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Purpose To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. Methods In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. Results Of 44 enrolled patients (median age, 53.5 years; range, 34–69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3–4.1) and median OS was 15.0 months (95% CI 12.1–17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. Conclusion PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.

To investigate the associations of milk intake (non-fermented and fermented milk), lactase persistence (LCT-13910 C/T) genotype (a proxy for long-term non-fermented milk intake), and gene-milk interaction with risks of cardiovascular disease (CVD) and CVD mortality. Also, to identify the CVD-related plasma proteins and lipoprotein subfractions associated with milk intake and LCT-13910 C/T genotype. The prospective cohort study included 20,499 participants who were followed up for a mean of 21 years. Dietary intake was assessed using a modified diet history method. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After adjusting for sociodemographic and lifestyle factors, higher non-fermented milk intake was significantly associated with higher risks of coronary heart disease (CHD) and CVD mortality, whereas higher fermented milk intake was significantly associated with lower risks of CVD and CVD mortality. The genotype associated with higher milk (mainly non-fermented) intake was positively associated with CHD (CT/TT vs. CC HR = 1.27; 95% CI: 1.03, 1.55) and CVD (HR = 1.22; 95% CI: 1.05, 1.42). The association between rs4988235 genotype and CVD mortality was stronger in participants with higher milk intake than among participants with lower intake (P for interaction LCT-13910 C/T genotype were identified. In conclusion, non-fermented milk intake was associated with higher risks of CHD and CVD mortality, as well as leptin and HDL, whereas fermented milk intake was associated with lower risks of CVD and CVD mortality.

Purpose PUFFIN (NCT02896855), a Chinese bridging study in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer, assessed consistency of efficacy and safety of pertuzumab plus trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel, with CLEOPATRA (NCT00567190). Methods Eligible patients, n = 243, were randomized 1:1, stratified by visceral disease and hormone receptor status, to pertuzumab, trastuzumab, and docetaxel or placebo, trastuzumab, and docetaxel. Primary endpoint: investigator-assessed progression-free survival (PFS). Secondary endpoints: safety and overall survival (OS). After primary analysis, patients could cross over to the pertuzumab arm. Results Updated median PFS: 16.5 months (pertuzumab arm) and 12.5 months (placebo arm), with a hazard ratio (HR) of 0.60 [95% confidence interval (CI) 0.45, 0.81; p = 0.0008]. Median OS was not reached in either arm; the OS HR was 0.68 (95% CI 0.45, 1.03; p = 0.0658). Safety was similar in both arms with no new safety signals: 73.8% (pertuzumab arm) and 69.2% (placebo arm) experienced grade ≥ 3 adverse events. No heart failure, symptomatic left ventricular systolic dysfunction, or left ventricular ejection fraction decline of Conclusions The PUFFIN final analysis showed, per the primary analysis, that overall efficacy of pertuzumab plus trastuzumab and docetaxel was consistent with CLEOPATRA. Safety remained consistent with the known pertuzumab profile. Overall, PUFFIN contributes to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit–risk profile of pertuzumab in Chinese patients. Trial registration: ClinicalTrials.gov, NCT02896855, registered 7 September 2016.

Background Salivary amylase, encoded by the AMY1 gene, initiate the digestion of starch. Whether starch intake or AMY1 copy number is related to disease risk is currently rather unknown. The aim was to investigate the association between starch intake and AMY1 copy number and risk of cardiovascular disease (CVD) and mortality and whether there is an interaction. In addition, we aim to identify CVD-related plasma proteins associated with starch intake and AMY1 copy number. Methods This prospective cohort study used data from 21,268 participants from the Malmö Diet and Cancer Study. Dietary data were collected through a modified diet history method and incident CVD and mortality were ascertained through registers. AMY1 gene copy number was determined by droplet digital polymerase chain reaction, a risk score of 10 genetic variants in AMY1 was measured, and a total of 88 selected CVD-related proteins were measured. Cox proportional hazards regression was used to analyze the associations of starch intake and AMY1 copy number with disease risk. Linear regression was used to identify plasma proteins associated with starch intake and AMY1 copy number. Results Over a median of 23 years’ follow-up, 4443 individuals developed CVD event and 8125 died. After adjusting for potential confounders, a U-shape association between starch intake and risk of CVD (P-nonlinearity = 0.001) and all-cause mortality (P-nonlinearity = 0.03) was observed. No significant association was found between AMY1 copy number and risk of CVD and mortality, and there were no interactions between starch intake and AMY1 copy number (P interaction > 0.23). Among the 88 plasma proteins, adrenomedullin, interleukin-1 receptor antagonist protein, fatty acid-binding protein, leptin, and C-C motif chemokine 20 were associated with starch intake after adjusting for multiple testing. Conclusions In this large prospective study among Swedish adults, a U-shaped association between starch intake and risk of CVD and all-cause mortality was found. Several plasma proteins were identified which might provide information on potential pathways for such association. AMY1 copy number was not associated with CVD risk or any of the plasma proteins, and there was no interaction between starch intake and AMY1 copy number on disease risk.

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.

Air-cooling process is a very complex heat transfer involving the heat transfer theory and the fluid dynamics. In the paper, the experiment and numerical simulation methods are used to study the interfacial heat transfer and gas flow in the process of air-cooling, and an axisymmetric model is established to simulate the air-cooling process based on the fluid-thermal-solid coupling method. In the experiment and numerical simulation, the high-speed compressed air is used to impinge and cool the hot metallic surface. The temperatures attained in the experiment and numerical simulation are used to calculate the interfacial heat transfer coefficient (IHTC) by a self-developed inverse heat transfer analysis software. Considering the influence of turbulence model on flow, it found that the SST $$k - \omega$$ turbulence model is more appropriate for the air-cooling process. Based on the SST $$k - \omega$$ model, the effect of sample diameter and jet distance (distance from jet to cooling surface) on the flow pattern and temperature fields is studied, the results show that the temperatures attained in the numerical simulation are in good agreement with those of experiment, and the smaller the jet distance is, the bigger the IHTC is. Finally, the IHTCs under the different jet distance and inlet flow velocity are calculated based on the temperature curves attained in the numerical simulation.

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.

The possibility of raising the impact toughness of medium-manganese TRIP-steel Fe – 0.2% C – 6% Mn – 3% Al by application of a novel heat treatment involving quenching from the intercritical temperature range and subsequent tempering is investigated. Electron microscope and x-ray diffraction studies are performed after the heat treatment. The quenching mode providing the highest impact toughness is determined.

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

Background We report a rare case of Gardnerella vaginalis found in the cerebrospinal fluid of a young boy. Case presentation A 14-year-old boy was admitted to hospital with headache, vomiting, fever, drowsiness and positive meningeal irritation signs on examination. Cerebrospinal fluid (CSF) shows white blood cell and protein were elevated, and glucose was low. Traditional aerobic and anaerobic culture of CSF did not grow any organisms. However, metagenomic next-generation sequencing (mNGS) reveals G. vaginalis in his CSF. The patient was diagnosed with purulent meningitis, and treated with intravenous meropenem and linezolid for a week, followed by oral administration of amoxicillin for two weeks. He recovered without sequelae. Conclusions Purulent meningitis caused by Gardnerella vaginalis is extremely rare. Metagenomic next-generation sequencing of CSF should be highlighted for early diagnosis. With effective antibiotic treatment, the prognosis was excellent.

Background The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized. Methods Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance. Results Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications. Conclusions This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression. Trial registration: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529.

In this paper, the scientific challenges associated with obtaining high impact toughness in the medium-Mn TRIP steel, Fe-0.2C-6Mn-1.5Al, have been explored. This was enabled by a novel and effective heat treatment involving the combination of intercritical hardening and tempering to obtain high impact toughness. Electron microscopy and x-ray diffraction studies clearly underscored absence of TRIP effect in Fe-0.2C-6Mn-1.5Al medium manganese steel during impact and the volume fraction of austenite played a determining role in governing impact toughness. The highest impact toughness of 180.17 J/cm2 was obtained when the steel was subjected to intercritical hardening temperature of 630 °C and low tempering temperature of 200 °C. The presence of martensite in the microstructure reduced the impact toughness on quenching from 670 to 700 °C. When the quenching temperature was increased to 750 °C, the impact toughness of steel was slightly increased, which is ascribed to the supersaturated carbon in martensite that precipitated as carbides. The fracture mode was ductile after intercritical hardening in the temperature range of 600-700 °C.

Masson pine (Pinus massoniana Lamb.) is an economically important conifer tree that can be widely used for timber, pulp, and resin production. However, the phosphate (Pi) deficiency in tropical and subtropical forest soils poses severe challenges for the productivity of masson pine. WRKY transcription factors (TFs) have been proven to play important roles in plant responses to biotic and abiotic stresses, including low Pi stress; however, little is known about their roles in masson pine. To understand the roles of P. massoniana WRKY (PmWRKY) in low Pi stress, 25 putative WRKY TFs with complete WRKY domain from transcriptome sequencing data were identified. Based on their conserved domains and zinc-finger motif, the P. massoniana WRKY were divided into three groups. Structural feature analysis shows that PmWRKY proteins contain WRKYGQK/GKK/GRK domains and a C2H2/C2HC-type zinc-finger structure. To putatively identify the function of PmWRKY members involved in low Pi stress, transcriptional profiles of 17 PmWRKYs in masson pine under different Pi stresses were systematically established using real-time quantitative RT-PCR analysis. Analysis demonstrates that the candidate PmWRKYs were involved in responses to Pi starvation—for example, PmWRKY11, 12, and 13 were upregulated both in P1 (Phosphorus content of 0.01 mM) and P2 (Phosphorus content of 0.06 mM) stresses. The available evidence conclusively sheds light on protein structures, evolutionary relationships, and expression patterns of WRKYs in response to low Pi stress of masson pine, which facilitates further functional identification and molecular breeding for the enhancement of low-phosphorous tolerance in this species.

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

In recent years, graphene oxide (GO), prepared by the modified Hummers’ method, and its derivatives have become a focus of research owing to their outstanding physical and chemical properties and low cost. Drawing inspiration from the mussel protein, a facile and environmentally-friendly method was employed to fabricate superhydrophobic/superoleophilic reduced graphene oxide (rGO) derivative. The preparation comprises two steps: coating GO nanosheets with polydopamine (PDA) and subsequent reaction with 1 H ,1 H ,2 H ,2 H -perfluorodecanethiol. Due to the excellent adhesive ability of PDA, the resulting f PDA modified rGO nanosheets (rGO- f PDA) were firmly immobilized onto polyurethane (PU) sponge skeleton by a simple drop-coating method. The as-prepared rGO- f PDA functionalized sponge exhibited superhydrophobic behavior with a water contact angle of 162°±2°, high organic adsorption capacity, recyclability and stable oil/water separation behavior under different acidic/alkaline conditions. Due to its facile fabrication technique and outstanding properties, the superhydrophobic-superoleophilic PU-rGO- f PDA sponge holds great promise as an oil adsorbent for cleaning up large-scale pollution of oil and organic solvents, and dehydrating crude oil.

Breast cancer in young Asian women has distinctive clinicopathological characteristics; hence, we question the universal generalizability of treatment recommendations based on data from predominantly non-Asian postmenopausal women. The Asian Breast Cancer Cooperative Group (ABCCG) reviewed current ESO-ESMO and St. Gallen recommendations for treating hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) breast cancer in premenopausal women. Points disputed by ≥ 3/12 members were discussed, and statements on contentious issues formulated for anonymous voting; consensus required a ≥ 75% majority. The ABCCG contends that: (1) Trials in premenopausal women are not only necessary, but also worthwhile if performed separately from others that also enroll postmenopausal participants. (2) Not all premenopausal women with HR+ early breast cancer need adjuvant ovarian function suppression (OFS). (3) Certain clinical factors might influence decision-making about prescribing OFS. (4) For early HR+/HER2− breast cancer in premenopausal patients with OFS, tamoxifen is preferred for intermediate-risk cases; for high risk, near-consensus supported aromatase inhibitor, despite no clear overall survival benefit versus tamoxifen. (5) Oncotype DX Breast Recurrence Score® has different treatment implications in patients aged ≤ 50 versus > 50 years. (6) High-risk patients (if premenopausal after chemotherapy) should receive adjuvant chemotherapy and OFS plus aromatase inhibitor. (7) For patients with advanced disease receiving OFS on a backbone of tamoxifen, gonadotrophin-releasing hormone agonists may be given 12-weekly. (8) For premenopausal women who decline OFS or oophorectomy, tamoxifen alone is still an option but is considered less effective; other monotherapies are also less effective than OFS plus such treatments. Premenopausal Asian women with breast cancer have unique disease characteristics and may benefit from treatment that differs somewhat from international guidelines. Given the great diversity of patients and clinical settings worldwide, the ABCCG advocates evidence-based yet flexible and individualized use of all potential options to improve breast cancer outcomes.

The interfacial heat transfer coefficient (IHTC) is one of the most important thermal-physical parameters in heat conduction problem. To solve the IHTC in gas cooling, a 304 stainless steel sample is heated up to 800 °C by an induction heating device and then cooled by a high-pressure gas source. The IHTC between the high-pressure gas and the sample is evaluated by ZFA-FEM (normal distribution method, firefly algorithm (FA) and finite element method (FEM)) and ZGFA-FEM (normal distribution method, global optimization factor (G), firefly algorithm and finite element method) according to the temperature curve attained in the experiment. The research results show that, these IHTCs attained in the solution of IHCP according to those temperature curves of CFD simulation and the experiment are consistent, and the trend of IHTC attained in the experiment is consistent with that in the literature. The group scale of fireflies in ZGFA is much smaller than that in ZFA. Only 20 fireflies in ZGFA can ensure all fireflies move to the optimal position due to global optimization factor used in ZGFA. The convergence, iteration and CPU time of ZGFA are better than ZFA.

To investigate the efficacy and safety of nintedanib versus placebo in Chinese patients with idiopathic pulmonary fibrosis (IPF). The INPULSIS® trials consisted of two replicate, randomized, placebo-controlled, double-blind trials comparing nintedanib 150 mg bid with placebo over a 52-week treatment period. The primary endpoint was annual rate of decline in forced vital capacity (FVC); key secondary endpoints were change from baseline in Saint George’s Respiratory Questionnaire’s total score and time to first investigator-reported acute exacerbation. Data from both trials were pooled for the Chinese subgroup analyses. A total of 101 Chinese patients (nintedanib/placebo: 61/40) were treated. The demographic characteristics were generally balanced between treatment arms. Over 52 weeks, the rate of decline in FVC was lower in nintedanib-treated patients compared with placebo-treated patients in the Chinese subgroup [− 126.43 vs. − 229.82 mL/year; ∆ = 103.39 mL/year (95% confidence interval, CI: − 19.40 to 226.18)]. The proportion of patients with adverse events (AEs) over 52 weeks was similar between treatment arms. The most commonly reported AEs with nintedanib treatment were gastrointestinal symptoms (diarrhoea, nausea, and vomiting). Nintedanib is clinically efficacious in Chinese patients with IPF with approximately 50% reductions in the rate of decline in FVC, demonstrating slowed disease progression. Similar to the overall INPULSIS® population, nintedanib has a favourable benefit/risk profile in Chinese patients with IPF. NCT01335464, NCT01335477. Boehringer Ingelheim. Plain language summary available for this article.

Free amino acids, including theanine, glutamine and glutamate, contribute greatly to the pleasant taste and multiple health benefits of tea. Amino acids in tea plants are mainly synthesized in roots and transported to new shoots, which are significantly affected by nitrogen (N) level and forms. However, the regulatory amino acid metabolism genes have not been systemically identified in tea plants. Here, we investigated the dynamic changes of free amino acid contents in response to N deficiency and forms in tea plant roots, and systemically identified the genes associated amino acid contents in individual metabolism pathways. Our results showed that glutamate-derived amino acids are the most dynamic in response to various forms of N and N deficiency. We then performed transcriptomic analyses of roots treated with N deficiency and various forms of N, and differentially expressed amino acid metabolic genes in each pathway were identified. The analyses on expression patterns and transcriptional responses of metabolic genes to N treatments provided novel insights for the molecular basis of high accumulation of theanine in tea plant root. These analyses also identified potential regulatory genes in dynamic amino acid metabolism in tea plant root. Furthermore, our findings indicated that the dynamic expression levels of CsGDH, CsAlaDC, CsAspAT, CsSDH, CsPAL, CsSHMT were highly correlated with changes of amino acid contents in their corresponding pathways. Herein, this study provides comprehensive insights into transcriptional regulation of amino acid metabolism in response to nitrogen deficiency and nitrogen forms in tea plant root.

Adjuvant docetaxel-based chemotherapy is frequently used in the treatment of operable early breast cancer (EBC). This study investigated patterns of docetaxel use in patients with EBC in real-world clinical practice in China. This was a multicenter, prospective, observational study of Chinese women with operable breast cancer in tier 1 non-oncology-specific hospitals and other city hospitals in China. Adult Chinese female patients (≥ 18 years) with newly diagnosed breast cancer who underwent surgery and received docetaxel-containing adjuvant chemotherapy were eligible for inclusion. The primary end point of the study was to assess patterns of docetaxel use for adjuvant therapy in Chinese clinical practice. Secondary end points included factors associated with treatment selection, patterns of G-CSF use and safety. In total, 502 patients were enrolled, 475 of whom were included in the analysis. The results showed that 31.6% of patients received docetaxel and anthracyclines in combination, 47.2% received docetaxel and anthracyclines sequentially, 18.5% received docetaxel and other medication either in combination or sequentially and 2.7% received ‘other’ chemotherapy regimens. Factors influencing selection of docetaxel/anthracycline in combination versus sequentially included age, breast cancer subgroup, PR status, and preoperative neoadjuvant chemotherapy. A total of 258 (54.3%), 35 (7.4%), and 108 (22.7%) patients received G-CSF as primary prevention, secondary prevention and treatment, respectively. Treatment-emergent adverse events (TEAEs) occurred in 54.5% (259) of patients, and the most frequently reported TEAEs (≥ 5% of patients) included bone marrow failure (10.1%), granulocytopenia (9.9%), nausea (8.8%) and vomiting (6.9%). Neutropenia and febrile neutropenia were reported by 10 and 12 patients, respectively. Docetaxel for adjuvant chemotherapy of operable EBC in China was most commonly given in combination or sequentially with anthracyclines. The study also showed that in China G-CSF is most frequently used as primary prophylactic, and no unexpected safety events were observed during docetaxel treatment. Sanofi (China).

The microstructure evolution of a typical nickel-based superalloy was studied in the strain range of 0.1–0.9 at 1110 °C/0.01 s−1 by using the electron backscattered diffraction technique. It was found that the evolution of recrystallized microstructures, grain boundary characteristics, and textures was closely related to strain level. With the increasing strain level, the fraction of equiaxed dynamic recrystallization (DRX) grains increased significantly at the expense of the large non-recrystallized grains, and there was a decrease in total low angle grain boundaries fraction and a simultaneous increase in the fraction of high angle grain boundaries. In addition, the occurrence of DRX promoted the formation of Σ3 boundaries, and the coherent Σ3 boundaries were much easier to form at the strain above 0.5. On the other hand, component of the textures became stronger with the increasing strains, and the lack of orientations can also be observed in the textures at high strains above 0.7.

Microstructure and mechanical properties after induction hardening have a significant effect on the wear resistance performance and lifetime of 55CrMo steel ball screw. In the paper, the dilatometric curves were recorded at the different heating rate by a Gleeble-1500D thermo-mechanical simulator to determine the effect of heating rate on the austenitizing temperature of 55CrMo steel. Heat treatment of some specimens was performed by the Gleeble-1500D thermal simulator at the different heating temperature, holding time and cooling rate to investigate the effect of induction hardening parameters on the phase transformation, microstructure and microhardness of 55CrMo steel. Microstructure of specimen was analyzed using an optical microscope and a scanning electron microscope. Volume fraction of retained austenite was measured using an x-ray diffractometer. The mechanical properties were evaluated by a microhardness tester. The results show that the austenitizing temperature of 55CrMo steel increases with the increasing heating rate. Increasing the heating temperature, holding time and cooling rate of specimen is helpful in obtaining a uniform cryptocrystalline martensite. Volume fraction of retained austenite is less as the heating temperature is in the range of 900-950 °C. In the induction hardening of 55CrMo steel, the heating temperature should be in the range of 900-1000 °C.

The distribution and evolution of stress-strain in the sheared zone at elevated temperature is an important theoretical basis for studying the hot blanking mechanism. The fracture criterions and fracture thresholds are the main factors affecting the accuracy of numerical simulation for the hot blanking. To research the mechanism of hot blanking, B1500HS steel sheet with full austenitization was blanked at the different temperatures (650, 700, 750, and 800 °C). Finite element model of hot blanking was established, and five fracture criterions (normalized Cockroft and Latham, Brozzo, Freudenthal, Oyane, and Rice and Traccy) were used to simulate the hot blanking of B1500HS steel. According to the results of numerical simulation and experiment, the fracture thresholds of five fracture criterions were evaluated using the method of “regression fitting-calculation-prediction-correction.” The fracture thresholds attained by this method were used to simulate the hot blanking, and the location where crack occur initially and fracture shape was obtained. Comparing the simulation results and the experimental results, the results show that the crack occurs at the edges of die and punch as the hydrostatic stress reaches to the maximum value, and the simulation results based on the Oyane fracture criterion and Brozzo fracture criterion are well consistent with the experiment results. The fracture thresholds attained by the method of “regression fitting-calculation-prediction-correction” have the better reliability and practicability.

The interfacial heat transfer coefficient (IHTC) is one of the most important thermal physical parameters which have significant effects on the calculation accuracy of physical fields in the numerical simulation. In this study, the artificial fish swarm algorithm (AFSA) was used to evaluate the IHTC between the heated sample and the quenchant in a one-dimensional heat conduction problem. AFSA is a global optimization method. In order to speed up the convergence speed, a hybrid method which is the combination of AFSA and normal distribution method (ZAFSA) was presented. The IHTC evaluated by ZAFSA were compared with those attained by AFSA and the advanced-retreat method and golden section method. The results show that the reasonable IHTC is obtained by using ZAFSA, the convergence of hybrid method is well. The algorithm based on ZAFSA can not only accelerate the convergence speed, but also reduce the numerical oscillation in the evaluation of IHTC.

Warm and hot blanking processes were developed for solving problems in piercing and trimming of press-hardened parts, some fine blank parts with comprehensive mechanical properties could be produced by hot blanking. To establish the optimum blanking processes and evaluate the effect of blanking temperature on the sheared section surface and fracture direction. Along with the fracture mechanism and microstructure of the parts, a series of hot blanking experiments for B1500HS steels were carried out at different blanking temperatures (450–800°C) and an 8% die clearance. The experimental results show that with the blanking temperature, the smooth (burnish) zone width increases, and the fracture direction becomes nearly normal. The sheared section surface of the parts mainly demonstrates ductile fracture mainly, accompanied by local brittle fracture over the blanking temperature range of 450–600°C. A ductile fracture region contains a great amount of fine equiaxed dimples over the blanking temperature range of 650–800°C, their microstructure is of complete martensite.

Hot blanking process could be used for producing diverse fine blanking parts with comprehensive mechanical properties and to solve the problems in the piercing and trimming of press-hardened parts. To explore the optimal hot blanking process and evaluate the effects of some technological parameters on the phase transformation, fracture quality, and dimensional accuracy of the parts, several different blanking temperatures (450–800 °C) and die clearances (8–25%) were used in the hot blanking of B1500HS steel. The experimental results show that as the blanking temperature increases at a certain die clearance, the dimensional accuracy shows a trend of “negative growth–positive growth–negative growth,” and a higher dimensional accuracy of blanked parts can be attained at blanking temperatures 450–500, 600–650, or 750–800 °C. Besides, the burnish zone width increases, and the burnish and rollover zone widths account for ~ 80% of the steel sheet thickness at 800 °C. At blanking temperatures 650–800 °C, the microstructure of blanked parts is completely martensite, the microhardness of parts is ~ 550 HV, and the perpendicularity of fracture increases as the blanking temperature increases. Parts with a high-dimensional accuracy, better fracture perpendicularity, wide burnish zone, better mechanical properties, and wear resistance can be obtained at blanking temperatures 750–800 °C.

To study the effects of the deformation degree and cooling rate on the microstructure and phase transformation temperature for the B1500HS steel, the samples were heated at 900 °C for 5 min, compressed by 10, 20, 30 and 40% at the strain rate of 0.1 s−1, and then cooled down at the rates of 50, 40, 25, 20 and 15 °C/s by the thermo-mechanical simulator, respectively. The start and finish temperatures of the phase transformation were determined by the tangent method, and the volume fraction of the phase transformation was ascertained by the level principle according to the dilatometric curves. The volume fraction of the retained austenite was determined by X-ray diffraction. The results show that the volume fraction of the bainite rises with an increase in the deformation degree as the cooling rate is lower than the critical rate. At the same cooling rate, the phase transformation temperature rises with an increase in the deformation degree, and the sizes of both the martensite and bainite phases reduce due to the austenite grain refinement induced by the deformation. The volume fraction of the retained austenite reduces as the deformation degree increases. The critical cooling rate of the un-deformed samples is approximately 25 °C/s and the critical cooling rate rises as the deformation degree increases.

In order to solve the problem of tracking flocs during complex flocculating process, we propose an improved algorithm combining particle filter (PF) with compressed sensing (CS). The feature of flocs image is extracted via CS theory, which is used to detect the single-frame image and get the detection value. Simultaneously, the optimal estimation of particle in the space model of non-linear and non-Gaussian state is obtained by PF. Then, we correlate the optimal estimate with the detected value to determine the trajectory of each particle and to achieve flock tracking. Experimental results demonstrate that this improved algorithm realizes the real-time tracking of flocs and calculation of sedimentation velocity. In addition, it eliminates the shortcomings of heavy computation and low efficiency in the process of extracting image features , and thus guarantees the accuracy and efficiency of tracking flocs.

S-Adenosylmethionine decarboxylase (SAMDC) is a key rate-limiting enzyme involved in polyamines biosynthesis, and it plays important roles in plant growth, development and stresses response. However, no SAMDC gene was reported in rubber tree. Here we report characteristics of an SAMDC gene (HbSAMDC1) in rubber tree. HbSAMDC1 contains a 1080 bp open reading frame (ORF) encoding 359 amino acids. Quantitative real-time PCR analyses revealed that HbSAMDC1 exhibited distinct expression patterns in different tissues and was regulated by various stresses, including drought, cold, salt, wounding, and H2O2 treatments. HbSAMDC1 5′ untranslated region (UTR) contains a highly conserved overlapping tiny and small upstream ORFs (uORFs), encoding 2 and 52 amino acid residues, respectively. No introns were located in the main ORF of HbSAMDC1, whereas two introns were found in the 5′ UTR. In transgenic tobaccos, the highly conserved small uORF of HbSAMDC1 is found to be responsible for translational repression of downstream β-glucuronidase reporter. To our knowledge, this is the first report on molecular cloning, expression profiles, and 5′ UTR characteristics of HbSAMDC1. These results lay solid foundation for further elucidating HbSAMDC1 function in rubber tree.

Trastuzumab is a standard treatment for HER2-positive (HER2+) breast cancer, but some patients are refractory to the therapy. MicroRNAs (miRNAs) have been used to predict therapeutic effects for various cancers, but whether miRNAs can serve as biomarkers for HER2+ metastatic breast cancer (MBC) patients remains unclear. Using miRNA microarray, we identify 13 differentially expressed miRNAs in the serum of HER2+ MBC patients with distinct response to trastuzumab, and four miRNAs are selected to construct a signature to predict survival using LASSO model. Further, our data show that miR-940 is mainly released from the tumor cells and miR-451a, miR-16-5p and miR-17-3p are mainly from the immune cells. All these four miRNAs directly target signaling molecules that play crucial roles in regulating trastuzumab resistance. In summary, we develop a serum-based miRNA signature that potentially predicts the therapeutic benefit of trastuzumab for HER2+ MBC patients and warrants future validation in prospective clinical trials., Resistance to therapy is a significant issue for patients with metastatic breast cancer (MBC). Here the authors analyze total miRNA from serum samples of 386 MBC patients before treatment with a follow up of 31 months and define a four miRNA signature that predicts the therapeutic benefit of trastuzumab.

The thermal physical parameters have significant effects on the calculation accuracy of physical fields, and the boundary heat transfer coefficient between the die and water is one of the most important thermal physical parameters in the hot stamping. In order to attain the boundary heat transfer coefficient, the testing devices and test procedures are designed according to the characteristic of heat transfer in the hot stamping die. A method of estimating the temperature-dependent boundary heat transfer coefficient is presented, and an inverse heat conduction software is developed based on finite element method, advance-retreat method and golden section method. The software is used to calculate the boundary heat transfer coefficient according to the temperatures measured by NiCr–NiSi thermocouples in the experiment. The research results show that, the convergence of the method given in the paper is well, the surface temperature of sample has a significant effect on the boundary heat transfer coefficient between the die and water. The boundary heat transfer coefficient increases as the surface temperature of sample reduces, and the variation is nonlinear.

The design mind of SOPC (System on Programmable Chip), hardware & software co-design, will bring the system optimization with larger degree of freedom. It will establish the foundation on realizing the miniaturization and more efficient local preprocessing in smart cooperative sensor networks. In this contribution, a solution is proposed for smart multimedia sensor nodes based on the SOPC framework, aiming at improving the on-board processing capability and the degree of freedom in development. This paper mainly presents the structure and design method of the smart cooperative multimedia sensor node based on SOPC. The on-board feature extraction is realized and some correlative experimental data and results are presented as well. The experimental results evaluate the feasibility and efficiency of the proposed node design method.

We aim to characterize the clinical features and genetic causes for two affected siblings from a Chinese family with cone dystrophy (CD). Two patients and four unaffected family members were recruited and received complete ophthalmic examinations. Genomic DNA was isolated from the peripheral blood samples from all patients. Targeted next-generation sequencing (NGS) approach followed by intrafamilal cosegregation and in silico analyses were employed to determine the genetic defects. Ophthalmic evaluations finalized the clinical diagnosis of CD for the two patients in this family, both of whom presented macular atrophy with no remarkable changes in the peripheral retina. Comprehensive genetic screening approach revealed biallelic missense mutations in the Leber congenital amaurosis 5 (LCA5) gene, p.[Ala212Pro];[Tyr441Cys], as disease causative for this family. Both mutations were novel. The first substitution was predicted to eliminate a hydrogen bond and alter the tertiary structure of lebercilin, protein encoded by LCA5. We for the first time report novel biallelic LCA5 mutations in causing CD. Our study extends the phenotypic and genotypic spectrums for LCA5-associated retinopathies and better illustrates its genotype-phenotype correlations, which would help with better genetic diagnosis, prognosis and personalized treatment for CD patients.

Background Medical schools have been making efforts to develop their own problem-based learning (PBL) approaches based on their educational conditions, human resources and existing curriculum structures. This study aimed to explore a new framework by integrating the essential features of PBL and coaching psychology applicable to the undergraduate medical education context. Methods A participatory research design was employed. Four educational psychology researchers, eight undergraduate medical school students and two accredited PBL tutors participated in a four-month research programme. Data were collected through participatory observation, focus groups, semi-structured interviews, workshop documents and feedback surveys and then subjected to thematic content analysis. The triangulation of sources and member checking were used to ensure the credibility and trustworthiness of the research process. Results Five themes emerged from the analysis: current experience of PBL curriculum; the roles of and relationships between tutors and students; student group dynamics; development of self-directed learning; and coaching in PBL facilitation. On the basis of this empirical data, a systematic model of PBL and coaching psychology was developed. Conclusions The findings highlighted that coaching psychology could be incorporated into the facilitation system in PBL. The integrated framework of PBL and coaching psychology in undergraduate medical education has the potential to promote the development of the learning goals of cultivating clinical reasoning ability, lifelong learning capacities and medical humanity. Challenges, benefits and future directions for implementing the framework are discussed in this paper.

The aim of this work was to further investigate the glycolysis performance of lager and ale brewer’s yeasts under different fermentation temperature using a combined analysis of metabolic flux, glycolytic enzyme activities, and flux control. The results indicated that the fluxes through glycolytic pathway decreased with the change of the fermentation temperature from 15 °C to 10 °C, which resulted in the prolonged fermentation times. The maximum activities (V max) of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) at key nodes of glycolytic pathway decreased with decreasing fermentation temperature, which was estimated to have different control extent (22–84 %) on the glycolytic fluxes in exponential or flocculent phase. Moreover, the decrease of V max of PFK or PK displayed the crucial role in down-regulation of flux in flocculent phase. In addition, the metabolic state of ale strain was more sensitive to the variation of temperature than that of lager strain. The results of the metabolic flux and nodes control analysis in brewer’s yeasts under different fermentation temperature may provide an alternative approach to regulate glycolytic flux by changing V max and improve the production efficiency and beer quality.

High gravity (HG) or very high gravity (VHG) brewing has become popular in modern breweries due to its economic and product quality advantages. However, there are the negative impacts such as the fermentation performance of brewer’s yeast in HG or VHG wort, which are closely related to changes in cell physiological activity. In the present study, 3 kinds of worts, with different gravities, were used to examine the systematic effects on fermentation performance and physiological activity of lager yeast FBY009505 (Saccharomyces pastorianus) and ale yeast FBY0099 (Saccharomyces cerevisiae), as well as the resulting beer flavor. Results showed that the responses of FBY009505 and FBY0099 to the HG or VHG worts were similar. The specific fermentation rate and viability of cropped yeast of FBY009505 and FBY0099 were decreased with increasing wort gravity. The increased wort gravity resulted in the increase of energy charge and the decrease of α-glucosides transport rate and glycolytic enzyme activities. Moreover, the environmental stresses in the HG or VHG wort showed a higher inhibitory activity against α-glucoside transport than glycolytic enzymes. The content of intracellular trehalose and glycerol of FBY009505 and FBY0099 increased with the increase in wort gravity. The results from this study provided a potential means to systematically understand the physiology of brewer’s yeast under HG or VHG conditions.

Apriona germari is a destructive stem-boring pest. To date, the control of the pest is still based largely on the chemical insecticides. To meet the needs of people’s high pesticide efficacy and environment safety, the alternative management strategy must be proposed. Beauveria bassiana is one of the most widely studied and used entomopathogenic fungi. The potential of Beauveria bassiana used to control Apriona germari was here evaluated. The result showed that the infective rate of B. bassiana to adults was 20%, with no pathogenicity to eggs. But it showed a high pathogenicity to larvae. The laboratory bioassays showed that the mortality, when concentration was 1 × 108 conidia/mL, was 96.47% ten days after inoculation. LT50 of B. beauveria to Apriona germari larvae was 4.53 d at the concentration of 1 × 108 conidia/mL; LC50 was 6.76 × 105 conidia/mL. The infecting experiments in field showed that, 20 days after control, the mortality was 68.4%. The present results suggested that B. bassiana has an excellent potential for biological control of A. germari larvae.

22MnB5 is one of the most typical hot stamping boron steels. In order to study the effect of austenitizing temperature and holding time on the mechanical properties of hot stamping boron steel 22MnB5, a series of quenching process are done. The tensile strength and hardness of 22MnB5 samples are measured. The results show that 22MnB5 has a good quenching performance, and the tensile strength and hardness of samples quenched in a water-cooled steel die are similar to those of water quenching. The higher tensile strength and HRC hardness are achieved when austenitizing at temperatures of 880–910 °C. Holding at 910 °C for 5 min and then quenching gives rise to a better combination of tensile strength, hardness and ductility.