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Purpose: To better clarify the efficacy of neoadjuvant bevacizumab plus chemotherapy (BEV + CT) vs chemotherapy (CT) alone in the treatment of HER2-negative nonmetastatic breast cancer. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant articles published from January 1, 2000 to July 31, 2018. Review Manager software version 5.3 was used to perform this meta-analysis. Results: Six randomized controlled trials matched the selection criteria, yielding a total of 4,354 patients with early outcomes and 3,777 patients with late outcomes. Pooled pathological complete response (pCR) and 5-year disease-free survival (DFS) rates were higher for the neoadjuvant BEV + CT group (OR =1.37 [1.19, 1.58]; P<0.001 and HR =0.84 [0.72, 0.98]; P=0.020, respectively), but 5-year overall survival (OS) rate showed no significant difference (HR =0.79 [0.55, 1.11]; P=0.180). Subgroup analysis showed that the pCR rate was significantly higher in both patients with hormone receptor (HR)-positive breast cancer (OR =1.30 [1.01, 1.66]; P=0.040) and those with HR-negative breast cancer (OR =1.52 [1.25, 1.83]; P<0.001) in BEV + CT group. Conclusion: Compared with CT alone, neoadjuvant BEV + CT significantly improved the 5-year DFS rate of HER2-negative breast cancer patients, but showed no benefit in terms of 5-year OS rate. [ABSTRACT FROM AUTHOR]

Background: Studies had suggested increased risk of death of residents was associated with typhoons, particularly coastal regions. However, these findings ignored the impact of inland typhoons on the health of residents, especially the indirect death risk caused by typhoons. This study aimed to investigate the acute death risk of residents during inland typhoon Lekima in Jinan, further identify vulnerable populations and areas. Methods: We selected the daily death from 11 to 27th August 2019 in Jinan as case period, and conducted a time-stratified case-crossover design to match the contemporaneous data from 2016 to 2018 as control period. We used the generalized linear Poisson models to estimate the related effects of death risk during typhoon Lekima and lag days. Results: During the Lekima typhoon month, there were 3,366 deaths occurred in Jinan. Compared to unexposed periods, the acute death risk of non-accidental diseases (especially circulatory diseases), female and the older adults increased significantly in the second week after the typhoon. The maximum significant effect of circulatory disease deaths, female and older adult deaths were appeared on lag9, lag9, and lag13 respectively. And the typhoon-associated RR were 1.19 (95%CI:1.05,1.34), 1.28 (95%CI:1.08,1.52), and 1.22 (95%CI:1.06,1.42) respectively. The acute death risk of residents living in TQ and CQ increased significantly on Lag2 and Lag6 after the typhoon, respectively, while those living in LX, LC, HY, JY, and SH occurred from Lag 8 to Lag 13 after the typhoon. LC lasted the longest days. Conclusions: Typhoons would increase the vulnerability of residents living in Jinan which mainly occurred from the seventh day after the typhoon. Residents suffering from non-accidental diseases (circulatory diseases), female and the older adults were more vulnerable. The vulnerability of TQ and CQ occurred on Lag2 and Lag6 after typhoon Lekima, respectively, and the other areas except ZQ and PY occurred from Lag 8 to Lag 13. LC lasted the longest duration. Our findings emphasized the importance of the emergency response, which would help policymakers to identify vulnerable regions and populations accurately during typhoons and formulate the emergency response plan. [ABSTRACT FROM AUTHOR]

Objective: There is limited information from population‐based cancer registries regarding prognostic features of bilateral primary breast cancer (BPBC). Methods: Female patients diagnosed with BPBC between 2004 and 2014 were randomly divided into training (n = 7740) and validation (n = 2579) cohorts from the Surveillance, Epidemiology, and End Results Database. We proposed five various models. Multivariate Cox hazard regression and competing risk analysis were to explore prognosis factors in training cohort. Competing risk nomograms were constructed to combine significant prognostic factors to predict the 3‐year and the 5‐year survival of patients with BPBC. At last, in the validation cohort, the new score performance was evaluated with respect to the area under curve, concordance index, net reclassification index and calibration curve. Results: We found out that age, interval time, lymph nodes invasion, tumor size, tumor grade and estrogen receptor status were independent prognostic factors in both multivariate Cox hazard regression analysis and competing risk analysis. Concordance index in the model of the worse characteristics was 0.816 (95% CI: 0.791‐0.840), of the bilateral tumors was 0.819 (95% CI: 0.793‐0.844), of the worse tumor was 0.807 (0.782‐0.832), of the first tumor was 0.744 (0.728‐0.763) and of the second tumor was 0.778 (0.762‐0.794). Net reclassification index of the 3‐year and the 5‐year between them was 2.7% and −1.0%. The calibration curves showed high concordance between the nomogram prediction and actual observation. Conclusion: The prognosis of BPBC depended on bilateral tumors. The competing risk nomogram of the model of the worse characteristics may help clinicians predict survival simply and effectively. Metachronous bilateral breast cancer presented poorer survival than synchronous bilateral breast cancer. [ABSTRACT FROM AUTHOR]

• The epidemiological and virological characteristics of H7N9 avian influenza virus in the newly affected western Chinese provinces were analyzed. • A delayed peak of human infections was observed. • G11 and G3 were the dominant genotypes of prevalent low pathogenic (LP)- and highly pathogenic (HP)-H7N9 virus, respectively. • Reassortment has been ongoing. Eight additional provinces in western China reported human infections for the first time during the fifth wave of human H7N9 infections. The aim of this study was to analyze the epidemiological and virological characteristics of this outbreak. The epidemiological data of H7N9 cases from the newly affected western Chinese provinces were collected and analyzed. Full-length genome sequences of H7N9 virus were downloaded from the GenBank and GISAID databases, and phylogenetic, genotyping, and genetic analyses were conducted. The peak of human infections in the newly affected western Chinese provinces was delayed by 4 months compared to the eastern Chinese provinces, and both low pathogenic (LP) and highly pathogenic (HP) H7N9-infected cases were found. The LP- and HP-H7N9 virus belonged to 10 different genotypes (including four new genotypes), of which G11 and G3 were the dominant genotypes, respectively. Almost all of these viruses originated from eastern and southern China and were most probably imported from neighboring provinces. Genetic characteristics of the circulating viruses were similar to those of the viruses from previously affected provinces during Wave Five. A delayed peak of human infections was observed in the newly affected western Chinese provinces, and reassortment has been ongoing since the introduction of H7N9 viruses. This study highlights the importance of continued surveillance of the circulation and evolution of H7N9 virus in western China. [ABSTRACT FROM AUTHOR]

Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer. [ABSTRACT FROM AUTHOR]

Cyanobacterial blooms can impair drinking water quality due to the concomitant extracellular organic matter (EOM). As copper is often applied as an algicide, cyanobacteria may experience copper stress. However, it remains uncertain whether algal growth compensation occurs and how EOM characteristics change in response to copper stress. This study investigated the changes in growth conditions, photosynthetic capacity, and EOM characteristics of M. aeruginosa under copper stress. In all copper treatments, M. aeruginosa experienced a growth inhibition stage followed by a growth compensation stage. Notably, although chlorophyll-a fluorescence parameters dropped to zero immediately following high-intensity copper stress (0.2 and 0.5 mg/L), they later recovered to levels exceeding those of the control, indicating that photosystem II was not destroyed by copper stress. Copper stress influenced the dissolved organic carbon (DOC) content, polysaccharides, proteins, excitation–emission matrix spectra, hydrophobicity, and molecular weight (MW) distribution of EOM, with the effects varying based on stress intensity and growth stage. Principal component analysis revealed a correlation between the chlorophyll-a fluorescence parameters and EOM characteristics. These results imply that copper may not be an ideal algicide. Further research is needed to explore the dynamic response of EOM characteristics to environmental stress. [Display omitted] • Compensatory growth of M. aeruginosa was confirmed following exposure to copper stress. • Post-copper stress, M. aeruginosa 's chlorophyll-a fluorescence surpassed control. • Low copper concentration (0.05 mg/L) enhance short- and long-term EOM content. • EOM characteristics of M. aeruginosa varied with copper stress intensity and the specific growth stage. [ABSTRACT FROM AUTHOR]

Background: The incidence of hand foot and mouth disease (HFMD) has increased in recent years, making it a very common childhood illness worldwide. The relationship between different enterovirus genotypes and disease severity is not clearly understood. Given that enteroviruses are transmitted through the gastrointestinal tract, we hypothesized that variation in intestinal microorganisms of the host might play a role in the prognosis of HFMD.Methods: We carried out a meta-transcriptomic-wide association study of fecal samples obtained from a cohort of children (254 patients, 227 tested positive for enterovirus, including 16 patients co-infectied with 2 kinds of enterovirus) with mild and severe HFMD and healthy controls.Results: We found there was no significant difference in the amount of each virus type between the mild and severe cases. Genes of enterovirus 71 (EV71) and coxsackievirus A (CV-A) from the severe and mild cases did not show significant clustering. Clostridium sp. L2-50 and Bacteroides stercoris ATCC 43183 were enriched in the guts of children with severe HFMD and KEGG enrichment was found between mild and severe cases.Conclusions: Intestinal microorganisms appear to interact with enterovirus to determine the progression of HFMD. Genes of Bacteroides and Clostridium may be used as predictive markers for a more efficient prognosis and intervention. The enrichment of intestinal bacteria genes with functions may facilitate the development of severe symptoms for HFMD patients. [ABSTRACT FROM AUTHOR]

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19. Author summary: Currently, a novel coronavirus called SARS-COV-2 is spreading across many parts of the world. Unfortunately, there is still a lack of effective drugs against the virus. Additionally, it usually takes much longer time to develop a new drug using traditional methods. Thus, it is now better to rely on some alternative methods to develop drugs that can treat such a disease effectively. In this paper, we have proposed a deep learning and molecular dynamics simulation based hybrid drug screening procedure for identifying potential drug candidates targeting RdRp from 1906 market available drugs. Our screening have successfully identified a FDA-approved drug called Pralatrexate that strongly inhibits the replication of 2019-nCoV in vitro with EC50 values of 0.008μM. This work demonstrated the feasibility of accurate virtual drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19. [ABSTRACT FROM AUTHOR]

Importance: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments.Objective: To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Design, Setting, and Participants: Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion.Exposures: Patients received transfusion with convalescent plasma with a SARS-CoV-2-specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission.Main Outcomes and Measures: Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion.Results: All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2-specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion.Conclusions and Relevance: In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials. [ABSTRACT FROM AUTHOR]

Short-term traffic flow forecasting is one of the key issues in the field of dynamic traffic control and management. Because of the uncertainty and nonlinearity, short-term traffic flow forecasting remains a challenging task. In order to improve the accuracy of short-term traffic flow forecasting, a short-term traffic flow forecasting method based on LSSVM model optimized by GA-PSO hybrid algorithm is put forward. Firstly, the LSSVM model is constructed with combined kernel function. Then the GA-PSO hybrid optimization algorithm is designed to optimize the kernel function parameters efficiently and effectively. Finally, case validation is carried out using inductive loop data collected from the north-south viaduct in Shanghai. The experimental results demonstrate that the proposed GA-PSO-LSSVM model is superior to comparative method. [ABSTRACT FROM AUTHOR]

Background: High-mobility group box 2 (HMGB2) is implicated in tumorigenesis in various cancers. However, the clinical significance of HMGB2 signaling in human breast cancer progression remains unknown. Methods: We investigated HMGB2 expression in 185 cases of primary breast cancer and matched normal breast tissue specimens, and explored the underlying mechanisms of altered HMGB2 expression as well as the impact of this altered expression on breast cancer growth and on aerobic glycolysis using in vitro and animal models of breast cancer. Results: HMGB2 was more highly expressed in tumor-cell nuclei of breast cancer cells than in the adjacent normal breast tissues (P < 0.05). Higher HMGB2 expression correlated with larger tumor size (P = 0.003) and advanced tumor stage (P = 0.033). A Cox proportional hazards model revealed that HMGB2 expression was an independent prognostic factor for breast cancer after radical resection (P < 0.05). Experimentally, knockdown of HMGB2 expression by stable transfected shRNA significantly decreased the growth and glycolysis of breast cancer cells both in vitro and in mouse models. Mechanically, promotion of breast cancer progression by HMGB2 directly and significantly correlated with activation of LDHB expression and inactivation of FBP1 expression. Conclusions: These results disclose a novel role for HMGB2 in reprogramming the metabolic process in breast cancer cells by targeting LDHB and FBP1 and provide potential prognostic predictors for breast cancer patients. [ABSTRACT FROM AUTHOR]

We aimed to investigate the acute effect of extreme cold weather on circulatory disease mortality of older adults in Jinan, with individual and regional-scale characteristics as subgroup analyses to further identify vulnerable populations. This study contained the death data of Jinan from 2011 to 2020 (Nov–Mar). A time-stratified case-crossover method was used to estimate the effects of extreme cold weather and lags 0–8 days, controlling for holiday and relative humidity. To evaluate the impact of different durations and thresholds of extreme cold weather, we considered 4 cold day and 12 cold wave definitions Our results showed an increase in circulatory disease deaths under several definitions. The number of older adults died of circulatory diseases totaled 92,119 during the study period. In the definitions of cold day, the maximum significant effect ranging from 1.08 (95% CI: 1.03,1.14) to 1.13 (95% CI: 1.04,1.24) and appeared on Lag5 or Lag6. In the definitions of cold wave, the maximum significant effect ranging from 1.07 (95% CI: 1.02, 1.12) to 1.14 (95% CI: 1.03, 1.25). The cold effect is mainly attributable to cold day rather than an added effect related to the duration. Our research confirmed that extreme cold weather had a stronger impact on women [maximum effects with an OR of 1.21 (95% CI: 1.08, 1.36) in P1, 1.19 (95% CI: 1.05, 1.36) in M12)], and the effect gradient increased with age. Our findings support the evidence on the impact of extreme cold weather on circulatory disease mortality and provide a basis for policymakers to select target groups to develop policies and reduce the public health burden. • Extreme cold weather increased the death risk of older adults from circulatory diseases. • The cold effect on death risk of circulatory diseases was mainly attribute to "main effect". • Maximum significant estimates mostly appeared on the Lag5 or Lag6. • Stronger effect estimates were observed in women, and the effect gradient of vulnerability increased with age. [ABSTRACT FROM AUTHOR]

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing, as is research on the molecular mechanisms underlying cellular infection by coronaviruses, with the hope of developing therapeutic agents against this pandemic. Other important respiratory viruses such as 2009 pandemic H1N1 and H7N9 avian influenza virus (AIV), influenza A viruses, are also responsible for a possible outbreak due to their respiratory susceptibility. However, the interaction of these viruses with host cells and the regulation of post-transcriptional genes remains unclear. In this study, we detected and analyzed the comparative transcriptome profiling of SARS-CoV-2, panH1N1 (A/California/07/2009), and H7N9 (A/Shanghai/1/2013) infected cells. The results showed that the commonly upregulated genes among the three groups were mainly involved in autophagy, pertussis, and tuberculosis, which indicated that autophagy plays an important role in viral pathogenicity. There are three groups of commonly downregulated genes involved in metabolic pathways. Notably, unlike panH1N1 and H7N9, SARS-CoV-2 infection can inhibit the m-TOR pathway and activate the p53 signaling pathway, which may be responsible for unique autophagy induction and cell apoptosis. Particularly, upregulated expression of IRF1 was found in SARS-CoV-2, panH1N1, and H7N9 infection. Further analysis showed SARS-CoV-2, panH1N1, and H7N9 infection-induced upregulation of lncRNA-34087.27 could serve as a competitive endogenous RNA to stabilize IRF1 mRNA by competitively binding with miR-302b-3p. This study provides new insights into the molecular mechanisms of influenza A virus and SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) resulted from the outbreak of SARS-CoV-2 in December 2019. Currently, multiple efforts are being made to rapidly develop vaccines and treatments to fight COVID-19. Current vaccine candidates use inactivated SARS-CoV-2 viruses; therefore, it is important to understand the architecture of inactivated SARS-CoV-2. We have genetically and structurally characterized β-propiolactone-inactivated viruses from a propagated and purified clinical strain of SARS-CoV-2. We observed that the virus particles are roughly spherical or moderately pleiomorphic. Although a small fraction of prefusion spikes are found, most spikes appear nail shaped, thus resembling a postfusion state, where the S1 protein of the spike has disassociated from S2. Cryoelectron tomography and subtomogram averaging of these spikes yielded a density map that closely matches the overall structure of the SARS-CoV postfusion spike and its corresponding glycosylation site. Our findings have major implications for SARS-CoV-2 vaccine design, especially those using inactivated viruses. • β-propiolactone-inactivated SARS-CoV-2 viruses display postfusion spikes • Cryo-ET structure of SARS-CoV-2 postfusion spikes was determined at 11 Å resolution • This study calls for crucial structural characterization of vaccine candidates Several vaccine candidates using inactivated SARS-CoV-2 viruses are under development. Liu et al. used state-of-the-art cryoelectron microscopy technologies to characterize the architecture of inactivated SARS-CoV-2 viruses. They found that the viral spikes are mostly in a postfusion state, which is not desirable for vaccine development. [ABSTRACT FROM AUTHOR]