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Silkworm, as a model organism, has very high economic value due to its silk secretion ability. Although a large number of studies have attempted to elucidate the mechanism of silk secretion, it remains unclear. In this study, the fibroin light chain (Fib-L) gene of silkworm was subjected to CRISPR/Cas9 editing, which yielded premature termination of translation at 135 aa. Compared with those of the wild type, the posterior silk glands (PSGs) of the homozygous mutants on the third day of the fifth instar showed obvious premature degeneration. Comparative transcriptome and proteomic analyses of the PSGs of wild-type individuals, heterozygous mutants and homozygous mutants were performed on the fourth day of the fifth instar. A GO enrichment analysis showed that the differentially expressed genes (DEGs) between homozygous mutants and wild-type individuals were enriched in cytoskeleton-related terms, and a KEGG enrichment analysis showed that the upregulated DEGs between homozygous mutants and wild-type individuals were enriched in the phagosome and apoptosis pathways. These results indicated that apoptosis was activated prematurely in the PSGs of homozygous mutants. Furthermore, autophagy and heat shock response were activated in the PSGs of homozygous mutants, as demonstrated by an analysis of the DEGs related to autophagy and heat shock. A comparative proteomic analysis further confirmed that autophagy, apoptosis and the heat shock response were activated in the PSGs of homozygous mutants, which led to premature degradation of the PSGs. These results provide insights for obtaining a more in-depth understanding of the mechanism of silk secretion in silkworms.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an “ion therapy” approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis., Graphical abstract Image 1, Highlights ● A novel treatment of pulmonary fibrosis based on ion therapy using bioactive ionic solution derived from silicate bioceramics (CS) was demonstrated. ● CS solution can stimulate the alveolar epithelial cells to repair damaged lung tissue. ● CS solution can regulate immune cells to inhibit inflammatory factor secretion and reduce the number of inflammatory cells in lung tissue.

Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients.

Background There is ongoing debate about the associations between drug therapies targeting the renin–angiotensin–aldosterone system (RAAS) and adverse outcomes in coronavirus disease 2019 (COVID-19). Objective This study aims to examine the associations between using medications for the cardiovascular system and the risks associated with COVID-19 in middle-aged and older adults. Methods A total of 77,221 participants (aged 50–86 years) from UK Biobank were tested for SARS-CoV-2 RNA. The medications included angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), β-blockers, calcium channel blockers (CCB), statins, and aspirin. COVID-19 outcomes comprised a positive test result and severity of COVID-19 (defined as mild, hospitalization or death). We evaluated the risk among total participants and for sub-groups based on sex. Propensity score matching was performed 1:1 and logistic regression models were used. Results Among the middle- and older aged participants, no significant associations between any class of medications and the likelihood of COVID-19 infection were observed. ACEI were associated with a higher mortality risk from COVID-19 (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01–1.32) and CCB were associated with a lower hospitalization risk for COVID-19 (OR 0.87, 95% CI 0.79–0.96) among the male patients with COVID-19, while a lower mortality risk from COVID-19 (OR 0.67, 95% CI 0.47–0.96) was observed with ARB among the female patients with COVID-19. Conclusions The study suggested sex differences in the risk of death from COVID-19 with the use of ACEI and ARB among middle-aged and older adults. Sex differences in the risk of hospitalization for COVID-19 with the use of CCB was observed as well. It is of clinical importance that clinicians adopt different CVD treatment approaches for female and male patients with COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s40266-021-00886-y.

Purpose To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. Methods The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. Results GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. Conclusion GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

To explore the efficacy and safety of palbociclib combined with endocrine therapy (ET) in advanced breast cancer (ABC). We conducted a retrospective study involving patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) ABC who received palbociclib combined with ET in the first- to third-line at three centers in China between January 2018 and October 2020. A total of 151 patients were included in this study. The median age of the patients at palbociclib initiation was 56 years (range 30-86 years) with a median follow-up of 10.9 months (range 2.0-41.2 months). Among these patients, 88 patients received palbociclib combined with ET as first-line therapy, and achieved a median progression-free survival (mPFS) of 19.8 months and an objective response rate (ORR) of 40.9%, meanwhile, in the first-line setting, 62 patients received palbociclib at an initial dose of 125 mg, achieving a mPFS of 20.9 months and an ORR of 46.8%. There were 39 and 24 patients who received palbociclib combined with ET as second- and third-line therapy, the mPFS were 10.0 months and 6.1 months, respectively. The most common and serious adverse events (AEs) were leukopenia and neutropenia. A total of 64 patients (42.4%) underwent palbociclib dose reduction due to AEs. Palbociclib combined with ET is an effective therapeutic regimen for HR+/HER2- ABC, particularly in the first-line setting with palbociclib initial dose of 125 mg, and AEs were manageable.

BACKGROUND The aim of our study is to investigate the impact of the simple breathing exercises (LHP's respiratory rehabilitation for pulmonary fibrosis, LHP's RRPF) on patients with idiopathic pulmonary fibrosis (IPF). METHODS (I) The safety and effectiveness of LHP's RRPF were first verified in 20 healthy individuals. (II) A total of 101 patients with IPF administrated in Shanghai Pulmonary Hospital between January 2015 and May 2017 were screened, and 82 cases were randomly assigned to receive a 12-month LHP's RRPF program (exercise group) or usual medical care (control group). Lung function, chest X-ray, 6-minute walk distance (6MWD), quality of life (St. George's Respiratory Questionnaire, SGRQ), and EKG were measured at the 6th and 12th month during the trial. RESULTS At the 6th month visit, the exercise group showed improved SGRQ score and lung function parameters (FVC, FEV1, and DLCO). At the 12th months visit, the exercise group had significantly improved SGRQ score, 6MWD, and lung function (FVC, FEV1, and DLCO) compared to the control group (P

Background Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2−) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations. Objective To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2− MBC. Patients and methods Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a “3+3” dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy. Results The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%). Conclusion Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2− MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population. Trial Registration NCT02833155.

Results of in vitro and in vivo studies showed that green leafy vegetables (GLV) could attenuate liver steatosis. However, little is known regarding the association between GLV intake and nonalcoholic fatty liver disease (NAFLD) in human. We examined the association of GLV intake with NAFLD in a large-scale adult population.This cross-sectional study investigated 26,891 adults in China who participated in health examinations from 2013 to 2017. Newly diagnosed NAFLD was detected by liver ultrasonography. Dietary intake was assessed by using a validated and standardized food frequency questionnaire. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) across categories of GLV intake. After adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the OR (95% CI) for comparing the highest vs. lowest GLV intake categories (≥7 times/week vs. almost never) was 0.72 (0.59, 0.90) (P 0.0001). In addition, a linear inverse association was demonstrated between GLV intake and NAFLD in women (P for trend = 0.04), but ORs for any intake category did not reach significance. Stratified analyses suggested a potential effect modification by obesity status; the ORs (95% CIs) for comparing the highest vs. lowest GLV intake categories was 0.72 (0.54, 0.97) in normal/overweight individuals and 1.04 (0.65, 1.65) in obese individuals (P-interaction 0.0001).This large population-based study shows that high GLV intake is inversely associated with NAFLD, particularly in women and non-obese participants.

This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China. Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments. By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed. Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile. NCT02499146

Han Bai,1 Jianjun Yu,2 Shidong Jia,2 Xiaoran Liu,1 Xu Liang,1 Huiping Li1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; 2Huidu Shanghai Medical Sciences, Shanghai, 201499, People’s Republic of ChinaCorrespondence: Xu Liang; Huiping LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, People’s Republic of ChinaTel/Fax +86-10-88196739Email liangxu15@outlook.com; huipingli2012@hotmail.comPurpose: The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.Patients and Methods: Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.Results: Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5– 8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P< 0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P< 0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.Conclusion: TP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.Keywords: advanced breast cancer, TP53 mutation, NGS, adjuvant endocrine therapy, DNA-binding domain

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.

Background: Sarcopenia is an aging-related loss of muscle mass and function, which induces numerous adverse outcomes. Capsaicin and capsiate, separately extracted from chilies and sweet peppers, have the potential to induce muscle hypertrophy via activation of transient receptor potential vanilloid 1. The present study aimed to investigate whether chili and sweet pepper consumption are related to sarcopenia in the elderly general population. Methods: A cross-sectional study with 2,451 participants was performed. Dietary chili and sweet pepper consumption were assessed using a validated self-administered food frequency questionnaire. Sarcopenia was defined according to the consensus of the Asian Working Group for Sarcopenia. Logistic regressions were performed to measure the effect of chili and sweet pepper consumption on sarcopenia. Results: The prevalence of sarcopenia was 16.1%. After adjustment for potential confounding variables, the odds ratios (95% confidence intervals) for sarcopenia across chili and sweet pepper consumption categories were 1.00 (reference) for almost never, 0.73 (0.55, 0.97) and 0.73 (0.56, 0.96) for ≤1 time/week, 0.60 (0.39, 0.90) and 0.66 (0.45, 0.95) for ≥2-3 times/week (both P for trend

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.

Background Breast cancer (BC) is a leading cause of cancer-related death in females worldwide. Previous studies have demonstrated that matrix metalloproteinases (MMPs) play key roles in metastasis and are associated with survival in various cancers. The prognostic values of MMP2 and MMP9 expression in BC have been investigated, but the results remain controversial. Thus, we performed the present meta-analysis to investigate the associations between MMP2/9 expressions in tumor cells with clinicopathologic features and survival outcome in BC patients. Methods Eligible studies were searched in PubMed, Web of Science, EMBASE, CNKI and Wanfang databases. The associations of MMP2/9 overexpression in tumor cells with overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) were assessed by hazard ratio (HR) and 95% confidence interval (CI). The associations of MMP2/9 overexpression with clinicopathological features were investigated by calculating odds ratio (OR) and 95% CI. Subgroup analysis, sensitivity analysis, meta-regression, and analysis for publication bias were performed. Results A total of 41 studies comprising 6517 patients with primary BC were finally included. MMP2 overexpression was associated with an unfavorable OS (HR = 1.60, 95% CI 1.33 –1.94, P P P = 0.005) and MMP9 overexpression correlated with lymph node metastasis (OR = 2.90, 95% CI 1.86 – 4.53, P Conclusions Tumoral MMP2 and MMP9 are promising markers for predicting the prognosis in patients with BC.

Objectives: To investigate changes in sUA in patients with TBI or patients after cerebral tumor surgery and the possible mechanism of these changes. Methods: This prospective cohort study enrolled patients with TBI or underwent cerebral tumor surgery at West China Hospital, China, from November 2014 to May 2018. Serum UA (sUA) levels, urine excretion, UA oxidant product allantoin and other clinical parameters were assessed. Results: 100 patients were enrolled for analysis. sUA in patients with TBI or underwent cerebral tumor surgery started to decline from day 1 after injury or surgery compared to control. This decreasing trend continued from day 3 (143.2±59.3 μmol/L, 188.8±49.4 μmol/L vs 287.3±80.2 μmol/L, p

Background Previous studies suggest that muscle-derived cytokines (myokines) are linked with brain function. Although muscle strength measured by handgrip strength is a prognostic indicator of functional decline, epidemiological studies directly examining the association between grip strength and mental health remain scarce. The aim of this study is to clarify the association between grip strength and depressive symptoms in the general adult population. Methods This is a cross-sectional study of 24,109 Chinese adults (41. 5 ± 11.9 years; 46.0% females). Grip strength was measured by dynamometer and the greatest force was normalized to body weight (NGS, kg/kg). Depressive symptoms were assessed using the Self-Rating Depression Scale (SDS). Models of logistic regression were conducted to assess the association between NGS and depressive symptoms, with adjustment for established confounding factors. Results Of the 24,109 participants, the prevalence of depressive symptoms (SDS ≥45) was 16.8% (males 15.7%, females 18.0%). After adjusting for multiple confounding factors, the odds ratios and 95% confidence interval for depressive symptoms in the quartiles of NGS were 1.00, 0.96 (0.84–1.10), 0.91 (0.79–1.05), and 0.91 (0.78–1.07) (P = 0.03) in males; 1.00, 0.92 (0.80–1.06), 0.90 (0.77–1.04), and 0.80 (0.69–0.94) (P = 0.0002) in females, respectively. Limitations This cross-sectional study cannot determine causality. Conclusions Grip strength was inversely associated with depressive symptoms, with stronger association observed among females than males. Further prospective studies or randomized trials are required to clarify these findings.

BACKGROUND Animal studies have shown that soy protein and isoflavones can increase antioxidant capacity and improve insulin resistance, and thus ameliorate nonalcoholic fatty liver disease (NAFLD). However, only limited epidemiological studies have examined the association of soy food intake with NAFLD. OBJECTIVES We investigated the association between soy food intake and NAFLD in a Chinese cohort. METHODS A total of 24,622 participants aged 20-90 y were included in the study. Diet information was collected using a validated 100-item FFQ. NAFLD was defined as having fatty liver diagnosed by ultrasonography and excluding men and women who consumed >210 g alcohol/wk and >140 g/wk, respectively. Logistic regression analysis was used to assess the association of soy food intake with NAFLD. RESULTS After adjustment for potential confounders, and taking those with

Research evidence supports a positive link between sugar-containing soft beverages and hyperuricemia. However, data thus far are mostly from Caucasian populations. And in sugar-containing soft beverages overall, sugar-containing carbonated beverages are purchased most often. Therefore, we investigated whether the high consumption of sugar-containing carbonated beverages was associated with the prevalence of hyperuricemia among adults in China.A cross-sectional study was conducted with 25,507 adults (13,013 men and 12,494 women) in Tianjin, China. Sugar-containing carbonated beverages intake was assessed by a validated semi-quantitative food frequency questionnaire. Hyperuricemia was defined as serum uric acid levels ≥7.0 mg/dL in men and ≥ 6 mg/dL in women. The association between carbonated beverages consumption and hyperuricemia was assessed by multiple logistic regression analysis. The prevalence of hyperuricemia in men and women was 23.4% and 8.2%, respectively. After adjustments for potential confounding factors, the odds ratios (95% confidence interval) for hyperuricemia across sugar-containing carbonated beverages consumption were 1.00 (reference) for almost never, 1.18 (1.05, 1.32) for1-3 cups/week, 1.49 (1.25, 1.77) for ≥4 cups/week in men (P for trend 0.005) and 1.11 (0.91, 1.34) for1-3 cups/week (P for trend = 0.27), 1.70 (1.23, 2.31) for ≥4 cups/week in women (P for trend0.001), respectively.This cross-sectional survey demonstrated that increased consumption of sugar-containing carbonated beverages is associated with hyperuricemia among adults in China. Restricted sugar-containing carbonated beverages intake might be beneficial to the prevention of hyperuricemia in the general population.

Objective Patients with HER2-positive metastatic breast cancer (MBC) benefit from trastuzumab-based therapy but eventually develop intrinsic or acquired resistance. Whether plasma HER2 gene copy number (GCN) could predict survival after trastuzumab treatment remained controversial. We evaluated the prognostic value of plasma HER2 GCN using low-coverage whole-genome sequencing (LC-WGS). Methods The plasma was collected from HER2-positive MBC patients whose pre-therapeutic samples were available before first-line trastuzumab-based treatment. Plasma DNA was extracted and assessed by LC-WGS for HER2 GCN. The optimal cut-off point for HER2 GCN to shorter survival was determined by receiver operating characteristic (ROC) curve analysis. Results A total of 49 patients were retrieved from 2013 to 2017, among whom 21 had multiple organ involvement (≥3 sites). Variations of HER2 GCN in pre-therapeutic plasma ranged from 1.89 to 23.86 (median = 2.59). ROC analysis identified the optimal cut-off point for HER2 GCN as 2.82 (P = 0.005), with 23 patients had high-level HER2 GCN and 26 in the low-level group. Both progression-free survival (PFS, P = 0.032) and overall survival (OS, P = 0.006) were adversely associated with high-level HER2 GCN. In multivariate analyses, high HER2 GCN was independently associated with shorter PFS [hazard ratio (HR) = 2.042, P = 0.037], while both high HER2 GCN (HR = 4.909, P = 0.004) and more metastatic organs (HR = 4.019, P = 0.011) were negative prognostic factors for OS. Conclusion In this population of patients with HER2-positive MBC, individuals with high HER2 GCNs in plasma had worse prognosis after trastuzumab-based therapy. Plasma HER2 GCN may be a prognostic marker in these patients.

Breast cancer (BC) represents the most commonly diagnosed cancer among females worldwide. Although targeted therapy has greatly improved the efficacy of treating BC, a large proportion of BC patients eventually develop recurrence or metastasis. Traditional invasive tumor tissue biopsy is short of comprehensiveness in tumor assessment due to heterogeneity. Liquid biopsy, an attractive non-invasive approach mainly including circulating tumor cell and circulating tumor DNA (ctDNA), has been widely utilized in a variety of cancers with the advances of sequencing technologies in recent years. The ctDNA that is found circulating in body fluids refers to DNA released from tumor cells and has shown clinical utility in metastatic breast cancer (MBC). With the results of genomic variants detection, ctDNA could be used to predict clinical outcomes, monitor disease progression, and guide treatment for patients with MBC. Moreover, the drug resistance problem may be addressed by ctDNA detection. In this review, we summarized the technological developments and clinical applications of ctDNA in MBC.

Thyroid hormones (THs) have multiple effects on lipid synthesis, mobilization, and degradation, suggesting that THs may affect the development of dyslipidemia. However, prospective studies on the association between serum THs levels and incident dyslipidemia in euthyroid subjects are limited. Therefore, we conducted a cohort study (~5-year follow-up period, median: 3.0 years) to explore whether THs can affect incident dyslipidemia in a general euthyroid population aged 18 years old and over. Dyslipidemia is characterized by elevated total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C), or reduced high-density lipoprotein cholesterol (HDL-C). Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were determined by chemiluminescence immunoassay. Multivariable Cox proportional hazards regression models were used to assess the association between baseline FT3, FT4, TSH, and the risk of various dyslipidemias. During follow-up period, the incidence of elevated TC, TG, LDL-C, and reduced HDL-C was 29.3%, 20.7%, 24.8%, and 19.5%, respectively. After adjustment for multiple confounders, we found that per unit increase in FT3 concentrations were associated with decreased incidence of elevated TC and LDL-C, and the hazard ratios (95% confidence interval) were 0.87 (0.79–0.97) (P

Banana contains many kinds of substances that are beneficial to depressive symptoms. However, there are no epidemiological researches directly to explore the association between banana consumption and depressive symptoms. This study aimed to investigate whether the banana consumption is related to depressive symptoms in a general adult population.A cross-sectional study was performed in 24,673 adults in Tianjin. Banana consumption was evaluated via a validated food frequency questionnaire. Depressive symptoms were assessed by using Self-Rating Depression Scale (SDS). The association between banana consumption and depressive symptoms was analyzed by multiple logistic regression analysis.The prevalence of depressive symptoms was 16.1% in males and 18.4% in females (SDS ≥ 45), respectively. In males, comparing to the reference group (almost never), the multivariable adjusted odds ratios (ORs) (95% confidence intervals) of depressive symptoms across banana consumption were 0.86 (0.74, 0.99) for1 time/week, 0.76 (0.66, 0.88) for 1-3 times/week and 0.97 (0.82, 1.16) for ≥4 times/week. By contrast, the multivariable adjusted ORs (95% confidence intervals) were 1.11 (0.94, 1.32) for1 time/week, 0.99 (0.85, 1.16) for 1-3 times/week and 1.22 (1.02, 1.46) for ≥4 times/week in females. Similar association was observed when other cut-offs (SDS ≥ 48 and 50) were used to define depressive symptoms.This is a cross-sectional study, causality remains unknown.Findings from this study suggested a negative association between moderate banana consumption and depressive symptoms in males. In females, high banana consumption is positively related to depressive symptoms.

Background Non-small-cell lung cancer (NSCLC) is one of the common cancers in the world. Circular RNA 0072083 (circ_0072083, circZFR) has been reported to be associated with the progression of NSCLC. In this study, we intended to explore the role and the potential mechanism of circ_0072083 in NSCLC. Methods Quantitative real time polymerase chain reaction (qRT-PCR) was performed to detect the expression of circ_0072083, its matching linear RNA (zinc finger RNA binding protein (ZFR)) and microRNA-545-3p (miR-545-3p) in NSCLC cells. The ability of colony formation in NSCLC cells was detected by colony formation assay. The apoptosis and cell cycle were measured by flow cytometry. The metastasis was determined by transwell migration and invasion assays. The protein expression of E-cadherin, N-cadherin, Vimentin and Cbl proto-oncogene like 1 (CBLL1) was examined by western blot assay. The interaction between miR-545-3p and circ_0072083 or CBLL1 was predicted by starBase or Targetscan software. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were applied to validate these interactions. Nude mice bearing tumors were used to confirm the role of circ_0072083 and cisplatin (DDP) in vivo. Results The level of circ_0072083 was higher in NSCLC tissues and cells relative to that in adjacent non-tumor tissues and normal lung cells. The transfection of si-circ_0072083 inhibited colony formation, cell cycle and metastasis while promoted the apoptosis of NSCLC cells stimulated by DDP. MiR-545-3p was a direct functional target of circ_0072083 in NSCLC cells. CBLL1 could bind to miR-545-3p in NSCLC cells. Circ_0072083 promoted the progression of NSCLC induced by DDP through sponging miR-545-3p and enhancing the enrichment of CBLL1 in vivo and in vitro. Conclusion Circ_0072083 depletion contributed to DDP-triggered inhibition of NSCLC tumor through miR-545-3p/CBLL1 axis.

Background: Androgen receptor (AR) blocker has become an increased interest in the treatment of BC, in which about 60-80% patients showed AR positive. However, currently no AR blocker has been approved in mBC. GT0918 is a new chemical entity of AR blocker with possible AR down-regulation. This study is an open-label, single-center, dose escalation phase I trial to assess GT0918 in mBC female patients who have progressed after systemic treatments in China. The primary objectives are to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The secondary objectives are to assess pharmacokinetics and pharmacodynamics of GT0918 with single and multiple dosage applications. (CTR20170757) Methods: Patients (pts) with historically confirmed mBC who had progressed after either chemotherapy, hormonal or targeted therapy, or could not tolerate currently standard therapies were eligible. With the starting dose at 100 mg of GT0918, the decision of dose escalation in the 3+3 design was based on the safety and tolerability assessments. GT0918 was administered orally once, followed by a 7-day off-treatment period for single dose PK analysis of drug elimination. Then GT0918 oral administration was resumed once daily for 28 consecutive days and multiple dose PK analysis was assessed at the end of first cycle (28 days). The first 28-days on treatment (cycle 1) was defined as DLT period. Pts manifesting an objective response or stable disease and likely to have clinical benefit from continued treatment were continued on GT0918 thereafter until they experienced one of following events of intolerable toxicities, disease progression or withdrew consent. Results: 18 pts were enrolled and treated with GT0918 since 9/6/2017 as defined in protocol at five dose levels: 100 mg (n = 3), 200 mg (n = 4), 300 mg (n = 4), 400 mg (n = 4) and 500 mg (n = 3) (as to 7/2/2019). All pts progressed more than two lines of therapies with 83.3% (15/18) pts were treated ≥3rd lines. Out of 6 confirmed AR positive pts, two (33.3%) at 300 mg cohort had finished 17 and 19 cycles individually and continue treatment (as 7/2/19). No DLT was observed and MTD has not been reached. GT0918 related adverse events (AEs) were grade 1 or 2 as per CTCAE v4.03, including fatigue, hypertriglyceridemia, anemia, hypercholesterolemia, increased LDL, nausea, loss of appetite, increased ALT, increase of weight loss, constipation and thrombocytopenia. PK profile analysis showed that in the single-dose study, GT0918 showed a fast absorption profile. In the multiple-dose study, the steady-state serum concentration level of GT0918 and its main metabolite were attained at 21 days. Conclusions: Proxalutamide (GT0918) administrated orally once a day is well tolerated in late-stage pts. No DLT has occurred at maximum dose 500 mg. Pts with AR positive biomarker could have better clinical outcomes with GT0918 treatment. GT0918 and its main metabolite exhibited a nonlinear pharmacokinetic profile over the dose range from 100mg to 500 mg. An expanded/phase Ib in AR positive mBC pts has launched in China to evaluate the anti-tumor activity and safety of GT0918. 200 mg and 300 mg were selected for dose expansion. Citation Format: Huiping Li, Ran Ran, Guohong Song, Hanfang Jiang, Ruyan Zhang, Yaxin Liu, Luping Meng, Phoebe Zhang, Ke Chen, Qiaoxia Zhou, Karl Zhou, Youzhi Tong. Evaluation of safety, pharmacokinetics and pharmacodynamics of proxalutamide (GT0918), a potent androgen receptor (AR) blocker, in patients with metastatic breast cancer (mBC): Phase I dose escalation trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-05.

Background: Angiogenesis is a key mechanism of tumour growth. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2) and blocks downstream signalling and inhibiting tumour angiogenesis. It was approved in China to treat gastric cancer in October 2014. However, as breast cancer with a chest wall metastasis (CWM) has rich vascular distribution, whether Apatinib is also effective for breast cancer with a chest wall metastasis remains unknown. Therefore, we designed this clinical study to address this question. Method: The trial involved four centres in China from September 2016 to July 2019. It enrolled patients (pts) who were diagnosed of HER2 negative breast cancer with CWM and experienced first line or could not afford standard treatment. The patients were given Apatinib 500mg/day (single or combined with endocrine therapy if hormone receptor positive (HR+)) until progression or side effect not tolerated. Each patient had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1.This study was approved by ethics committee at the Ethics Committee of Beijing Cancer Hospital, and all participants provided written informed consent. The trial was also Register to clinicaltrial.gov ( NCT02878057). Results: 30 pts were enrolled in the study with a median age of 50 (range 35-69) years old. Among the 30 pts, there were 23 ER positive pts (76.7%). 17 pts (56.7%) had more than 2 sites of metastasis, and 5 pts had invasive metastasis (16.6%). 15 pts (50%) were multi pre-treated. The response of 19 pts (63.3%) could be evaluated, and the overall response rate was 57.9% (no CR, 11 cases reached PR, 2 in HR-, 9 in HR+). and the median PFS was 8.6 months (range 0.5-29.5; 95% CI 0.0-18.7). The tumour in chest wall shrunk obviously. Side effects also existed. 15 pts (50%) had hypertension (grade 3: 6.7%); 10 pts (33.3%) had proteinuria (grade 3: 20%); 4 pts (13.3%) had fatigue (grade 3: 3.3%); 3 pts (10%) had bilirubin increase (grade 3: 6.7%). 8 pts discontinued the treatment due to side effects and 3 due to personal reasons. The Apatinib dose was reduced from 500mg to 250mg for most pts 18/30 (60%), and some pts took 500 mg and 250 mg every other day 10/30 (33.3). Conclusion: Apatinib was effective for pts with chest wall metastasis and pts could benefit from longer PFS. However, the side effects should be pay more attention from start on apatinib treatment. Citation Format: Huiping Li, Cuizhi Geng, Guohong Song, Hanfang Jiang, Zhongshen Tong, Junlan Yang, Ran Ran, Ruyan Zhang, Yaxin Liu, Xinyu Gui, Maorong Wei, Lu Xue. Apatinib in the treatment of HER-2 negative advanced breast cancer with chest wall metastasis multicenter phase II clinical study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-40.

Background: Fulvestrant 500mg has been proved better efficacy in breast cancer with hormone receptor positive (HR+),and then become an optional strategy for primary or second line treatment of HR+ positive metastasis breast cancer (MBC). Methods: In this real world study, we retrospectively analyzed the patients with HR+ HER 2 negative MBC who received fulvestrant 500mg treatment at Beijing cancer hospital during January 2015 to December 2018. Clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS) and adverse events were investigated. Results: There were 306 patients enrolled, median age was 48.7(range 20-75) years, median line of fulvestrant was 2.11(range 1-6), 68.3%(209/306) patients were involved with visceral metastasis. The CBR was 68.6%, median PFS was 8.41m (95%CI: 7.079m-9.743m, range 0.89m-80.16m). Among the patients received fulvestrant at the first line, the PFS was 10.55m(95%CI:6.46m-14.64m, range 0.92m-34.3m). The median OS hasn’t been obtained. In subgroup analysis, the patients without liver metastasis(12.49m vs. 4.60m, p4, 12.65m vs. 7.72m vs. 3.98m respectively, p2 lines, 14.06m vs. 7.79m vs. 3.52m respectively, p Conclusions: Fulvestrant was an effective and safe regimen in endocrine therapy for hormone receptor positive HER2 negative MBC. The patients who were in first line treatment, absence of liver metastasis and small tumor burden might be more benefit from fulvestrant. Corresponding authors: Huiping Li, huipingli2012@hotmail.com; Guohong Song, songguohong918@hotmail.com, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, 52 Fucheng Rd, Beijing 100142, China Citation Format: Wen Lei, Huiping Li, Guohong Song, Ruyan Zhang, Ran Ran, Ying Yan. Efficacy observation of 306 patients with fulvestrant 500mg treatment in hormone-receptor positive HER2 negative metastasis breast cancer, a real world study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-20.

Objective To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP). Materials and methods A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019. Results Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324–15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods. Conclusion Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP. Trial registration NCT01983657. Registered 16 April 2013.

Objective To compare the efficacy of platinum- and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer (TNBC) and analyze the relationship between their efficacy and BRCA gene status. Methods Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology, Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy. A total of 114 patients had BRCA1/2 gene tested by next generation sequencing (NGS) using peripheral blood, and we analyzed the correlation between their efficacy and BRCA1/2 gene status. Results Non-platinum-based chemotherapy (NPCT) was administered to 129 and platinum-based chemotherapy (PBCT) to 91 study patients. The clinical benefit rate (CBR) and median progression-free survival (PFS) were not statistically different between NPCT and PBCT groups. The median overall survival (OS) was 30.0 and 22.5 months for PBCT and NPCT group, respectively [P=0.090, hazard ratios (HR)=0.703]. BRCA status was assessed in 114 patients, 14 of whom had deleterious germline BRCA1/2 (gBRCA) mutations (seven in each group). In PBCT group, the CBR was 85.7% and 35.1% for patients with and without deleterious gBRCA mutations, respectively (P=0.039). The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious gBRCA mutations, respectively (P=0.001, P=0.161, respectively). Patients in PBCT group had significantly greater rates of grade 3-4 anemia (5.5%vs. 0%) and thrombocytopenia (8.8% vs. 0%), whereas palmar-plantar erythrodysesthesia (12.4% vs. 0%) and peripheral neuropathy (8.6% vs. 1.1%) occurred more frequently in NPCT group. Conclusions Platinum-based regimens are more effective in patients with deleterious gBRCA mutations, but no difference in patients without BRCA gene mutations, so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect. And we recommend that patients with advanced TNBC should have BRCA gene test.

Objective Fluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer. Methods This was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity. Results Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8-9.3] months in OC, 9.3 (95% CI, 7.2-9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0-28.0) months in BC. In patients with germline BC susceptibility gene mutation (gBRCA Mut) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0-23.2; 95% CI, 1.0-16.8) and 14 and 28 months for BC (those two patients both also had somaticBRCA Mut). Conclusions The MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCA Mut and platinum-sensitive OC.

Background: Fulvestrant 500mg has proved its clinical effectiveness in previous trials as primary or second line treatment of hormone receptor positive, human epidermal receptor 2 negative (HR+/HER2˗) post-menopausal advanced breast cancer. This real-world study aimed to investigate the efficacy and safety of Fulvestrant in HR+/HER2˗ Chinese advanced breast cancer patients. Method: HR+/HER2˗ advanced breast cancer patients who received Fulvestrant 500mg from January 2015 to December 2018 in Beijing Cancer Hospital were enrolled in this retrospective study. Progression free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and adverse events (AEs) of Fulvestrant were investigated. Result: In total 303 enrolled patients [median age was 51 years (range: 21-82)], 255 (84.2%) patients were at postmenopausal status at the start of Fulvestrant treatment and 264 patients (87.1%) had advanced breast cancer. The median PFS (95% confidence interval) was 14.1 months (10.1-18.0) for the first-line, 11.2 months (2.2-20.3) for the second-line and 6.7 months (4.8-8.5) for ≥third-line of Fulvestrant. The ORR and CBR were 3.8% and 86.8% for the first-line, 5.5% and 75.4% for the second-line, 1.1% and 61.1% for ≥third-line of Fulvestrant. The multivariate subgroup analyses showed, PFS was significantly longer for the patients with light tumor burden, less palliative chemotherapy before Fulvestrant and long disease-free interval. For patients receiving Fulvestrant after palliative chemotherapy, the median PFS was numerically greater in maintenance treatment group than those who progressed after chemotherapy. Only 5.0% of patients (15/303) experienced adverse events and majority were grade 1-2. The most common adverse event was headache and palpitation, with merely one patient had severe adverse event (pulmonary embolism). Conclusion: Fulvestrant is an effective, safe and well-tolerated treatment regimen in endocrine therapy for HR+/HER2˗ metastatic breast cancer. Light tumor burden, less palliative chemotherapy before Fulvestrant and long disease-free survival (DFS) might be the ideal condition of Fulvestrant treatment. Fulvestrant can be effective for premenopausal patients with drug-induced menopause. Patients of different luminal subtypes can benefit from Fulvestrant. For patients with visceral metastases, presence of liver metastases rather than lung metastases was poor prognostic factor. Fulvestrant may also be considered as a maintenance treatment after first-line palliative chemotherapy.

Neuroimmune interactions have been studied for decades. Several neurodevelopmental disorders have been associated with immune dysfunction. However, the effects of immune system on neuronal function remain unknown. Herein, based on c-Fos protein expression, we characterized the brain areas that are activated after contextual fear conditioning (CFC) training or retrieval in severe combined immune deficiency (SCID) and wild-type mice. Further, we analyzed the interregional correlations of c-Fos activity that are affected by deficiency in adaptive immunity. Results showed significantly lower c-Fos density in learning and memory-associated brain regions of SCID mice after memory retrieval, but not during the CFC training. Moreover, SCID mice exhibited remarkably discordant interregional neuronal activities of learning neuron circuits after CFC training, which could be the cause of inefficient activation of the memory circuit after retrieval. These results provide a new perspective on how adaptive immunity affects neuronal function. Adaptive immune deficiency impairs the coordination of neural activity after training and retrieval, which might be a potential therapeutic target for neurodevelopmental disorders.

Background: Basic studies have found that xanthine oxidase inhibitors extracted from mushrooms have inhibitory effects on hyperuricemia. However, the association between mushroom consumption and hyperuricemia is unknown in humans. Objective: We therefore designed a large-scale cohort study to examine whether mushroom consumption is a protective factor for developing hyperuricemia in adults. Methods: This prospective cohort study investigated 19 830 participants (mean age: 39.4 years; and 9906 [50.0%] men) who were free of hyperuricemia, cardiovascular disease, and cancer at the baseline. Mushroom consumption was measured at the baseline using a validated food frequency questionnaire. Hyperuricemia is defined as serum uric acid levels >420 μmol L−1 in men and >350 μmol L−1 in women. Cox proportional hazards regression models were used to examine the association of mushroom consumption with incident hyperuricemia. Restricted cubic spline regression was used to estimate the dose–response relationship between mushroom consumption and risk of hyperuricemia. Results: A total of 4260 first incident cases of hyperuricemia occurred during 61 421 person-years of follow-up (median follow-up of 4.2 years). After adjusting for demographic characteristics, lifestyle factors, dietary intake, and inflammatory markers, the multivariable hazard ratios (95% confidence intervals) for incident hyperuricemia were 1.00(reference) for 5.52 g per 1000 kcal per day, respectively (P for trend = 0.007). Conclusions: This population-based prospective cohort study has firstly demonstrated that higher mushroom consumption is significantly associated with lower incidence of hyperuricemia among general adults.

SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3)-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in SHANK3-deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without SHANK3 deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without SHANK3 defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with SHANK3 defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with SHANK3 defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without SHANK3 defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with SHANK3 defects, but not in those without. In addition, ASD children with SHANK3 defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without SHANK3 defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without SHANK3 deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD.