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Dobutamine (DOB) is recommended as an inotrope for septic patients with low cardiac output, but its long-term impact on sepsis-induced cardiomyopathy remains unclear. This study investigated the long-term effect of DOB on septic myocardial dysfunction and injury. Rats were exposed to cecal ligation and puncture (CLP), the intrinsic myocardial function, other organ functions, hemodynamics, inflammatory response, serum myocardial injury biomarkers, myocardial apoptosis, and vascular permeability were determined. At 6 h after CLP, the left ventricular ±dP/dt were significantly depressed, cardiac tumor necrosis factor-α and vascular cell adhesion molecule-1 expression were increased, but not serum cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine, and urea nitrogen concentrations in CLP group compared with controls. At 9 h after CLP, hepatic dysfunction was present in CLP rats compared with controls. At 6 h after CLP, DOB treatment did not affect hemodynamics, the left ventricular ±dP/dt, cytokine levels in serum and myocardium, as well as cardiomyocyte apoptosis and cardiac vascular hyperpermeability at 20 h after CLP. However, DOB (10.0 μg/kg) increased serum IL-10 level and improved survival in septic rats. These results indicate that the intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in sepsis and serum cTnI, NT-proBNP, and H-FABP are not suitable as early biomarkers for sepsis-induced myocardial dysfunction. Although DOB treatment (10.0 μg/kg) in the presence of myocardial dysfunction improves survival in septic rats, it neither improves myocardial function and hemodynamics nor attenuates myocardial injury at the later stage of sepsis.

Background and aim: Buyang Huanwu Decoction (BHD) is a traditional Chinese herbal medicine that is effective for treating cerebral ischemia (CI). However, the molecular mechanisms of BHD in CI have not been fully elucidated. In this study, we integrated the circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) network of middle cerebral artery occlusion (MACO) rats treated with BHD. Methods: SD rats were randomly divided into a control group, model group, model+BHD group (2.5, 5, 10 g/kg) and model+butylphthalide (NBP) group (54 mg/kg). The neurological functions of the rats were evaluated by a modified neurological severity scoring (mNSS) system. Pathological lesions were assessed by Nissl staining, and the effects of BHD on neurovascular unit (NVU) associated protein microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP) and von Willebrand factor (VWF) were assessed by immunohistochemistry. CeRNA and miRNA microarrays were used to establish the circRNA, miRNA, and mRNA profiles. Finally, a circRNA-miRNA-mRNA ternary transcription network was constructed. Results: BHD improved the neurobehavioral test scores (P

Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.

Objective To investigate the expression of Linc00342 in peripheral blood lymphocytes in patients with chronic kidney disease (CKD) and healthy people and to identify Linc00342 as a biomarker of chronic kidney disease. Methods Peripheral blood samples were collected from 30 patients with chronic kidney disease and 10 healthy volunteers at the First Affiliated Hospital of Bengbu Medical College, China. According to CKD classification, the patients were divided into three CKD groups (the CKD1/2 group, CKD3/4 group and CKD5 group) and a healthy volunteer group (the H group). The relative expression of Linc00342 in lymphocytes was detected by RT-PCR, while the IL-6 and IL-10 levels in the serum were detected by ELISA. In addition, the general data of the patients and healthy volunteers were recorded. Finally, SPSS software was used for statistical analysis. Results The expression level of Linc00342 in the peripheral blood lymphocytes of the four groups increased significantly as the CKD grade increased, and there were statistically significant differences (p < 0.01). There was a positive linear correlation between the expression of Linc00342 in peripheral blood lymphocytes and the eGFR (p < 0.05), which was expressed by the linear model equation: Y = 2.532 + 0.012X. Among the inflammatory factors for the early diagnosis of CKD, the area under the ROC curve for the expression of Linc00342 in peripheral blood lymphocyte was 0.953, the standard error was 0.034 and the 95% confidence interval was 0.000-1.000. Conclusion The expression level of Linc00342 in peripheral blood lymphocytes can reflect the severity of CKD, and Linc00342 is possibly used as a molecular marker of CKD.

Aim: To systematically profile and characterize the circular RNA (circRNA) expression pattern in estrogen receptor (ER)-positive breast cancer (BC). Materials & methods: CircRNA expression profile was performed in ER-positive BC and adjacent nontumor tissues. The differentially expressed circRNAs (DECs) was analyzed by bioinformatics. The analysis findings were validated by quantitative real-time PCR. Results: In total, 3653 DECs were detected in our ER-positive BC compared with the control. Bioinformatics analysis showed that some pathways related to cancer, especially BC, were significantly enriched. Additionally, hsa_circ_0087378 was validated to be downregulated in ER-positive BC and the hsa_circ_0087378-miR-1260b-SFRP1 axis was proposed to be a key regulatory pathway. Conclusion: This study revealed the general expression characteristics of specific DECs in ER-positive BC and hsa_circ_0087378 might be a promising candidate target.

BACKGROUND: The expression and function of long noncoding RNA (lncRNA) LOC100505851 in breast cancer are still unknown. We aimed to examine the expression of lncRNA LOC100505851 in breast cancer and adjacent tissues and preliminarily explore its predictive value and function in breast cancer patients receiving neoadjuvant therapy (NAT). METHODS: The expression of lncRNA LOC100505851 was tested by qRT-PCR. The correlation between LOC100505851 expression and clinicopathological factors as well as pathological complete response (pCR) was analyzed by chi-squared test and logistic regression, respectively. The online database Kaplan-Meier plotter (KM plotter) was used to compare relapse-free survival (RFS) and overall survival (OS) between groups with different LOC100505851 expression levels. Subcellular localization of LOC100505851 was determined by nuclear and cytoplasmic extraction. A bioinformatics tool was used to predict RNA-binding proteins (RBPs) and interaction among these proteins. RESULTS: LncRNA LOC100505851 was significantly expressed at lower levels in cancer tissues than in adjacent tissues (P

Background With the explosion of COVID-19 globally, it was unclear if people with Parkinson’s disease (PD) were at increased risk for severe manifestations or negative outcomes. Objectives To report on people with PD who had suspected or confirmed COVID-19 to understand how COVID-19 manifested in PD patients. Methods We surveyed PD patients who reported COVID-19 to their Movement Disorders specialists at Columbia University Irving Medical Center and respondents from an online survey administered by the Parkinson’s Foundation that assessed COVID-19 symptoms, general clinical outcomes and changes in motor and non-motor PD symptoms. Results Forty-six participants with PD and COVID-19 were enrolled. Similar to the general population, the manifestations of COVID-19 among people with PD were heterogeneous ranging from asymptomatic carriers (1/46) to death (6/46). The most commonly reported COVID-19 symptoms were fever/chills, fatigue, cough, weight loss, and muscle pain. Worsening and new onset of motor and non-motor PD symptoms during COVID-19 illness were also reported, including dyskinesia, rigidity, balance disturbances, anxiety, depression, and insomnia. Conclusion We did not find sufficient evidence that PD is an independent risk factor for severe COVID-19 and death. Larger studies with controls are required to understand this further. Longitudinal follow-up of these participants will allow for observation of possible long-term effects of COVID-19 in PD patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-021-10784-3.

Background: Homologous recombination repair gene mutations are associated with increased platinum-based chemosensitivity, whereas few studies have reported the predictive value of family history of cancer for breast cancer in the neoadjuvant setting. This study aimed to construct a brief and effective novel family history scoring system and explore its association with pathological complete response (pCR), survival outcomes, and safety for locally advanced breast cancer receiving platinum-based neoadjuvant chemotherapy. Methods: A total of 262 patients treated with neoadjuvant cisplatin and paclitaxel were included. Neo-Family History Score (NeoFHS) was calculated according to cancer type, age at diagnosis, kinship, and number of affected relatives. Logistic regression was performed to analyze the association between pCR and NeoFHS. Survival rates were compared by Kaplan-Meier curves, examined by log-rank test and Cox proportional hazard regressions. Results: For all patients enrolled in this study, clinical tumor stage (p=0·048), estrogen receptor status (p=0·001), progesterone receptor status (p=0·036), human epidermal growth factor receptor 2 (HER2) status (p=0·013), and molecular subtype (p=0·016) were significantly related to NeoFHS. The multivariate logistic regression revealed that NeoFHS is an independent predictive factor of pCR (OR=2·262, 95% CI 1·159-4·414, p=0·017), especially in node-positive (OR=3·088, 95% CI 1·498-6·367, p=0·002), hormone receptor-positive (OR=2·645, 95% CI 1·164-6·010, p=0·020), and HER2-negative subgroups (OR=4·786, 95% CI 1·550-14·775, p=0·006). Kaplan-Meier estimates suggested that NeoFHS could serve as an independent prognostic factor for relapse-free survival in the whole group (adjusted HR=0·305, 95% CI 0·102-0·910, p=0·033) and node-positive subgroup (adjusted HR=0·317, 95% CI 0·103-0·973, p=0·045). Furthermore, alopecia (p=0·001), nausea (p=0·001), peripheral neuropathy (p=0·018), diarrhea (p=0·026), constipation (p=0·037) of any grade and leukopenia of grade 3 or greater (p=0·005) were more common in patients with higher NeoFHS. Conclusions: Our study revealed that NeoFHS is a practical and effective biomarker for predicting not only pCR and survival outcomes but also chemotherapy-induced AEs for neoadjuvant platinum-based chemotherapy for breast cancer. It may help screen candidate responders and guide safety managements in the future. Trial Registrion: SHPD001 (ClinicalTrials.gov identifier: NCT02199418) and SHPD002 (ClinicalTrials.gov identifier: NCT02221999). Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Shanghai Natural Science Foundation [grant numbers 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant numbers 2018-15 and 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49 and ZH2018QNA42], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01 and PY2018-III-15], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shanghai Municipal Key Clinical Specialty Declaration of Interest: None to declare. Ethical Approval: Ethical approvals were granted for both trials by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University.

ObjectiveLinc00665 is a novel long non-coding RNA that can promote the progression of breast cancer, but its value in predicting the efficacy of neoadjuvant chemotherapy (NAC) for breast cancer has not been reported. We aim to analyze the correlation between Linc00665 expression and pathological complete response (pCR) in breast cancer patients.Materials and MethodsThe present study examined the predictive role of Linc00665 expression in pCR after NAC using both univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve and area under curve (AUC) were utilized to evaluate the performance of Linc00665 in predicting pCR. The Kyoto Encyclopedia of Gene and Genome (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) were also conducted to determine the biological processes where Linc00665 may participate in.ResultsThe present study study totally enrolled 102 breast cancer patients. The univariate analysis showed that Linc00665 level, human epidermal growth factor receptor 2 (HER2) status and hormone receptor (HR) status were correlated with pCR. The multivariate analysis showed that Linc00665 expression was an independent predictor of pCR (OR = 0.351, 95% CI: 0.125–0.936, P = 0.040), especially in patients with HR-positive/HER2-negative subtype (OR = 0.272, 95% CI: 0.104–0.664, P = 0.005). The KEGG analysis indicated that Linc00665 may be involved in drug metabolism. The GSEA analysis revealed that Linc00665 is correlated to DNA damage repair.ConclusionLinc00665 may be a potential novel predictive biomarker for breast cancer in NAC, especially for HR-positive/HER2-negative patients.

As the COVID-19 pandemic continues to affect the international community, very little is known about its impact on the health and day-to-day activities of people with Parkinson’s disease (PwPD). To better understand the emotional and behavioral consequences of the public health policies implemented to mitigate the spread of SARS-CoV-2 in PwPD, and to explore the factors contributing to accessing alternative health care mechanisms, such as telehealth, we administered an anonymous knowledge, attitude, and practice survey to PwPD and care partners, via the mailing lists of the Parkinson’s Foundation and Columbia University Parkinson’s Disease Center of Excellence with an average response rate of 19.3%. Sufficient information was provided by 1,342 PwPD to be included in the final analysis. Approximately half of respondents reported a negative change in PD symptoms, with 45–66% reporting mood disturbances. Telehealth use increased from 9.7% prior to the pandemic to 63.5% during the pandemic. Higher income and higher education were associated with telehealth use. Services were more often used for doctor’s appointment than physical, occupational, speech, or mental health therapies. Almost half (46%) of PwPD preferred to continue using telehealth always or sometimes after the coronavirus outbreak had ended. Having received support/instruction for telehealth and having a care partner, friend, or family member to help them with the telehealth visit increased the likelihood of continuous use of telehealth after the pandemic ended. Taken together, PD symptoms and management practices were markedly affected by COVID-19. Given the observed demographic limitations of telehealth, expanding its implementation to include additional physical, occupational, psychological, and speech therapies, increasing support for telehealth, as well as reaching underserved (low income) populations is urgently required.

Background Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy. Methods This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression. Findings A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc. Interpretation This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms. Funding This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shanghai Municipal Key Clinical Specialty.

Background: a2A adrenoceptor receptor (a2A-AR) plays an important role in inflammatory response in Kupffer cells in sepsis. Blockage of a2A-AR inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF-a) production and protects the target organ functions in sepsis animal models; however, its expression and function in microglia have remained obscure. This study aimed to determine whether a2A-AR was expressed in microglia and whether its activation would exacerbate microglial inflammation and sepsis-related neurological dysfunction. Methods: Western blotting and immunofluorescence were used to detect a2A-AR expression in BV-2 microglia. Enzyme-linked immunosorbent assay (ELISA) was used to assess the TNF-a production in the supernatant after LPS induced BV-2 cells were pretreated with a2A-AR agonist BHT933, and/or a2A-AR antagonist BRL44408, and also in the supernatants derived from BV-2 cells treated with BHT933 and/or PKC inhibitor. Signaling pathways including JNK，P38，ERK，IκBa, CREB and PCK were detected by western blotting. a2A-AR gene knock-out (KO) and wild type (WT) mice were prepared by intraperitoneal injection of LPS. Lectin /TNF-a labeled microglia and synaptophysin/NeuN expression in the hippocampus were localized by immunofluorescence. Morris water maze test, Rotating-stick test, Elevated plus maze test and Open-field test were conducted over 4 weeks.Results: a2A-AR was constitutively expressed in BV-2 microglia, which was enhanced by LPS. Pretreatment with BHT933 promoted LPS-induced IκB and JNK phosphorylation, and TNF-a secretion in BV-2 microglia which were abrogated by BRL44408. Activation of a2A-AR by BHT933 also increased PKC phosphorylation in LPS-treated BV-2 microglia. PKC inhibitor significantly reversed the promoting effects of BHT933 on IκB and JNK phosphorylation as well as TNF-a secretion in LPS-treated BV-2 microglia. Furthermore, LPS treatment significantly increased hippocampal microglia activation and TNF-a expression, decreased hippocampal synaptophysin expression, and impaired cognitive and motor functions in WT mice, all of which were markedly reversed by a2A-AR gene knockout. Conclusion: a2A-AR activation promotes LPS-induced IκB and JNK phosphorylation as well as TNF-a production in microglia through the PKC signaling pathway. Knockout of a2A-AR gene significantly improves LPS-induced cognitive and motor impairments in mice, indicating that a2A-AR is a potential therapeutic target for sepsis-associated encephalopathy.

Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.

Introduction: The Montreal Cognitive Assessment (MoCA), an instrument widely used for cognitive screening in Parkinson's disease (PD), is validated in Hebrew and English. However, it remains unknown whether the scores are comparable. Methods: The MoCA was analyzed in 483 Ashkenazi Jewish PD patients in Tel-Aviv and New York who had MoCA ≥21. Each section of the MoCA was compared between English and Hebrew. Linear regression models were used to test the association between MoCA performance and language. Results: Total MoCA scores were lower in Hebrew than in English (25.4 versus 26.1; P = 0.007), even after adjustment for age, sex, PD duration, genotype, levodopa equivalent dose, the Unified Parkinson's Disease Rating Scale (UPDRS-III), and Geriatric Depression Scale score in a linear model (P

Background: Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Methods: The concentration of sphingosine 1-phosphate (S1P) was detected by high-performance liquid chromatography-tandem mass spectrometry. The Oxygen consumption rate was measured by XF96 metabolic flux analyzer. The interaction between TIM and Specificity protein 1 (Sp1) was confirmed by Co-immunoprecipitation. Chromatin immunoprecipitation and luciferase report assay were performed to demonstrate whether SP1 binds on the Alkaline Ceramidase 2 (ACER2) promotor. Findings: The expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with Sp1 which contributes to upregulate the expression of ACER2. Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Interpretation: Our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81672358, No. 81802890, No. 81172505, No. 81302302). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The SHPD001 and SHPD002 trials were approved by the Independent Ethical Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Before enrollment, all patients signed written informed consent. All animal experiments were approved by the Institutional Animal Care and Use Committee of East China Normal University.

With the rapid development of ultra-high-voltage direct-current (UHVDC) transmission, the strength of environmental static electric field (SEF) around UHVDC transmission lines increased substantially, which has aroused widely public attention on the potential health effects of SEF. In this study, the effect of SEF exposure on learning and memory ability was investigated. Institute of Cancer Research mice were exposed to 56.3 kV/m SEF for a short term (7 days) or long term (49 days). Behaviors in the Morris water maze (MWM) test, hippocampal neurotransmitter contents, and oxidative stress indicators were examined. Results showed that short-term SEF exposure significantly prolonged escape latency and decreased the number of platform-site crossovers, as well as decreased the time spent in the target quadrant in the MWM test. Meanwhile, serotonin level and the ratio of glutamate level to γ-aminobutyric acid level changed significantly. Besides, malondialdehyde content and glutathione peroxidase activity increased significantly, while superoxide dismutase activity decreased significantly. After long-term SEF exposure, all indices above showed no significant differences between the SEF and sham exposure groups. These data indicated that short-term exposure to 56.3 kV/m SEF could cause abnormal neurotransmitter levels and oxidative stress in the hippocampus, which led to the decline in learning and memory ability. Under the condition of long-term exposure, the SEF-induced disturbances in neurotransmitter contents and redox balance were offset by the compensatory responses of mice, and thus, the learning and memory ability returned to normal level. The temporary and reversible decline in learning and memory ability was only a common biological effect of SEF rather than a health hazard.

Background Homologous recombination deficiency is associated with platinum-based chemosensitivity, whereas few studies reported the predictive value of family history of cancer for breast cancer in the neoadjuvant setting. This study aimed to construct a novel family history scoring system and to explore its association with clinical outcomes for patients with breast cancer receiving neoadjuvant platinum-based chemotherapy. Methods This study included 262 patients with locally advanced breast cancer enrolled in the SHPD001 and SHPD002 trials from October 2013 to June 2018. The Neo-Family History Score (NeoFHS) was calculated according to cancer type, age at diagnosis, kinship, and number of affected relatives. Findings Clinical tumor stage (p=0·048), estrogen receptor status (p=0·001), progesterone receptor status (p=0·036), human epidermal growth factor receptor 2 status (p=0·013), and molecular subtype (p=0·016) were significantly related to NeoFHS. NeoFHS could serve as an independent predictive factor of pathological complete response (pCR) (OR=2·262, 95% CI 1·159-4·414, p=0·017) and an independent prognostic factor of relapse-free survival (adjusted HR=0·305, 95% CI 0·102-0·910, p=0·033). Alopecia (p=0·001), nausea (p=0·001), peripheral neuropathy (p=0·018), diarrhea (p=0·026), constipation (p=0·037) of any grade and leukopenia of grade 3 or greater (p=0·005) were more common in patients with higher NeoFHS. Interpretation NeoFHS is a practical and effective biomarker for predicting not only pCR and survival outcomes but also chemotherapy-induced adverse events for neoadjuvant platinum-based chemotherapy in breast cancer. It may help screen candidate responders and guide safety managements. Funding Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shanghai Municipal Key Clinical Specialty.

Uric acid (UA) is a natural antioxidant and iron scavenger in the human body, which has been hypothesized to exert an anti-oxidative effect in Parkinson’s disease (PD). This study aimed to investigate the relationship between serum UA levels and freezing of gait (FOG) in PD. A total of 321 Chinese PD patients with fasting serum UA evaluated were included in the cross-sectional study. Demographics, clinical features, and therapeutic regimen were collected. The Unified PD Rating Scale (UPDRS) III and Hoehn and Yahr (H and Y) stage were used to evaluate the severity of disease, and the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA) scales were used to assess the cognitive function. Patients with FOG showed lower proportion of male, longer disease duration, lower body mass index, lower concentrations of serum UA, higher total levodopa equivalent daily dosage, higher UPDRS III score, greater median H and Y stage, lower scores of FAB and MoCA, and higher frequencies of motor fluctuation, dyskinesia, falls, and festination compared to patients without FOG (P

With the rapid development of traffic facilities in China, traffic noise pollution is increasingly prominent. This research aims to explore the influences of combined traffic noise on receptors' anxiety. Institute of cancer research mice were exposed to combined traffic noise (CTN) from highway and high-speed railway for 52days, whose day-night equivalent continuous A-weighted sound pressure level (Ldn) was 70dB(A). The impacts of CTN on anxiety were explored by behavior tests and monoamine neurotransmitter assays. The results were in depth discussed in comparison to two previous studies on the impacts of single high-speed railway noise (HSRN) and aircraft noise (AN), but data from the three studies were not merged and statistically compared. No significant differences were shown in the behavioral indicators and the monoamine levels between the experimental and control groups after CTN exposure, indicating no obvious impacts of 70dB(A) CTN on anxiety in mice were found in this study. When Ldn was approximately 70dB(A), CTN had less obvious impacts on anxiety than HSRN and AN, which is mainly related to that both the acoustical parameters of noise events [maximum noise level (LAmax), noise events duration, slope of rise, difference of LAmax from 1-min background equivalent continuous A-weighted sound pressure level] and modified day-night equivalent continuous R-weighted sound pressure level (considering animal auditory sensitivity to different sound frequencies and circadian rhythms) of CTN are smaller than those of HSRN and AN.

Background: Lymphocytes, neutrophils, and monocytes are vital effector cells in innate immunity. We postulated that lymphocyte to red blood cell ratio (LRR), neutrophil to red blood cell ratio (NRR), monocyte to red blood cell ratio (MRR) could represent the intensity of systemic inflammatory immunological reaction reflected through the lymphocyte, neutrophil and monocyte respectively. This study aimed to access the predictive and prognostic value of LRR, NRR, MRR and LRR-NRR-MRR score for locally advanced breast cancer. Methods: A total of 137 patients from two clinical trials SHPD002 and SHPD003 were included. Logistic regression analysis was used to evaluate the association between ratios and pathological complete response (pCR). Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier method and cox regression analysis. Results: Lower LRR-NRR-MRR score (OR =0.593; 95% CI: 0.369–0.954; P=0.031) was more easily to achieve pCR in multivariate analysis. Lower LRR (P=0.022), NRR (P=0.027) and MRR (P=0.024) were significantly associated with better DFS. LRR-NRR-MRR score was an independently prognostic factor for both DFS (HR =3.318; 95% CI: 1.601–6.876; P=0.001) and OS (HR =3.160; 95% CI: 1.030–9.696; P=0.044). Conclusions: The LRR-NRR-MRR score could be identified as a new predictive biomarker for the therapeutic effect of neoadjuvant therapy and an independent prognostic factor for both DFS and OS for locally advanced breast cancer.

With the rapid development of high voltage direct current transmission, the possibility of health effects associated with static electric field (SEF) has caused wide public concern. To examine the effects of long-lasting, full-body exposure to SEF on cognition, Institute of Cancer Research mice were exposed to SEF for 35 d. The intensities of SEF in experimental group I (EG-I), experimental group II (EG-II) and control group (CG) were 2.30∼15.40 kV/m, 9.20∼21.85 kV/m and 0 kV/m, respectively. The performance in learning and memory of mice were tested by Morris water maze (MWM) on days 2∼6, 16∼20 and 30∼34 during the exposure period. The concentrations of hippocampal amino acid neurotransmitters were evaluated on days 7, 21 and 35. Results showed that the latency in the MWM test had no significant difference among the EG-I, EG-II and CG (P > 0.05) during the exposure period. The percentage of time spent in the target quadrant was significantly decreased in the EG-II on day 34 during the exposure period (P < 0.05), whereas the percentage of time spent in the opposite quadrant increased markedly (P < 0.01). The glutamate and gamma-aminobutyric acid concentrations showed no significant differences among the EG-I, EG-II and CG (P > 0.05) during the exposure period. These results indicated that long-lasting, full-body exposure to SEF with certain intensity would not cause significant influence on learning ability, but it might associate with memory impairment of receptors. Meanwhile, this effect of memory impairment was dose-dependent and not causally linked to the glutamate and gamma-aminobutyric acid levels in the hippocampus.

Background The association between the polymorphism rs3794087 in the solute carrier family 1, member 2 ( SLC1A2 ) and the risk of essential tremor (ET) among different studies is controversial. Considering the overlap of the clinical manifestations and pathological characteristics of ET, Parkinson's disease (PD), multiple system atrophy (MSA), as well as amyotrophic lateral sclerosis (ALS), we explored the possible genetic association of rs3794087 with ET, PD, MSA and ALS in a Chinese cohort. Methods A total of 112 ET, 621 PD, 356 MSA, 513 sporadic ALS (SALS) patients and 437 healthy controls (HCs) were genotyped for rs3794087 using the Sequenom iPLEX Assay technology. Results Significant association was found between SLC1A2 rs3794087 and PD in the additive model ( p = 0.006), which was more obvious in early onset PD. The minor allele of rs3794087 decreased the risk for early onset PD ( p = 0.011, OR: 0.73, 95% CI: 0.56–0.94). However, no significant differences in the genotype distributions and allele frequency were observed in the allelic, additive, dominant or recessive genetic models of SLC1A2 rs3794087 between ET patients and HCs, between SALS patients and HCs, and between MSA and HCs. Conclusions Our results suggested SLC1A2 rs3794087 may decrease the risk for PD in a Chinese cohort, but do not support a role in the susceptibility to SALS or MSA.

Background The rs156429 polymorphism in the glycoprotein nonmetastatic melanoma protein B (GPNMB) gene was found to be associated with the risk for Parkinson disease (PD) in Caucasian population by genome-wide association studies (GWAS). Recently, encoded protein, GPNMB, was identified as a novel neuro-protective factor in amyotrophic lateral sclerosis (ALS). The overlapping of clinical manifestations and pathologic characteristics among PD, ALS, and multiple system atrophy (MSA) are observed. Object This study aimed at investigating the possible associations of the polymorphism and the three neurodegenerative diseases: PD, ALS and MSA in a Chinese population. Methods All of the subjects, including PD (n = 1096), sporadic ALS (SALS) (n = 876) and MSA (n = 356) patients, and 829 health controls (HCs) were included. All subjects were genotyped for this polymorphism using Sequenom iPLEX Assay technology. Results No differences were found in the genotype distributions and minor allele frequency of GPNMB rs156429 between PD patients and HCs, between SALS patients and HCs, between MSA patients and HCs, and between subgroups of PD, ALS and MSA patients with regard to clinical features such as sex, age of onset, presence or absence of cognitive abnormality, depression and anxiety. Conclusion Lack of association identified in our study suggests that it may be premature to conclude associations between GPNMB rs156429 and SALS, PD and MSA. More studies on such an association involving a larger number of participants are needed to confirm the present findings.

With the rapid development of ultra high voltage alternating current (UHV AC) transmission, the intensity of environmental power frequency electric field (PFEF) near UHV AC transmission lines increased continuously, which has attracted considerable public attention on the potential health effects of PFEF. In this study, the effect of PFEF exposure on the kidney was explored. Institute of Cancer Research (ICR) mice were exposed to 35 kV/m PFEF (50 Hz). Two indicators relating to renal function (urea nitrogen and creatinine) were tested after the exposure of 7d, 14d, 21d, 35d and 49d. The pathological morphology and cellular ultrastructure of kidney were observed respectively by light microscopy and electron microscopy after the exposure of 25d and 52d. Results showed that compared with that of the control group, the concentration of urea nitrogen of 35 kV/m PFEF exposure group significantly increased on the 21st and 35th days, and the concentration of creatinine significantly increased on the 14th, 21st and 35th days. However, the concentrations of creatinine and urea nitrogen both returned to normal levels on the 49th day. Furthermore, an enlarged Bowman's space, the vacuolation of renal tubular epithelial cells and the foot process effacement of podocyte were found after 25d exposure, but no abnormality was observed after 52d exposure. Obviously, a short-term (35d) exposure of 35 kV/m PFEF could cause kidney injury, which could be recovered after a longer-term (52d) exposure. Based on this study and relevant literatures, one explanation for this two-way effect is as follows. Kidney injury was caused by the disequilibrium of mitochondrial dynamics under 35 kV/m PFEF exposure. PFEF could also activate Wnt/β-catenin signal to promote the recovery of renal tubular epithelial cells and glomerular podocytes, so kidney injury could be repaired.

Background: EPIC1 is an oncogenic long non-coding ribonucleic acid (RNA) that promotes cell growth and cell-cycle progression and inhibits apoptosis in several cancer cell lines. However, clinical studies on EPIC1 in breast cancer, specifically in the neoadjuvant setting, are relatively few. Methods: Patients treated with weekly paclitaxel–cisplatin-based neoadjuvant chemotherapy after core-needle biopsy were included in the study. Real-time quantitative polymerase chain reaction assays were performed to detect EPIC1 expression. Results: Among all patients included in this study ( n = 111), higher EPIC1 expression was associated with estrogen receptor negativity, human epidermal growth factor receptor 2 positivity, higher Ki67 index, and higher histologic grade. Multivariate analysis suggested that EPIC1 expression was an independent predictive factor for pathological complete response, with a significant interaction between EPIC1 expression and age. The Kaplan–Meier Plotter dataset suggested that the EPIC1 high-expression group showed a worse 10-year distant metastasis-free survival and post-progression survival when compared with the EPIC1 low-expression group. The Cancer Genome Atlas dataset suggested that the overall survival in the EPIC1 high-expression group was inferior to that in the EPIC1 low-expression group, specifically in hormone receptor (HorR)-positive patients and patients aged Conclusions: Our study suggests that EPIC1 may be a promising biomarker for both neoadjuvant chemosensitivity and long-term clinical outcomes in breast cancer, specifically in the HorR-positive premenopausal subgroup. It may also help identify candidate responders and determine treatment strategies.

With the development of ultra-high-voltage direct-current transmission, the intensity of static electric field (SEF) under transmission lines increased, which has aroused public attention on its potential health effects. In order to examine effects of SEF exposure on liver, institute of cancer research mice were exposed to SEF with intensities of 27.5 kV/m, 34.7 kV/m and 56.3 kV/m, respectively. In each intensity of SEF exposure, a corresponding sham exposure group was used. Several indices relating to liver function (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and oxidative stress (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA)) were tested after exposure of 7, 14, 21 and 35 days. Results showed that exposure to SEF with intensities of 27.5 kV/m and 34.7 kV/m for 35 days did not significantly influence any detected indices above. Under SEF exposure with intensity of 56.3 kV/m, the SOD activity in liver was significantly increased after exposure of 7 and 14 days. However, no significant increase was found in MDA content as well as the activities of AST and ALT between exposure group and sham exposure group during SEF exposure of 56.3 kV/m. It suggested that from three SEF intensities, only exposure to SEF with intensity of 56.3 kV/m (7 and 14 days) caused a temporary oxidative stress response in liver expressed by the increase in activity of SOD, but it did not produce oxidative damage. This biological effect may be related to the increase of mitochondrial membrane potential of hepatocytes caused by SEF exposure. When the membrane potential exceeds a threshold, Q cycle in mitochondria will be affected, which will result in an increase of superoxide anion concentration and ultimately an oxidative stress.

In order to explore the effects of combined traffic noise (CTN) on learning and memory function, young Sprague-Dawley (SD) rats were exposed to CTN from highway and high-speed railway for 52 days, whose day-night equivalent continuous A-weighted sound pressure level (Ldn) was 70 dB(A) (corresponding sound pressure level was 80 dB). The synaptic ultrastructure and the expressions of phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and N-methyl-D-aspartate receptor 1 (NMDAR1 or NR1) in the hippocampus were tested by transmission electron microscopy (TEM) and Western blot, respectively. Results showed that there was no significant difference in the synaptic ultrastructure and the expressions of p-CaMKII and NR1 in the hippocampus of young rats between the experimental group and control group. Compared with single high-speed railway noise (HSRN) with Ldn of 70 dB(A), CTN had less influences on learning and memory function, which was closely related to smaller intermittency of CTN and less anxiety caused by CTN. In comparison with white noise with a sound pressure level of 80 dB, CTN had less impacts on learning and memory function, which was mainly associated with CTN’s smaller R-weighted sound pressure level based on rats’ auditory sensitivity.

Background and Purpose: We sought to determine when transporting patients directly to a comprehensive stroke center (CSC; the “mothership”) is favorable compared to a “drip-and-ship” approach while accounting for the varying predictive abilities of pre-hospital large vessel occlusion (LVO) screening methods. Methods: We built a decision analysis model to compare anticipated functional outcomes for patients who are within IV-tPA treatment window in “mothership” and “drip-and-ship”. Key branches included IV-tPA eligibility, IV-tPA only or endovascular therapy (ET), successful reperfusion after ET, and treatment effects. In terms of the probability of requiring ET, we assessed three pre-hospital LVO screening methods: no LVO screening, the Rapid Arterial oCclusion Evaluation (RACE) Scale for Stroke, and in-ambulance CT angiography for LVO. Good outcome was defined as mRS 0-1 and, secondarily, mRS 0-2. Imputed probabilities and workflow times were extracted from published studies. We used one-way and two-way sensitivity analyses to vary two key inputs: time from onset to arrival at primary stroke center (PSC) and additional travel time to CSC. Results: The relative benefit of the “mothership” approach varied with the likelihood of pre-hospital LVO identification for outcome of mRS 0-1. In the absence of pre-hospital LVO screening, “drip-and-ship” was always favored. When pre-hospital CT angiography is used, “mothership” is always favored. When modeling the use of the RACE Scale for patients with onset-to-PSC arrival time less than 70 minutes, “mothership” was favored if the additional travel time to CSC was less than 21 minutes. When onset-to-PSC arrival time passed 70 minutes, “mothership” was favored for additional travel times up to 48 minutes (Figure). Conclusion: The results of our decision analysis model suggest that, in addition to transport times, pre-hospital LVO screening and time from stroke onset could influence triage decision making.

Although the copper/zinc superoxide dismutase-1 (SOD1) gene has been identified in both familial ALS (FALS) and sporadic ALS (SALS), it has rarely been studied in Chinese patients with ALS, and there are few studies with large samples. This study sought to assess the prevalence of SOD1 mutations in Chinese ALS patients. We screened a cohort of 499 ALS patients (487 SALS and 12 FALS) from the Department of Neurology at the West China Hospital of Sichuan University and analyzed all coding exons of SOD1 by Sanger sequencing. In addition, we reviewed the mutation frequencies of common ALS causative genes in Chinese populations. Eight missense mutations in SOD1 were found in 8 ALS individuals: two novel mutations (p.G73D and p.V120F) and six previously reported mutations. The frequencies of SOD1 mutations were 1.03% (5/487) in SALS and 25% (3/12) in FALS from Southwest China. A literature review indicated that the mutation rates of major ALS causative genes were 53.55% in FALS and 6.29% in SALS. In Chinese SALS and FALS, the highest mutation frequency was in the SOD1 gene. Our results suggest that SOD1 mutation is the most common cause of ALS in Chinese populations and that the mutation spectrum of ALS varies among different ethnic populations.

Background Parkinson’s disease (PD) is a common heterogeneous neurodegenerative disorder in elder population. Parkinson’s disease dementia (PDD) is one of the most common non-motor manifestations in PD patients. No comprehensive review has been conducted to assess risk factors for PDD. Methods A systemic search for studies on PDD risk factors was performed. Cohort and case–control studies that clearly defined PDD and presented relevant data were included. The data were analyzed to generate a pooled effect size and 95 % confidence interval (CI). Publication bias was assessed using the Egger’s test and the Begg’s test. Results A systematic search was conducted and yielded 5195 articles. After screening, 25 studies were included in the current analysis. Development of PDD was positively associated with age (odds ratio [OR] 1.07, 95 % CI 1.03-1.13), male (OR 1.33, 95 % CI 1.08-1.64), higher Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores (relative risk [RR] 1.04, 95 % CI 1.01-1.07), hallucination (OR 2.47, 95 % CI 1.36-4.47), REM sleep behavior disorder (RBD) (OR 8.38, 95 % CI 3.87-18.08), smoking (ever vs. never) (RR 1.93, 95 % CI 1.15-3.26) and hypertension (OR 1.57, 95 % CI 1.11-2.22). An inverse association was found between education (RR 0.94, 95 % CI 0.91-0.98) and PDD. Other reported factors, including age of onset, disease duration of PD, Hoehn and Yahr stage and diabetes mellitus were not significantly associated with PDD. Conclusions Advanced age, male, higher UPDRS III scores, hallucination, RBD, smoking and hypertension increase the risk of PDD, whereas higher education is a protective factor for PDD. Electronic supplementary material The online version of this article (doi:10.1186/s40035-016-0058-0) contains supplementary material, which is available to authorized users.