted using RevMan 5.3. Ten intervention studies (four randomized controlled trials and six quasi-experimental studies) involving 588 patients were identified. Across the studies, most started in the early postoperative stage; however, there were differences in starting time, training time and duration, and type of training. We summarized four training methods: oral exercise, oral sensory stimulation, compensatory strategies and protective airway manoeuvres. The meta-analysis indicated that swallowing training could improve patients' swallowing function and quality of life in the short term, but the long-term effects were not obvious. Swallowing training mostly occurred in the early postoperative period and training measures were often used in combination. The timing, frequency and content of interventions varied between studies, and the effectiveness of any single measure was unclear. High-quality randomized controlled trials are necessary to study the efficacy and clinical applicability of various training measures, to provide a theoretical basis for their optimal selection and to develop a standardized training programme for postoperative oral cancer patients.

Background: Hypertension is associated with increased postoperative risk. However, no consensus was accepted whether elevated blood pressure in the operating room with normal blood pressure at rest related to additional cardiovascular risk. Methods: This was a single-center retrospective cohort study based on patients who underwent elective noncardiac surgery from 1 January 2012, to 31 December 2018. We evaluated the relationship between the delta SBP (the difference between first operating room blood pressure and baseline blood pressure) and the development of postoperative major adverse cardiac events (MACEs) in patients with normal baseline blood pressure. Multivariate logistic regression before and after propensity score weighting was performed to adjust for perioperative variables, and the minimum P value approach was used to identify the possible threshold of delta SBP that independently indicated the risk of MACE. Results: Of the 55 563 surgeries, in 4.1%, postoperative MACE occurred. The threshold for the delta SBP was 49 mmHg. The adjusted odds ratio for MACE before and after propensity score weighting for the delta SBP threshold was 1.35 (95% CI, 1.11--1.59); P less than 0.001 and 1.28 (1.03–1.60); P = 0.028, respectively. Conclusion: Delta SBP contributed to the elevated risk over and beyond the SBP at rest in patients who underwent elective noncardiac surgery. A rise of SBP of more than 49 mmHg from baseline in the operating room was significantly associated with an increased risk of postoperative MACE.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. The factors influencing CINV in breast cancer patients remain unclear. In this study we developed a nomogram for predicting the occurrence of CINV in this group using prospective clinical data from multiple sources Methods: We pooled data from several studies conducted in China on CINV caused by emetogenic chemotherapy. Demographic and clinical variables of 334 breast cancer patients at Hunan Cancer Hospital (training set) were analyzed to identify factors associated with CINV by multivariate logistic regression and construct a prediction nomogram. The external validation set comprised an additional 66 patients. The reliability of the nomogram was assessed by bootstrap resampling, and C-index and receiver operating characteristics curve (ROC) analyses were carried out to assess its discriminatory power. Results: Four risk factors were associated with CINV: history of CINV, chemotherapy target regimen, metastasis, and symptoms of distress. The C-index was 0.69 (95% confidence interval [CI], 0.63–0.75) for the training set and 0.83 (95% CI, 0.73–0.93) for the validation set. The area under the ROC curve indicated that the model had a specificity of 68.5% and 86.1% and sensitivity of 57.7% and 56.7%, for the training and validation sets, respectively. Calibration curves showed good concordance between predicted and actual occurrence of CINV. Conclusions: The developed nomogram can reliably predict the occurrence of CINV in breast cancer patients based on 4 variables, which can aid in clinical decision-making.

Background:. Delivery room resuscitation assists preterm infants, especially extremely preterm infants (EPI) and extremely low birth weight infants (ELBWI), in breathing support, while it potentially exerts a negative impact on the lungs and outcomes of preterm infants. This study aimed to assess delivery room resuscitation and discharge outcomes of EPI and ELBWI in China. Methods:. The clinical data of EPI (gestational age [GA]

BACKGROUND: Diastolic dysfunction is common and may increase the risk of cardiovascular complications. This study investigated the hypothesis that, in patients with isolated left ventricular diastolic dysfunction, higher grade diastolic dysfunction was associated with greater risk of major adverse cardiovascular events (MACEs) after surgery. METHODS: This was a retrospective cohort study. Data of adult patients with isolated echocardiographic diastolic dysfunction (ejection fraction, ≥50%) who underwent noncardiac surgery from January 1, 2015 to December 31, 2015 were collected. The primary end point was the occurrence of postoperative MACEs during hospital stay, which included acute myocardial infarction, congestive heart failure, stroke, nonfatal cardiac arrest, and cardiac death. The association between the grade of diastolic dysfunction and the occurrence of MACEs was assessed with a multivariable logistic model. RESULTS: A total of 2976 patients were included in the final analysis. Of these, 297 (10.0%) developed MACEs after surgery. After correction for confounding factors, grade 3 diastolic dysfunction was associated with higher risk of postoperative MACEs (odds ratio, 1.71; 95% confidence interval, 1.28–2.27; P < .001) when compared with grades 1 and 2. Patients with grade 3 diastolic dysfunction developed more non-MACE complications when compared with grades 1 and 2 (uncorrected odds ratio, 1.44; 95% confidence interval, 1.07–1.95; P = .017). CONCLUSIONS: In patients with isolated diastolic dysfunction undergoing noncardiac surgery, 10.0% develop MACEs during hospital stay after surgery; grade 3 diastolic dysfunction is associated with greater risk of MACEs.

Background PD-1/PD-L1 blockade has received approval for clinical application due to its encouraging benefit with improving prognosis in selected populations. Unfortunately, the response to immunotherapy for many patients remains unsatisfactory. It remains a great challenge to generate potential combinations that will outperform single agents alone with regard to anti-tumor activity. Methods Using NSCLC cell lines and mouse models, we explored the effects of combined niclosamide and PD-L1 blockade on tumor growth and T cell function. Furthermore, we investigated the relationship between PD-L1 and p-STAT3 expression in tumor samples from patients with NSCLC using IHC, as well as their relationship to patient survival. Results In vitro, niclosamide, an antihelmintic drug, enhanced the cancer cell lysis mediated by T cells in the presence of PD-L1 blockade. Accordingly, mice treated with niclosamide and PD-L1 antibody showed significant delay in tumor growth and increased survival which were associated with the increase of tumor infiltrating T cells and granzyme B release. Importantly, we found niclosamide could decrease the expression of PD-L1 in both a concentration- and time-dependent manner in NSCLC cells, which was linked to the blockage of p-STAT3 binding to the promoter of PD-L1. Conclusions An enhancement of PD-L1 antibody by niclosamide was observed in inhibition of NSCLC growth in vitro and in vivo, which was involved in blockage of p-STAT3 binding to promoter of PD-L1 and finally downregulation of PD-L1 expression. These encourage the combination therapy of niclosamide and PD-1/PD-L1 blockade to be further studied in clinic. Supplementary information Supplementary information accompanies this paper at 10.1186/s40425-019-0733-7.

Objective To investigate whether miR-203a-3p can regulate the biological behaviors of ovarian cancer cells by targeting ATM to affect the Akt/GSK-3β/Snail signaling pathway. Methods The expression levels of miR-203a-3p and ATM were detected by qRT-PCR, immunohistochemical staining and Western blotting in ovarian cancer tissues and adjacent normal tissues obtained from 152 subjects. A dual-luciferase reporter gene assay was performed to verify the relationship between miR-203a-3p and ATM. Human ovarian cancer cell lines (A2780 and SKOV3) were used to generate the Blank, miR-NC, miR-203a-3p mimic, Control siRNA, ATM siRNA, and miR-203a-3p inhibitor + ATM siRNA groups. The biological behaviors of ovarian cancer cells were evaluated by CCK-8, wound healing, and Transwell invasion assays, annexin V-FITC/PI staining and flow cytometry. The levels of Akt/GSK-3β/Snail pathway-related proteins were assessed by Western blotting. Results Ovarian cancer tissues showed lower miR-203a-3p levels and higher ATM levels than adjacent normal tissues, both of which were associated with the FIGO stage, grade and prognosis of ovarian cancer. As confirmed by a dual-luciferase reporter gene assay, miR-203a-3p could target ATM. Furthermore, the miR-203a-3p mimic had multiple effects, including the inhibition of the proliferation, invasion and migration of A2780 and SKOV3 cells, the promotion of cell apoptosis, the arrest of the cell cycle at the G1 phase, and the blockage of the Akt/GSK-3β/Snail signaling pathway. ATM siRNA had similar effects on the biological behaviors of ovarian cancer cells, and these effects could be reversed by a miR-203a-3p inhibitor. Conclusion miR-203a-3p was capable of hindering proliferation, migration, and invasion and facilitating the apoptosis of ovarian cancer cells through its modulation of the Akt/GSK-3β/Snail signaling pathway by targeting ATM, and therefore it could serve as a potential therapeutic option for ovarian cancer.

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.

Bufaviruses are small, nonenveloped, single-stranded DNA viruses belonging to the subfamily Parvovirinae. Human bufaviruses were first identified in 2012 in fecal samples from children with diarrhea. A new parvovirus of canines that was first detected in various samples from dogs with enteric and respiratory symptoms in Italy between 2014 and 2018 is closely related to the newly described human bufavirus. To explore the prevalence and genetic diversity of CBuV in Chinese dogs, 540 canine parvovirus (CPV)-positive serum and diarrhea samples were collected in Guangxi Province between 2016 and 2018. Among the samples, 6.25% (5/80) of rectal swabs and 2.5% (5/200) of CPV PCR-positive samples were positive for CBuV. However, the virus was not detected in CPV PCR-negative samples or nasal swabs. Two CBuV isolates were identified from CPV-positive fecal and serum samples by complete sequence analysis, with 99.8%–99.9% NS1 and VP2 protein identity to each another. Sequence analysis indicated that the CBuV GXNN01-2018 isolate VP2 protein shares 99.6% identity with the Italian CBuV ITA/2015/297 isolate and 62.3%–65.5% identity with human bufavirus. Phylogenetic analysis showed that CBuV was significantly distinct from other known bufaviruses and was most closely related to CBuV ITA/2015/297. This is the first report of the existence of CBuV in China, and our findings will strengthen the understanding of the epidemiology of bufaviruses in different animals.

The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1. Functionally, MID deletion results in the loss of self-renewal of mouse embryonic stem cells. Together, our data pinpoint NRDE2 as a nuclear exosome negative regulator that ensures mRNA stability and nuclear export.

The chalcone motif can be found in many molecules that contribute to essential biological processes, and many chalcone-containing compounds exhibit potent anti-cancer activity. Here, we synthesized two series of chalcone analogues (3a−s and 6a−s) based on substituting the chalcone B-ring or A-ring with a 4-oxoquinazolin-2-yl group, and then evaluated them for cytotoxic activity in human colorectal HCT-116 and breast cancer MCF-7 cell lines. Compounds 3a−s (in which a 4-oxoquinazolin-2-yl group functioned as the B-ring) were markedly more cytotoxic than compounds 6a−s (in which 4-oxoquinazolin-2-yl group functioned as the A-ring), based on their IC50 values to inhibit proliferation. Compound 3f was found as the most potent among 38 analogues and the mechanism of its cytotoxicity was investigated. Flow cytometry indicated that HCT-116 cells treated with compound 3f resulted in a dose-dependent accumulation of cells in the sub-G1 phase, which is representative of apoptotic cells. Subsequent assays (including Annexin V-FITC/PI, AO-EB, MitoSOX™ Red and JC-1 staining) confirmed that 3f exposure induced apoptosis in HCT-116 cells. Immunoblotting analysis indicated that cellular exposure to 3f increased the cleavage of PARP1 and caspases 3, 7, and 9. Taken together, this novel chalcone analogue has a cytotoxic effect on cultured cancer cell-lines that is likely mediated by inducing apoptosis via the mitochondrial death pathway.