Search

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p., Graphical abstract, Transcription factor SRF and NF-κB p65 regulate the co-expression of miR-199a-5p and -3p by positive feedback in the pathological cardiac remodeling. Ppargc1a and Sirt1, Rb1 and Smad1 mediate the pathological role of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively.

OBJECTIVE: Surgery is considered a relative contraindication in sarcoma tumor. Because of the unique characteristics of heart, whether surgery is optimally chosen in primary cardiac sarcoma (PCS) is unknown. In this study, we aimed to evaluate the 1-year survival after surgery for PCS. METHODS: Patients with PCS from the Surveillance, Epidemiology, and End Results Database (SEER) between 1975 and 2015 were recruited. The endpoints were defined as 1-year all-cause mortality (ACM) and 1-year cancer-specific mortality (CSM). RESULTS: The study population consisted of 335 patients diagnosed with PCS. The 1-year ACM and CSM were 49.0% and 42.1% respectively. The Kaplan-Meier curves revealed that decreased 1-year ACM&CSM were significantly associated with surgical treatment. Multiple COX regression analysis, surgery, and chemotherapy showed a significantly decreased rate of 1-year ACM and CSM. The adjusted hazard ratio of surgery was significant when the year of diagnosis was ≥2000, patients were aged 0.05). No interaction effects were detected between the variables and surgery (all p for interaction >0.05). CONCLUSION: Surgery should be highly recommended in patients with PCS to improve the 1-year survival rate, especially in younger patients with localized SEER stage and non-chemotherapy management.

Background Anthracycline‐based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. Methods We retrospectively analyzed the data of a nation‐wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). Results In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline‐taxane‐based combinations for neo‐ and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40‐65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease‐free survival (p < 0.001) were more likely to be recommended to ABC. Conclusion Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China., The nation‐wide study revealed that anthracycline‐based chemotherapy (ABC) remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy, and was predominantly used as a combination therapy. The correlation between clinicopathological characteristics and ABC choice varied at different settings, suggesting the preference and different perspectives of medication regarding the use ABC in China. The real‐world data contribute to guide the selection of the appropriate treatment and maximize the benefit of chemotherapy for patients.

BACKGROUND Advanced breast cancer (ABC) is difficult to treat due to the primary and acquired resistance, which is the main cause of rescue treatment failure. Thus, developing a new rescue treatment strategy for clinicians is a challenge. This study retrospectively collected the medical information of patients with refractory ABC who were treated with bevacizumab at our department to analyze the efficacy and safety of bevacizumab-containing therapy as a new treatment method for refractory ABC. METHODS The complete medical information of patients receiving bevacizumab treatment from November 2017 to November 2020 was collected, and patients' general medical history and disease characteristics were analyzed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), and safety were also analyzed using SPSS 20.0 statistical software. RESULTS The data of 68 women with refractory ABC who received bevacizumab-containing therapy were collected. The last follow-up examinations were performed on March 31, 2021. The ORR was 41.2% and the DCR was 88.2%. The median PFS, TTF, and OS were 6.0 months [95% confidence interval (CI): 3.4-8.6 months], 4.0 months (95% CI: 3.2-4.8 months), and 26.6 months (95% CI: 10.2-43.0 months), respectively. Treatment was discontinued in 2 patients due to chemo-related adverse reactions. The main adverse events related to bevacizumab were hypertension (7.4%) and bleeding (2 cases, 2.9%), both of which were grade 1. No specific adverse events causing the discontinuation of bevacizumab treatment were observed in the other patients. CONCLUSIONS Among patients with refractory ABC, bevacizumab-containing therapy is feasible and safe, and can be used as a new treatment strategy. However, the question of who can benefit the most from bevacizumab-containing therapy requires further exploration.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Background Patients undergoing cardiac operation are susceptible to anemia. Low hemoglobin concentration is a risk factor for composite adverse events and death after cardiac operation. Here we investigated the association of postoperative nadir hemoglobin with adverse outcomes in patients undergoing on-pump cardiac operation. Methods Adult patients in 2 medical centers were retrospectively analyzed. The primary outcome was postoperative composite adverse events. The secondary outcome was all-cause death in the hospital. Results Of the 8206 patients analyzed, 1628 (19.8%) experienced composite adverse events after operation and 109 (1.3%) died. Patients receiving on-pump cardiac operation with nadir hemoglobin of 9.0 to 9.9 g/L showed a low incidence of composite adverse events (175 of 1423 [12.3%]) and death (5 of 1423 [0.4%]). Compared with nadir hemoglobin at 9.0 to 9.9 g/dL, the relative risk (RR) of composite adverse events increased stepwise as nadir hemoglobin fell below 9.0 g/dL: adjusted RR was 1.44 (95% confidence interval [CI], 1.14-1.83) for 8.5 to 8.9 g/dL, 1.56 (95% CI, 1.23-1.99) for 8.0 to 8.4 g/dL, 1.66 (95% CI, 1.31-2.11) for 7.5 to 7.9 g/dL, 2.22 (95% CI, 1.75-2.83) for 7.0 to 7.4 g/dL, and 4.00 (95% CI, 3.18-5.04) for less than 7 .0 g/dL. Furthermore, the risk of death was significantly higher when nadir hemoglobin was below 7.0 g/dL than when it was 9.0 to 9.9 g/dL (RR, 5.36; 95% CI, 2.20-16.12). Conclusions Compared with the risks when nadir hemoglobin is 9.0 to 9.9 g/dL, the risk of composite adverse events increases when postoperative nadir hemoglobin is below 9.0 g/dL, whereas risk of death increases when nadir hemoglobin is below 7.0 g/dL.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1–T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1–T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1–T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov)

Background Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Methods Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. Results HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). Conclusions These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

Structured abstractLay abstract In this study, we aimed to elucidate the therapeutic mechanism of miRNA (miR)-498 in autophagy and macrophage polarization to M2-like phenotype in esophageal cancer. This study reports lower miR-498 expression in esophageal cancer tissues compared with adjacent normal tissues. According to the experimental results, miR-498 negatively targets MDM2 by binding to its 3′UTR, which leads to attenuated ubiquitination and degradation of ATF3 induced by MDM2. Specifically, overexpressed miR-498 reduces ratio of LC3II (a marker that is commonly utilized to detect cell autophagy) to LC3I and increases p62 (a common cargo receptor for autophagy) accumulation in KYSE-150 cells, and elevates macrophage polarization to M2-like phenotype by depressing MDM2-mediated ATF3 degradation. The present study deepened our understanding of the causes of esophageal cancer and provided at least three novel therapeutic targets for the development of effective targeted therapy for esophageal cancer.

Objective: To quantify the potential benefit of adjuvant chemotherapy (ACT) with respect to survival, and to identify factors for predicting prognoses in early gastric cancer patients. Methods: Patients with pT1 gastric cancer (GC) who underwent radical resection with D2 lymphadenectomy were retrospectively analyzed. Based on lymph node metastasis (LNM) status and treatment regimens, patients were classified into groups, and clinicopathological variables, overall survival (OS), and disease-specific survival (DSS) were compared. Results: Of 1,050 enrolled patients, 151 patients (14.4%) had a positive LNM status. Submucosal invasion, undifferentiated state, tumor size > 2 cm, ulceration, and lymphovascular invasion were independent risk factors for LNM using multivariate analyses. The 5-year OS of all patients was 96.4%. HER2 positive, perineural invasion, and LNM were independent factors for worse survival. Patients with pT1N3 GC had a worse 5-year OS and DSS than pT1N0, pT1N1, and pT1N2 patients (P < 0.001). The 5-year OS and DSS for pT1N1 patients showed no significant difference between ACT and surgery only patients. For pT1N2 patients, the 5-year OS and DSS showed no significant difference between S-1 and Xelox treatments. For pT1N3 patients, 7 (36.8%) received S-1, while 12 (63.2%) received Xelox treatment. Patients receiving Xelox treatment showed a better 5-year OS (75.0% vs. 14.3%) and DSS (81.8% vs. 20.0%) than patients receiving S-1 (P < 0.05). Conclusions: Curative surgery only was adequate for patients with pT1N0 and pT1N1. Xelox showed no survival benefits for pT1N2 patients. Therefore, S-1 is the optimal choice for pT1N2 patients, when considering adverse effects. Xelox is recommended for pT1N3 patients.

ObjectiveThis meta-analysis aimed to reach a summarised estimate of distress prevalence screened by Distress Thermometer (DT) among patients with breast cancer and compare different pooled prevalence estimated between different subgroups.MethodsTwo independent interviewers conducted a systematic search from PubMed, EMBASE, Ovid and Cochrane Library and checked related reviews and meta-analyses for eligible studies. The studies that identified distress of patients with breast cancer with DT were included. After extracting demographic characteristics and distress prevalence, the pooled analysis and the forest plot were completed by using STATA V.12.0 software. We conducted a subgroup analysis based on demographic and methodological characteristics of the studies. The publication bias was estimated by funnel plot.ResultsSeventeen studies describing 3870 patients with breast cancer were included in this meta-analysis. The distress prevalence of patients with breast cancer varied from 25.3% to 71.7% among these studies. The pooled distress prevalence was 50% (95% CI 49% to 52%) for the overall sample. The pooled distress prevalence rates in DT ≥7, DT ≥5 and DT ≥4 subgroups were 37% (95% CI 35% to 40%), 45% (95% CI 40% to 49%) and 62% (95% CI 60% to 65%), respectively. The distress prevalence had statistically significant differences between subgroups, which were differentiated by the initial time of distress identified, papers’ publication time, patients’ average age and country. There was no publication bias among the included studies.ConclusionThe distress prevalence was high among patients with breast cancer. Routine and timely screening of distress for patients with breast cancer is of great significance in oncology management.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.

Increasing evidence has shown that microRNAs (miRNAs) participate in cardiac fibrosis. We aimed to elucidate the effect of miRNA miR-25-3p on cardiac fibrosis. MiRNA microarray was used to profile miRNAs in the myocardium of angiotensin-II (Ang-II)-infused mice. Effect of miR-25-3p on expression of fibrosis-related genes, including Col1a1, Col3a1, and Acta2, was investigated both in vitro and in vivo. MiR-25-3p was shown increased in the myocardium of Ang-II-infused mice and patients with heart failure. MiR-25-3p enhanced fibrosis-related gene expression in mouse cardiac fibroblasts (mCFs) and in the myocardium of Ang-II-infused mice. Dickkopf 3 (Dkk3) was identified as a target gene of miR-25-3p, and Dkk3 could ameliorate Smad3 activation and fibrosis-related gene expression via enhancing Smad7 expression in mCFs. Additionally, NF-κB signal was proven to mediate upregulation of miR-25-3p in cardiac fibrosis. Our findings suggest that miR-25-3p enhances cardiac fibrosis by suppressing Dkk3 to activate Smad3 and fibrosis-related gene expression.

Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Funding Jiangsu Hengrui Medicine and National Key R&D Program of China. Translations For the Chinese translation of the abstract see Supplementary Materials section.

Tuberous sclerosis complex is a type of genetic multisystem disease that causes hamartomas in various organs. Facial angiofibromas commonly occur in 80% of patients and are prominently distributed over the cheek, chin, and nasolabial folds with severe disfigurement and emotional distress. Recently, photoelectric devices have been identified for the treatment of angiofibromas with great efficacy and fewer side effects. We report a case of a 42-year-old man with facial angiofibromas, who was treated with a combination of high-frequency electrocauterization, Ultrapulse CO2 laser, and microneedle fractional radiofrequency with 7 sessions and a 6-month follow-up. The patient showed great improvement in relation to the elevated lesions and nodules. A low recurrence rate was observed. This is the first study to investigate the efficacy of high-frequency electrocauterization and microneedle fractional radiofrequency in angiofibromas. It may provide an optimal approach for clinicians wherein a combined treatment of various lasers and electric devices is effective for complicated, protuberant, and firm angiofibromas of specific patients.

Background: In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4&6 inhibitor abemaciclib in combination with non-steroidal aromatase inhibitors (NSAI) or with fulvestrant compared with placebo demonstrated its efficacy and acceptable safety profile at interim analysis in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locoregionally recurrent or metastatic breast cancer. One of the most common treatment-emergent adverse event (TEAE) was diarrhea, typically low grade and of early onset. We will further characterize abemaciclib-associated diarrhea and describe its management in MONARCH plus trial. Methods: MONARCH plus study included two cohorts of patients. Cohort A enrolled patients with initial treatment of endocrine therapy, received abemaciclib or placebo plus NSAI (anastrozole or letrozole); Cohort B enrolled patients who progressed on prior endocrine therapy, receiving abemaciclib or placebo plus fulvestrant. The relative dose intensity was defined as the percentage of actual dose received relative to the planned dose. The severity of diarrhea was reported by investigators and graded according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Further analysis on diarrhea included time to onset, duration, supportive medication and dose modifications. Progression-free survival (PFS) was defined as time from randomization to death or progression (RECIST v1.1), and a stratified Cox proportional hazard model was used to estimate the hazard ratio (HR) between study intervention arm and placebo arm. Results: The median relative dose intensity of abemaciclib in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm were 96.77% and 96.30% respectively. In abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, the median time to onset of first reported diarrhea was 7 and 6 days and majority of diarrhea events occurred early (66.3% and 71.2% of patients reported diarrhea in Cycle 1 respectively). Diarrhea was typically of low grade (3.9% and 1.9% of patients reported Grade 3 in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, no Grade 4 diarrhea was reported in either arm). Median duration of grade ≥ 3 diarrhea was 2.5 and 3.5 days. Diarrhea was managed by dose adjustments and/or supportive medication (Table 1). Dose reductions were present in 2.0% and 2.9% of patients, and anti-diarrhea therapy was received in 30.2% and 32.7% of patients with abemaciclib plus NSAI and abemaciclib plus fulvestrant arm, respectively. As data cutoff, most diarrhea events were reported as resolved, and the incidence dropped below 10% (Grade 2) and 1% (Grade 3) by Cycle 2 in both arms and kept low incidence over time. Compared to the placebo arm, patients treated with abemaciclib combination who reported diarrhea within the first 7 days (abemaciclib + NSAI, HR [95% CI]: 0.289 [0.166, 0.502]; abemaciclib + fulvestrant, HR [95% CI]: 0.371 [0.213, 0.647]) had significant improvement in PFS. Conclusion: Majority of diarrhea events were of low grade in severity and well managed by anti-diarrheal medications, dose omissions or/and dose reductions in MONARCH plus patients. Table 1. Summary of dose adjustments and supportive medications in patients experiencing diarrheaCohort ACohort BAbemaciclib + NSAIAbemaciclib + FulvestrantN = 205N = 104Diarrhea (any grade), n (%)164 (80.0)82 (78.8)1105 (51.2)52 (50.0)251 (24.9)28 (26.9)38 (3.9)2 (1.9)Outcome, number of events, n796333Recovered/resolved, n (%)757 (95.1)318 (95.5)Not recovered/resolved, n (%)17 (2.1)7 (2.1)Treatment change, n (%)Dose reduction4 (2.0)3 (2.9)Dose omission3 (1.5)3 (2.9)Treatment discontinuation00Anti-diarrhea therapies, n (%)62 (30.2)34 (32.7)loperamide48 (23.4)21 (20.2)berberine6 (2.9)6 (5.8) Citation Format: Zefei Jiang, Xichun Hu, Qingyuan Zhang, Tao Sun, Yongmei Yin, Huiping Li, Min Yan, Zhongsheng Tong, Christina Pimentel Oppermann, Yunpeng Liu, Romulo Costa, Man Li, Xi Chen, Ying Cheng, Quchang Ouyang, Ning Liao, Xiaojia Wang, Xinhong Wu, Jifeng Feng, Roberto Hegg, Govindbabu Kanaka Setty, Amit Agarwal, Jyoti Bajpai, Jing Cheng, Gustavo Girotto, Chanchal Goswami, Wenjing Hu, Jian Huang, MA Coccia Portugal, Jin Yang, Rongsheng Zheng, Fabio Andre Franke, Qiang Liu, Yunjiang Liu, Yongkui Lu, Cristiano Souza, Shiying Yu, Nalini Kilara, Harsha Panchal, Ashish Singh, Shona Nag, Jian Liu, Bernardo Rapoport, Neonyana Keorapetse Rebecca Tabane, Hongxia Wang, Ning Wang, Rubing Han, Wanli Zhang. Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analysis of the MONARCH plus study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-25.

Objective: To preliminary study the significance of low molecular weight heparin (LMWH) in the treatment patients of with anemia of chronic diseases (ACD), and the changes in the serum levels of BMP6, hepcidin and IL-6. To preliminary study the significance of low molecular weight heparin (LMWH) in the treatment the patients with anemia of chronic diseases (ACD), and the changes in the serum levels of BMP6, hepcidin and IL-6. Methods: Used LMWH (4000 u/day, 7 - 15 days) to therapy 61 patients with ACD, and ELISA method was used to determine Hepcidin and BMP6 before and after treatment, and the determination of IL-6 by Electro-chemi-luminescence, and to analyze its clinical significance. Results: 1) In all 61 cases, the levels of Hepcidin in post-therapy were 0.82 ± 0.24 mg/L, which were lower than 1.05 ± 3.83 mg/L in pre-therapy (t = 2.5726, P P P > 0.05). However, The levels of Hb in post-therapy were higher than in pre-therapy (t = 1.9832, P P P P P > 0.05). 5) Although Hb level increased slightly in the non-tumor anemia group, there was no statistical significance (P > 0.05), and there was no statistical difference in other indexes (all P > 0.05). 6) After treatment, the level of Hb was negatively correlated with Hepcidin and IL-6 (respectively r = -0.2809, t = 2.2490, P P P < 0.05). There was no correlation between BMP6 and Hb, Hepcidin and IL-6 levels. Conclusion: LMWH could up-regulate the levels of Hb, and better for the degree of anemia in patients with ACD. The possible mechanism is to reduce the level of Hepcidin and IL-6.

Background: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. Objectives: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. Methods: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving Results: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. Conclusion: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

Introduction Previous studies of herpes zoster (HZ) have focused on acute patient manifestations and the most common sequela, postherpetic neuralgia (PHN), both serving to disrupt brain dynamics. Although the majority of such patients gradually recover, without lingering severe pain, little is known about life situations of those who recuperate or the brain dynamics. Our goal was to determine whether default mode network (DMN) dynamics of the recuperative population normalize to the level of healthy individuals. Methods For this purpose, we conducted resting‐state functional magnetic resonance imaging (fMRI) studies in 30 patients recuperating from HZ (RHZ group) and 30 healthy controls (HC group). Independent component analysis (ICA) was initially undertaken in both groups to extract DMN components. DMN spatial maps and within‐DMN functional connectivity were then compared by group and then correlated with clinical variables. Results Relative to controls, DMN spatial maps of recuperating patients showed higher connectivity in middle frontal gyrus (MFG), right/left medial temporal regions of cortex (RMTC/LMTC), right parietal lobe, and parahippocampal gyrus. The RHZ (vs HC) group also demonstrated significant augmentation of within‐DMN connectivity, including that of LMTC‐MFG and LMTC‐posterior cingulate cortex (PCC). Furthermore, the intensity of LMTC‐MFG connectivity correlated significantly with scoring of pain‐induced emotions and life quality. Conclusion Findings of this preliminary study indicate that a disrupted dissociative pattern of DMN persists in patients recuperating from HZ, relative to healthy controls. We have thus provisionally established the brain mechanisms accounting for major outcomes of HZ, offering heuristic cues for future research on HZ transition states., It is the first time to demonstrate that a disrupted dissociation pattern of DMN still exists in recuperative herpes zoster patients compared with healthy controls even the rash disappeared and pain was relieved. This study could provide heuristic cues for future research about herpes zoster transition mechanism.

Background: Postherpetic neuralgia (PHN) is one of the most common complications of herpes zoster (HZ). Heritable factors have been found to play a role in various clinical pain symptoms. However, the effect of gene variability on the susceptibility of PHN remains poorly understood. Objectives: The aim of this study was to evaluate whether genetic variation in pain pathway genes was associated with PHN susceptibility in the Chinese population. Study Design: Case–control study. Setting: Department of Anesthesiology and Pain Medicine in a university hospital. Methods: Seventy patients with PHN and 111 patients with HZ without developing PHN were enrolled. All patients received standardized antiviral agents and analgesics as needed during the acute phase of HZ. Twenty-four candidate genetic polymorphisms in 12 genes (IL1B, SCN9A, KCNK9, TRPV1, P2RX7, HTR1A, HTR2A, ADRB1, ADRB2, BDNF, COMT, and OPRM1) were genotyped in all patients. Multivariable logistic regression analyses were used to identify genetic variations associated with PHN susceptibility while controlling for potential confounders. Results: Our results suggested that only variation in P2RX7 gene was associated with PHN susceptibility. The P2RX7 rs7958311 AG heterozygous genotype carriers had a decreased risk for PHN in the overdominant model (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.21–0.77; P = 0.005), and codominant model (OR, 0.44; 95% CI, 0.20–0.98; P = 0.045). The P2RX7 rs7958311 GG homozygote genotype was associated with an increased risk for PHN under a recessive model (OR, 2.15; 95% CI, 1.01–4.56; P = 0.046). There were no significant associations between the other 23 single-nucleotide polymorphisms and PHN susceptibility. Limitations: Lack of validation cohort to verify the findings. Conclusions: In the present study in the Chinese population, we found purinergic receptor P2X7 rs7958311 may contribute to PHN development after HZ. Future larger independent cohorts are warranted to replicate these initial findings. Key words: Herpes zoster, postherpetic neuralgia, polymorphisms

Outbreaks of avian orthoreovirus (ARV) infection with primary symptoms of arthritis/tenosynovitis syndrome have been occurring more frequently in broiler flocks in China in recent years. This study aimed to investigate the genetic characteristics of ARV field strains in broiler flocks exhibiting arthritis/tenosynovitis syndrome from 9 cities in Shandong province during 2015 to 2017. A total of 64 synovial and tendon samples were obtained from broilers with significant arthritis/tenosynovitis syndrome, and 21 ARV field strains were obtained. Phylogenetic analysis of the σC nt/aa sequences revealed that only 4 isolates were clustered in genotype I, including vaccine strains S1133, 1733, and most of the ARV field strains identified previously in China. Eleven and 6 ARV field isolates were identified in genotypes II and V, sharing 70.9 to 76.0% and 53.0 to 55.2% nt identities with the vaccine strains, respectively. Previous studies in China have not reported these 2 serotypes of field strains, and prevalence of these ARV variants may be increasing in Chinese broiler flocks. Results of this study suggest that large-scale investigation of epidemic ARV should be conducted to explore the genetic diversity of ARV field isolates in China.

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/mOf 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

Summary: Background: Endoscopic submucosal dissection (ESD) has gained more popularity in the treatment of early gastric cancer (EGC). Although there is a lack of confirmed evidence for the feasibility of ESD for undifferentiated EGC. The aim of the study was to investigate the feasibility of ESD with expanded indications for undifferentiated EGC patients. Methods: Data from patients with undifferentiated EGC (including signet-ring cell carcinoma, mucinous adenocarcinoma, mixed adenocarcinoma, and poorly differentiated adenocarcinoma) who underwent radical surgical resection were retrospectively reviewed. The relationship between the clinical parameters and the incidence of lymph node metastasis (LNM) was investigated. Results: A total of 517 patients were included in this study. The results showed that LNM was significantly associated with ulceration, tumor size, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate stepwise logistic regression analysis revealed that tumor size (OR = 1.61, 95% CI = 1.03–2.52, P = 0.0367), depth of tumor invasion (OR = 2.77, 95% CI = 1.66–4.63, P = 0.0001), and lymphatic invasion (OR = 14.74, 95% CI = 1.58–137.36, P = 0.0182) were independent risk factors for LNM. In the patients who would be included under the new proposed guidelines for ESD, including men with mucosal tumors ≤2 cm and without ulceration or lymphatic or venous infiltration, LNM was present in 11.9% (14/118). Conclusion: Caution to be exercised in expanding application of ESD should be carefully weighed in undifferentiated EGC. Keywords: Early gastric cancer, Endoscopic submucosal dissection, Expanded indication, Lymph node metastasis

Sudden sensorineural hearing loss is a common otologic disease in clinic. Systemic and intratympanic steroid treatment have been proved to be effective, but the regimens vary from center to center. The purpose of the study is to analyze the effects of the combined application of intravenous dexamethasone and intratympanic methylprednisolone injection in different time strategies for the treatment of unilateral sudden sensorineural hearing loss. A retrospective chart review was performed for the period from March 2016 to June 2018 at our Department of Otorhinolaryngology—Head and Neck Surgery. A total number of 61 patients who met the academy criteria for unilateral sudden hearing loss were included and grouped based on the time to introduce intratympanic methylprednisolone. All the patients received intravenous dexamethasone 10 mg once daily for 5 days, followed 5 mg once daily for the next 7 days. Intratympanic methylprednisolone (40 mg) was injected every other day 4 times into all patients. This regimen was commenced on day 1 in group 1 and on day 6 in group 2. The pre and posttreatment pure-tone audiograms were analyzed. Sixty-one patients met our inclusion criteria. No significant differences were observed between patients’ demographics or pretreatment hearing thresholds. In the 3 months posttreatment pure-tone audiogram assessment, the mean hearing threshold improvement were similar between groups with no frequency specificity. The curative rate in both groups were similar and satisfying. Two patients with diabetes mellitus had persistent small perforations. Some patients had other transient discomfort that disappeared before discharge. The different timing of initiation of intratympanic methylprednisolone injection does not significantly affect the outcome of the treatment for sudden sensorineural hearing loss. Thus, we suggest that intratympanic steroid injection should not be applied as a first-line method except for patients who do not respond early to systemic steroid therapy.

Glycyrrhiza glabra is considered as potential drug for nasopharyngeal carcinoma (NPC). However, whether the long noncoding RNAs’ (lncRNAs) contributes to the anti-cancer function of this herb is unknown. In present study, we analyzed the differential expression of lncRNA between G. glabra-treated and untreated C666-1 cells. Out of those tumor-related lncRNAs, AK027294 had a strongest down-regulation upon G. glabra treatment. Knockdown of AK027294 suppresses the proliferation of C666-1 cells by inducing the apoptosis. Moreover, either G. glabra treatment or knockdown of AK027294 significantly increases the production of EZH1 (Enhancer of zeste 1 polycomb repressive complex 2 subunit). Collectively, we have identified a potential mechanism that the down-regulation of AK027294 contributes to the anti-cancer function of G. glabra and also provide the potential inter-relationship between AK027294 and EZH1.

Objective Intraperitoneal (IP) chemotherapy through subcutaneous port is an effective treatment for gastric cancer (GC) patients with peritoneal metastasis (PM). The objective of this study is to assess the port complications and risk factors for complications in GC patients with PM. Methods In retrospective screening of 301 patients with subcutaneous ports implantation, 249 GC patients with PM who received IP chemotherapy were screened out for analysis. Port complications and risk factors for complications were analyzed. Results Of the 249 analyzed patients, 57 (22.9%) experienced port complications. Subcutaneous liquid accumulation (42.1%) and infection (28.1%) were the main complications, and other complications included port rotation (14.1%), wound dehiscence (12.3%), inflow obstruction (1.7%) and subcutaneous metastasis (1.7%). The median interval between port implantation and occurrence of complications was 3.0 months. Eastern Cooperative Oncology Group (ECOG) performance status [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.12−2.69], albumin (OR, 3.67; 95% CI, 1.96−6.86), implantation procedure optimization (OR, 0.33; 95% CI, 0.18−0.61) and implantation groups (OR, 0.37; 95% CI, 0.20−0.69) were independent risk factors for port complications (P

Objective: To study the function of human bone morphogenetic protein-6 (BMP6) and hepcidin in cancer-related anemia.Methods: The levels of Hemoglobin (Hb), serum C-reactive protein (CRP), BMP6, hep...

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys ( Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3β,5,6β-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.

PURPOSE The aim of the current study was to assess treatment concordance and adherence to National Comprehensive Cancer Network breast cancer treatment guidelines between oncologists and an artificial intelligence advisory tool. PATIENTS AND METHODS Study cases of patients (N = 1,977) who were at high risk for recurrence or who had metastatic disease and cell types for which the advisory tool was trained were obtained from the Chinese Society for Clinical Oncology cancer database (2012 to 2017). A cross-sectional observational study was performed to examine treatment concordance and guideline adherence among an artificial intelligence advisory tool and 10 oncologists with varying expertise—three fellows, four attending physicians, and three chief physicians. In a blinded fashion, each oncologist provided treatment advice on an average of 198 cases and the advisory tool on all cases (N = 1,977). Results are reported as rates and logistic regression odds ratios. RESULTS Concordance for the recommended treatment was 0.56 for all physicians and higher for fellows compared with chief and attending physicians (0.68 v 0.54; 0.49; P = .001). Concordance differed by hormone receptor subtype–TNM stage, with the lowest for hormone receptor–positive human epidermal growth factor receptor 2/neu-positive cancers (0.48) and highest for triple-negative breast cancers (0.71) across most TNM stages. Adherence to National Comprehensive Cancer Network guidelines was higher for oncologists compared with the advisory tool (0.96 v 0.82; P < .003) and lower for fellows compared with attending physicians (0.93 v 0.98; 0.96; P = .04). CONCLUSION Study findings reflect a complex breast cancer case mix, the limits of medical knowledge regarding optimum treatment, clinician practice patterns, and use of a tool that reflects expertise from one cancer center. Additional research in different practice settings is needed to understand the tool’s scalability and its impact on treatment decisions and clinical and health services outcomes.

Background There are less studies focusing on the sedative therapy of acute myocardial infarction (AMI) critical patients. This study aim to compare the impact on the prognosis of AMI critical patients of using midazolam, propofol and dexmedetomidine. Methods We collected clinical data from the Medical Information Mart for Intensive Care III (MIMIC III) database. Data on 427 AMI patients with sedatives using were recruited from in Coronary Heart Disease Intensive Care unit (CCU). Results There were 143 patients in midazolam using, 272 in propofol using and 28 in dexmedetomidine using. The rate of 28-days mortality was 23.9% in overall patients. Through logistic regression analysis, only midazolam using was significant association with increased 28-days mortality when compared with propofol or dexmedetomidine using. In the subgroup analysis of age, gender, body mass index (BMI), white blood cell (WBC), beta-block, and revascularization, the association between midazolam using and increased 28-days mortality remained significantly. Through propensity score matching, 140 patients using midazolam and 192 using non-midazolam were successfully matched, the midazolam using presented with higher rate of CCU mortality, hospital mortality and 28-days mortality, longer of mechanical ventilation time and CCU duration. E-value analysis suggested robustness to unmeasured confounding. Conclusion Propofol or dexmedetomidine are preferred to be used in AMI critical patients for sedative therapy.

The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy.

BackgroundSchizophrenia (SCZ) is a severe psychiatric disease affected by genetic factors and environmental contributors, and premorbid abnormality of glucose metabolism is one of the SCZ characteristics supposed to contribute to the disease’s pathological process. Transmembrane protein 108 (Tmem108) is a susceptible gene associated with multiple psychiatric diseases, including SCZ. Moreover, Tmem108 mutant mice exhibit SCZ-like behaviors in the measurement of sensorimotor gating. However, it is unknown whether Tmem108 regulates glucose metabolism homeostasis while it involves SCZ pathophysiological process.ResultsIn this research, we found that Tmem108 mutant mice exhibited glucose intolerance, insulin resistance, and disturbed metabolic homeostasis. Food and oxygen consumption decreased, and urine production increased, accompanied by weak fatigue resistance in the mutant mice. Simultaneously, the glucose metabolic pathway was enhanced, and lipid metabolism decreased in the mutant mice, consistent with the elevated respiratory exchange ratio (RER). Furthermore, metformin attenuated plasma glucose levels and improved sensorimotor gating in Tmem108 mutant mice.ConclusionsHyperglycemia occurs more often in SCZ patients than in control, implying that these two diseases share common biological mechanisms, here we demonstrate that the Tmem108 mutant may represent such a comorbid mechanism.

BackgroundFor gastric cancer (GC) with extensive lymph node metastasis (bulky N2 and/or para-aortic lymph node metastases), there is no standard therapy worldwide. In Japan, preoperative chemotherapy (PCT) followed by D2 gastrectomy plus para-aortic lymph node dissection (PAND) is considered the standard treatment for these patients. However, in China, the standard operation for GC patients with only bulky N2 metastases was D2 gastrectomy. Besides, after PCT, whether doing PAND improves survival or not is debatable for GC patients with para-aortic lymph node (PAN) metastases. Therefore, we conducted this study to investigate whether D2 lymphadenectomy alone is suitable for these patients after PCT.MethodsWe retrospectively collected data on patients from our electronic medical record system. GC patients with bulky N2 and/or PAN metastases who underwent D2 lymphadenectomy alone after PCT were enrolled. The survival outcomes and chemotherapy responses were analyzed and compared with the results of the JCOG0405 study.ResultsFrom May 2009 to December 2017, a total of 83 patients met all eligibility criteria and were enrolled. The median survival duration for all patients was 40.0 months. The 3-year and 5-year OS rates for all patients were 50.3% and 45.6%, respectively. For patients with only bulky N2 metastasis, the 3-year and 5-year OS rates were 77.1% and 71.6%, respectively, which were similar to the results of the JCOG0405 study (82.7% and 73.4%). For patients with only PAN metastases, the 3-year and 5-year OS rates were 50.0% and 50.0%, respectively, which seemed to be lower than those of the JCOG0405 study (64.3% and 57.1%). For patients with bulky N2 and PAN metastases, the 3-year and 5-year OS rates were 7.4% and 0.0%, respectively, which were lower than those of the JCOG0405 study (20.0% and 20.0%).ConclusionThe results of our study suggest that D2 lymphadenectomy alone is suitable for GC patients with only bulky N2 metastasis after PCT. However, D2 lymphadenectomy alone perhaps is not suitable for patients with bulky N2 and PAN metastases after PCT.

Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.

ObjectiveTo determine the characteristics and spatiotemporal distribution of major gastrointestinal (GI) neoplasms in inpatients from 1995 to 2016 in Wuwei city, northwestern China.MethodData from all paper and electronic medical records entered between 1995 and 2016 at 12 major public hospitals in Wuwei city were retrospectively collected. Patients with GI neoplasms were identified and classified according to the International Classification of Diseases (ICD)-10. Trends in the incidence of major GI neoplasms were expressed as an annual percentage change (APC), and the Z test was used to assess the time fluctuation trends. Age-standardized incidence rates (ASIRs) were also calculated and the corresponding APC was estimated by the Joinpoint software for long-term trend analysis. Thematic maps of annual incidence at the township level were produced.ResultsAmong the 19,137 new inpatients identified with GI neoplasms in Wuwei, gastric cancer was the leading cause of morbidity, followed by cancers of the esophagus, colorectum, gastric cardia, liver, and pancreas with ASIRs of 21.8, 11.0, 5.8, 5.7, 4.4, and 1.7 per 100,000 person-years, respectively. Overall, there was a steady increase in the ASIR for all GI neoplasms, and male cases were 2.1 times more frequent than female cases. The ASIR significantly increased by 12.2% per year from 1995 to 2009 for all GI neoplasms, and the increase rates ranged 9.4%-16.7% per year for the individual GI neoplasm. Despite an increase by 1.4% per year from 2009 to 2016, the ASIR decreased for esophageal and gastric cardia cancers by 4.6% and 17.3% per year, respectively. The annual incidence of all GI neoplasms showed significantly differential geographic distributions among different townships of the city during the study period.

BackgroundFor locally advanced gastric cancer (LAGC) with serosal invasion (cT4NxM0), adjuvant chemotherapy (AC) after D2 gastrectomy is the standard therapy in Asia. However, perioperative chemotherapy (PCT) combined with D2 gastrectomy is mostly suggested in Europe and America. As a part of PCT, the value of neoadjuvant chemotherapy (NAC) is unclear. We investigated whether NAC could further improve survival and other outcomes for these patients.MethodsPatients with cT4NxM0 gastric cancer who underwent D2 gastrectomy were analyzed. The patients were divided into two groups based on whether they received NAC: the neoadjuvant chemotherapy (NAC) and direct surgery (S) groups. After propensity score matching (1:1 ratio), survival and perioperative outcomes were analyzed between the two groups.ResultsA total of 902 patients met all the eligibility criteria and were enrolled. After propensity score matching, 221 matched pairs of patients were identified. The median overall survival (OS) and disease-free survival (DFS) of all patients were 75.10 and 43.67 months, respectively. The median OS of patients in the NAC and S groups were undefined and 29.80 months, respectively (PConclusionThis study suggested NAC can further improve prognosis and prevent recurrence in LAGC (cT4NxM0) patients. NAC is feasible and safe for LAGC (cT4NxM0) patients, and does not increase the risk of perioperative surgery.

Yong Tan,&ast; Min Yan,&ast; Zhen Cheng,&ast; Xiangtao Pan Department of Haematology, The Taicang Hospital Affiliated of Soochow University, Taicang, 215400, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangtao PanDepartment of Haematology, The Taicang Hospital Affiliated of Soochow University, Taicang, 215400, Jiangsu, People’s Republic of ChinaTel +86 18915768003Email panxt_sci@163.comObjective: To provide a reference for the diagnosis and treatment of patients with immune thrombocytopenia (ITP) complicated with pulmonary thromboembolism (PTE) by analyzing the clinical characteristics of five such patients.Methods: This paper summarizes the clinical manifestations and hematological indexes of five patients with ITP complicated with pulmonary embolism.Results: In this study, the incidence of ITP complicated with PTE was 2.75%. All five cases were elderly patients with nonspecific clinical manifestations. Platelet counts were different when PTE occurred. The time from the diagnosis of ITP to the occurrence of PTE was from 5 to 24 months, with an average of 12.8 months. There was no significant change in hemoglobin, white blood cell levels, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen levels, or the international normalized ratio. Four patients had significantly increased D-dimer levels, while D-dimer was only slightly increased in one patient. Antithrombin (AT) was significantly decreased in four cases (less than 70%), and C-reactive protein (CRP) was increased in all five cases.Conclusion: PTE may be related to AT and CRP in patients with ITP, which is of great clinical significance to the diagnosis and treatment of ITP complicated with PTE.Keywords: immune thrombocytopenia, pulmonary thromboembolism, C-reactive protein, antithrombin, prognosis

Purpose: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). Patients and Methods: Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a “3+3” dose escalation rule followed by dose expansion. Results: Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2–8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). Conclusions: KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.

Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1–not reached versus 7.2, 95% CI = 5.6–9.2 months; hazard ratio = 0.42, 95% CI = 0.31–0.58; one-sided P

Neuroimaging studies have displayed aberrant brain activities in individual sensory- and emotional-linked regions in postherpetic neuralgia (PHN) patients. However, multi-dimensional dysfunction in chronic pain may rely on the interplay between networks. Little is known about the changes in the functional architecture of resting state networks (RSNs) in PHN. In this cross-sectional study, we recruited 31 PHN patients, 33 RHZ patients and 34 HCs; all participants underwent resting-state functional magnetic resonance imaging scans. We investigated the differences of within- and cross-network connectivities between different outcomes of HZ patients [including PHN and recuperation from herpes zoster (RHZ)] and healthy controls (HCs) so as to extract a characteristic network pattern of PHN. The abnormal network connectivities were then correlated with clinical variables in respective groups. PHN and RHZ patients could be similarly characterized by abnormal within-default mode network (DMN), DMN-salience network (SN) and SN-basal ganglia network (BGN) connectivity relative to HCs. Of note, compared with RHZ patients, PHN patients could be characterized by abnormal DMN-BGN and within-BGN connectivity. Furthermore, the within-DMN connectivity was associated with pain-induced emotional scores among PHN patients. Our study presented that network-level imbalance could account for the pain-related dysfunctions in different outcomes of herpes zoster patients. These insights are potentially useful for understanding neuromechanism of PHN and providing central therapeutic targets for PHN.

Background The signaling adapter protein CrkL plays vital roles in multiple cancers. However, the expression pattern of CrkL protein and its clinical significance have not been well characterized in human gastric cancer (GC) so far. Objective To investigate the association of tissue-based CrkL protein expression level with the clinicopathological characteristics and prognosis of GC patients. Methods The expression level of CrkL protein in 380 GC patients was analyzed by immunohistochemistry. The associations of CrkL protein expression level with clinicopathologicalal characteristics and clinical outcome were evaluated. Results Compared with the matched adjacent non-tumor tissues, CrkL protein expression level was significantly up-regulated in tumor tissues. In addition, there was a positive correlation between CrkL and Ki67 expression levels in GC patients. An elevated CrkL level statistically correlated with aggressive clinicopathologicalal characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified tissue-based CrkL level as an independent predictor for the unfavorable prognosis of GC. Conclusions These results indicate that CrkL protein may serve as a novel prognostic biomarker in GC.

The accumulation of somatic driver mutations in the human genome enables cells to gradually acquire a growth advantage and contributes to tumor development. Great efforts on protein-coding cancer drivers have yielded fruitful discoveries and clinical applications. However, investigations on cancer drivers in non-coding regions, especially long non-coding RNAs (lncRNAs), are extremely scarce due to the limitation of functional understanding. Thus, to identify driver lncRNAs integrating multi-omics data in human cancers, we proposed a computational framework, DriverLncNet, which dissected the functional impact of somatic copy number alteration (CNA) of lncRNAs on regulatory networks and captured key functional effectors in dys-regulatory networks. Applying it to 5 cancer types from The Cancer Genome Atlas (TCGA), we portrayed the landscape of 117 driver lncRNAs and revealed their associated cancer hallmarks through their functional effectors. Moreover, lncRNA RP11-571M6.8 was detected to be highly associated with immunotherapeutic targets (PD-1, PD-L1, and CTLA-4) and regulatory T cell infiltration level and their markers (IL2RA and FCGR2B) in glioblastoma multiforme, highlighting its immunosuppressive function. Meanwhile, a high expression of RP11-1020A11.1 in bladder carcinoma was predictive of poor survival independent of clinical characteristics, and CTD-2256P15.2 in lung adenocarcinoma responded to the sensitivity of methyl ethyl ketone (MEK) inhibitors. In summary, this study provided a framework to decipher the mechanisms of tumorigenesis from driver lncRNA level, established a new landscape of driver lncRNAs in human cancers, and offered potential clinical implications for precision oncology. Keywords: cancer drivers, long non-coding RNAs, copy number alterations, cancer hallmarks, immunosuppression

Anaplasma phagocytophilum-the causative agent of human granulocytic anaplasmosis (HGA)-is a tick-borne pathogen transmitted by Ixodid ticks infecting wild and domestic mammals as well as humans. Despite the availability of evidence regarding this emerging infection among vectors, host animals, and individuals in China, there is limited knowledge on the prevalence and distribution of A. phagocytophilum in the Yunnan Province. The aim of this study was to assess the seroprevalence of A. phagocytophilum in healthy adults and patients with acute undifferentiated fever from four regions in the Yunnan Province. The enzyme-linked immunosorbent assay and indirect immunofluorescence assay were used to detect immunoglobulin (Ig) G and IgM antibodies against A. phagocytophilum in sera obtained from 1185 healthy blood donors and 245 patients with acute undifferentiated fever, respectively. Demographic variables were assessed as potential risk factors using the chi-squared test. The rates of seropositivity rates were 7.59% and 4.49% in healthy donors and fever patients, respectively. Analysis of risk factors such as gender, age groups, and place of residence showed statistically significant differences. Infections with A. phagocytophilum occur widely among individuals residing in southwestern China. Our results indicate that there is serological evidence of HGA in this population and presence of acute A. phagocytophilum infections in patients with undifferentiated fever in the Yunnan Province.

Triple‐negative breast cancer (TNBC) has a relatively poor outcome. Acquired chemoresistance is a major clinical challenge for TNBC patients. Previously, we reported that kinase‐dead Aurora kinase A (Aurora‐A) could effectively transactivate the FOXM1 promoter. Here, we demonstrate an additional pathway through which Aurora‐A stabilizes FOXM1 by attenuating its ubiquitin in TNBC. Specifically, Aurora‐A stabilizes FOXM1 in late M phase and early G1 phase of the cell cycle, which promotes proliferation of TNBC cells. Knock‐down of Aurora‐A significantly suppresses cell proliferation in TNBC cell lines and can be rescued by FOXM1 overexpression. We observe that paclitaxel‐resistant TNBC cells exhibit high expression of Aurora‐A and FOXM1. Overexpression of Aurora‐A offers TNBC cells an additional growth advantage and protection against paclitaxel. Moreover, Aurora‐A and FOXM1 could be simultaneously targeted by thiostrepton. Combination of thiostrepton and paclitaxel treatment reverses paclitaxel resistance and significantly inhibits cell proliferation. In conclusion, our study reveals additional mechanism through which Aurora‐A regulates FOXM1 and provides a new therapeutic strategy to treat paclitaxel‐resistant triple‐negative breast cancer.

Avian orthoreovirus (ARV) infections of broiler flocks cause arthritis/tenosynovitis syndrome and significant economic losses. ARV variants were detected in the USA and Canada. Viral arthritis/tenosynovitis syndrome has occurred frequently in China in recent years. In this study, a variant ARV strain associated with viral arthritis/tenosynovitis syndrome was isolated from broilers and designated as LY383. Genomic sequence and phylogenetic analysis of the σC nucleic acid and amino acid sequences revealed that the isolate was closely related to ARV field strains Reo/PA/Layer/01224B/14, Reo/PA/Broiler/1551/13, GA/14602/2014, GA/13569/2013 and GA/13542/2013, in cluster V, but distinct from most Chinese field strains or commercial vaccine strains. Experimental challenge showed that the isolate could cause arthritis/tenosynovitis syndrome in broilers, which possessed a high level of maternal antibodies induced by commercial ARV vaccines (S1133, 1733 and T98). Furthermore, viral nucleic acid could be detected in cloacal swabs of all challenged birds throughout the entire test from 5 dpi onward. These results suggest that a novel ARV genotype emerges and might become prevalent in broiler flocks in China. RESEARCH HIGHLIGHTS A variant avian orthoreovirus was isolated from a vaccinated broiler flock in North China. The ARV field strain was distinct from previous China-origin ARV isolates and vaccine strains. The current commercial ARV vaccine could not provide effective protection of broilers against the field isolate infection. These findings indicated that variant ARV field strains might become frequent in broiler flocks in China and effective measures should be conducted to prevent and control the disease.

Background Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. Methods Immunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays. Results PA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of β-catenin through inactivation of GSK-3β via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data. Conclusions Our experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3β/β-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1049-7) contains supplementary material, which is available to authorized users.