Search

Using gas chromatography–tandem mass spectrometry and electrospun nanofibrous membrane, we developed and validated a simple, rapid, and sensitive methodology for quantifying eugenol residues in fish tissue and water samples. Fish tissue extract and water samples (315 samples) collected from three southeastern China provinces (Shanghai, Zhejiang, and Fujian), originating from eight provinces of Zhejiang, Jiangsu, Shandong, Guangdong, Fujian, Anhui, Shanghai, and Jiangxi, from April 2021 to April 2023 were filtered with an electrospun nanofiber membrane, extracted with trichloromethane/n-hexane, and directly concentrated to dry after simple purification. An internal standard of p-terphenyl in n-hexane and 5-µL injection volumes of the solutions was used to analyze eugenol via internal calibration with a minimum concentration of 0.5 µg/L in water samples and 0.1 µg/kg in aquatic product samples. The highest amount of eugenol was detected in Fujian province, possibly due to the higher temperature during transportation, while the lowest amount was found in Shanghai, which mainly uses temporary fish-culture devices. This is a fast, inexpensive, and effective method for testing large quantities of fish water and meat samples. [ABSTRACT FROM AUTHOR]

Greigite (Fe3S4), which have ferromagnetic in inverse thiospinel (AB2S4), is widely researched to use an adsorbent and biomedical field because non-toxicity and abundant in nature. Iron-based materials are known to have a high theoretical capacity because of their multivalent state including redox pairs, but still suffer from collapse and aggregate during the charge/discharge process. Here, the synthesized Fe3S4 nanosheet structure materials wrapped with reduced graphene oxide (Fe3S4NSs@rGO) were used as an anode electrode material for sodium-ion batteries (SIBs). The nano-sheet structure facilitates ion diffusion through expanded surface area, and rGO can effectively improve electrochemical conductivity and structure stability. As-prepared Fe3S4NSs@rGO were used as a host material to insert Na-ion via a conversion process, and the stabilized structure maintains the high capacity and long cycle performance. Thus, the Fe3S4NSs@rGO deliver a reversible capacity of 950 mAh g−1 after 200 cycles at a current density of 1A g−1 and 524 mAh g−1 after 400 cycles at a current density of 2A g−1, which is much higher than reported materials.

A multifunctional trastuzumab-nanoparticle-fluorocarbon system was developed to maximize the diagnostic effects in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The mesoporous silica nanoparticle shape (e.g. amorphous, spherical, and tubular) was altered to optimize the ultrasound contrast potential. Fluorocarbon conjugated mesoporous silica nanoparticles produced higher mean pixel intensities. At lower non-toxic concentrations, tubular shaped nanoparticles produced a higher mean pixel intensity compared to amorphous and spherical particles. All systems displayed a clear binding preference towards HER2-positive breast cancer cells. Increased incubation times and conjugation of fluorocarbon to mesoporous nanoparticles increased binding preference to HER2-positive breast cancer cells. The highest binding affinity was seen with tubular shaped nanoparticles as compared to amorphous and spherical particles. The trastuzumab-nanoparticlefluorocarbon system of each morphology displayed functionality of enhancing contrast in ultrasound. [ABSTRACT FROM AUTHOR]

Background: Infratentorial craniotomy patients have a high incidence of postoperative nausea and vomiting (PONV). Enhanced Recovery After Surgery (ERAS) protocols have been shown in multiple surgical disciplines to improve outcomes, including reduced PONV. However, very few studies have described the application of ERAS to infratentorial craniotomy. The aim of this study was to examine whether our ERAS protocol for infratentorial craniotomy could improve PONV.Methods: We implemented an evidence-based, multimodal ERAS protocol for patients undergoing infratentorial craniotomy. A total of 105 patients who underwent infratentorial craniotomy were randomized into either the ERAS group (n = 50) or the control group (n = 55). Primary outcomes were the incidence of vomiting, nausea score, and use of rescue antiemetic during the first 72 h after surgery. Secondary outcomes included postoperative anxiety level, sleep quality, and complications.Results: Over the entire 72 h post-craniotomy observation period, the cumulative incidence of vomiting was significantly lower in the ERAS group than in the control group. Meanwhile, the incidence of vomiting was significantly lower in the ERAS group on postoperative days (PODs) 2 and 3. Notably, the proportion of patients with mild nausea (VAS 0-4) was higher in the ERAS group as compared to the control group on PODs 2 or 3. Additionally, the postoperative anxiety level and quality of sleep were significantly better in the ERAS group.Conclusion: Successful implementation of our ERAS protocol in infratentorial craniotomy patients could attenuate postoperative anxiety, improve sleep quality, and reduce the incidence of PONV, without increasing the rate of postoperative complications.Trial Registration: ChiCTR-INR-16009662, 27 Oct 2016, Clinical study on the development and efficacy evaluation of Enhanced Recovery After Surgery (ERAS) in Neurosurgery. [ABSTRACT FROM AUTHOR]

Surrogate models have been widely adopted for reliability analysis. The common approach is to construct a series of surrogates based on a training set and then pick out the best one with the highest accuracy as an approximation of the time-consuming limit state function. However, the traditional method increases the risk of adopting an inappropriate model and does not take full advantage of the data devoted to constructing different surrogates. Furthermore, obtaining more samples is very expensive and sometimes even impossible. Therefore, to save the cost of constructing the surrogate and improve the prediction accuracy, an ensemble strategy is proposed in this paper for efficiently analyzing the structural reliability. The values of the weights are obtained by a recursive process and the leave-one-out technique, in which the values are updated in each iteration until a given prediction accuracy is achieved. Besides, a learning function is used to guide the selection of the next sampling candidate. Because the learning function utilizes the uncertainty estimator of the surrogate to guide the design of experiments (DoE), to accurately calculate the uncertainty estimator of the ensemble of surrogates, the concept of weighted mean square error is proposed. After the high-quality ensemble of surrogates of the limit state function is available, the Monte Carlo method is employed to calculate the failure probabilities. The proposed method is evaluated by three analytic problems and one engineering problem. The results show that the proposed ensemble of surrogates has better prediction accuracy and robustness than the stand-alone surrogates and the existing ensemble techniques. [ABSTRACT FROM AUTHOR]

Background. Nosocomial EVD-related ventriculitis is a major complication and a significant cause of morbidity and mortality in critically ill neurological patients. Questions remain about best management of EVDs. The purpose of this study is to compare our incidence of ventriculitis to studies using different catheters and/or antibiotic coverage schemes and determine whether c-EVD with prolonged antibiotics given for the duration of drain placement is inferior to ac-EVD with pp-abx or ac-EVD with prolonged antibiotics for prevention of ventriculitis. Methods. A retrospective chart review of all patients who had EVDs placed from January 2010 through December 2015 at home institution was performed. Statistical analysis was performed using Fisher’s exact test to compare incidence of ventriculitis identified in other studies with that of home institution. Results. The study included 107 patients, 66 (61.7%) males and 41 (38.3%) females. Average age was 56 years ranging from 18 to 95 years. Average length of drain placement was 7.8 days ranging from 2 to 23 days. Average length of drain placement in infected drains was 13.3 days ranging from 11 to 15 days. There were 3 cases with positive CSF cultures (Staphylococcus haemolyticus and Staphylococcus epidermidis x 2). There were 2 cases with a CSF having a positive gram stain but failed to yield any bacterial growth on culture and did not meet predefined criteria. Conclusions. The c-EVD with prolonged antibiotics given for the duration of drain placement is not inferior to ac-EVD with pp-abx or ac-EVD with prolonged antibiotics for prevention of ventriculitis. The c-EVD with prolonged antibiotics is superior to c-EVD with pp-abx and conventional EVD without antibiotics for prevention of ventriculitis. Selection should include considerations for antibiotic stewardship and cost effectiveness. Future studies should also utilize clinical and CSF profile criteria in addition to positive CSF cultures for identifying ventriculitis to prevent line colonization from classification as ventriculitis in analysis. [ABSTRACT FROM AUTHOR]

HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients. [ABSTRACT FROM AUTHOR]

Cladribine (2CdA), a synthetic purine analog interfering with DNA synthesis, is a medication used to treat hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, shows antitumor activity in various human cancers, including hematological malignancies. The therapeutic potential of cladribine and entinostat against multiple myeloma (MM) remains unclear. Here we investigate the combinatorial effects of cladribine and entinostat within the range of their clinical achievable concentrations on MM cells. While either agent alone inhibited MM cell proliferation in a dose-dependent manner, their combinations synergistically induced anti-proliferative/anti-survival effects on all MM cell lines (RPMI8226, U266, and MM1.R) tested. Further studies showed that the combinations of cladribine and entinostat as compared to either agent alone more potently induced mitotic catastrophe in the MM cells, and resulted in a marked increase of the cells at G1 phase associated with decrease of Cyclin D1 and E2F-1 expression and upregulation of p21waf−1. Apoptotic ELISA and western blot analyses revealed that the combinations of cladribine and entinostat exerted a much more profound activity to induce apoptosis and DNA damage response, evidenced by enhanced phosphorylation of histone H2A.X and the DNA repair enzymes Chk1 and Chk2. Collectively, our data demonstrate that the combinations of cladribine and entinostat exhibit potent activity to induce anti-proliferative/anti-survival effects on MM cells via induction of cell cycle G1 arrest, apoptosis, and DNA damage response. Regimens consisting of cladribine and/or entinostat may offer a new treatment option for patients with MM. Abbreviations: MM, multiple myeloma; HCL, hairy cell leukemia; HDAC, histone deacetylase; Ab, antibody; mAb, monoclonal Ab; FBS, fetal bovine serum; CI, combination index; PAGE, polyacrylamide gel electrophoresis; ELISA, enzyme-linked immunosorbent assay; PARP, poly(ADP-ribose) polymerase; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt [ABSTRACT FROM AUTHOR]

Introduction: Neurocritical care patients are at high risk for stress-related upper gastrointestinal (UGI) bleeding. The aim of this meta-analysis was to evaluate the risks and benefits of stress ulcer prophylaxis (SUP) in this patient group.Methods: A systematic search of major electronic literature databases was conducted. Eligible studies were randomized controlled trials (RCTs) in which researchers compared the effects of SUP (with proton pump inhibitors or histamine 2 receptor antagonists) with placebo or no prophylaxis in neurocritical care patients. The primary outcome was UGI bleeding, and secondary outcomes were all-cause mortality and nosocomial pneumonia. Study heterogeneity was sought and quantified. The results were reported as risk ratios/relative risks (RRs) with 95 % confidence intervals (CIs).Results: We included 8 RCTs comprising an aggregate of 829 neurocritical care patients. Among these trials, one study conducted in a non-intensive care unit setting that did not meet our inclusion criteria was ultimately included based on further evaluation. All studies were judged as having a high or unclear risk of bias. SUP was more effective than placebo or no prophylaxis at reducing UGI bleeding (random effects: RR 0.31; 95 % CI 0.20-0.47; P < 0.00001; I (2) = 45 %) and all-cause mortality (fixed effects: RR 0.70; 95 % CI 0.50-0.98; P = 0.04; I (2) = 0 %). There was no difference between SUP and placebo or no prophylaxis regarding nosocomial pneumonia (random effects: RR 1.14; 95 % CI 0.67-1.94; P = 0.62; I (2) = 42 %). The slight asymmetry of the funnel plots raised the concern of small trial bias, and apparent heterogeneity existed in participants, interventions, control treatments, and outcome measures.Conclusions: In neurocritical care patients, SUP seems to be more effective than placebo or no prophylaxis in preventing UGI bleeding and reducing all-cause mortality while not increasing the risk of nosocomial pneumonia. The robustness of this conclusion is limited by a lack of trials with a low risk of bias, sparse data, heterogeneity among trials, and a concern regarding small trial bias.Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO) identifier: CRD42015015802 . Date of registration: 6 Jan 2015. [ABSTRACT FROM AUTHOR]

The Kriging-based reliability method with a sequential design of experiments (DoE) has been developed in recent years for implicit limit state functions. Such methods include the efficient global reliability analysis, the active learning reliability method combining Kriging and MCS Simulations. In this research, a novel local approximation method based on the most probable failure point (MPFP) is proposed to improve such methods. In this method, the MPFP calculated in the last iteration is the center of the next sampling region. The size of the local region depends on the reliability index obtained by the First Order Reliability Method (FORM) and the deviation distance of the standard deviation. The proposed algorithm, which approximates the limit state function accurately near MPFP rather than in the whole design space, can avoid selecting samples in regions that have negligible effects on the reliability analysis results. In addition, a multi-point enrichment technique is also introduced to select multiple sample points in each iteration. After the high-quality approximation of limit state function is obtained, the failure probability is calculated by the Monte Carlo method. Four numerical examples are used to validate the accuracy and efficiency of the proposed method. Results show that the proposed method is very effective for an accurate evaluation of the failure probability. [ABSTRACT FROM AUTHOR]

The defect-rich unconventional phase Cu 7.2 S 4 Nanotubes are fabricated by a facile microwave-induced selective etching method. Benefitting from the unique one-dimensional crystal structure and lattice defect-rich hollow structure, the Cu 7.2 S 4 nanotubes exhibit high reversible capacity and remarkable cycling stability. [Display omitted] • The defect-rich Cu 7.2 S 4 nanotubes are fabricated for the first time. • The unique microwave-induced selective etching method is demonstrated. • The record cycling stability is achieved over the Cu 7.2 S 4 nanotube cathode. • The multistep reaction kinetics of the Cu 7.2 S 4 nanotube cathode are confirmed. Copper sulfide is promising great potential for capable cathode in rechargeable magnesium batteries. However, divalent Mg2+ diffusion in its host lattice is subject to high lattice strain and mechanical stress mainly due to strong Coulombic interaction. Herein, a microwave-induced selective etching strategy is reported to construct non-stoichiometric-phase robust Cu 7.2 S 4 nanotubes with rich lattice defects, which can proceed with ultra-long-cycling stability over 1600 cycles with ultra-low capacity decay of 0.0109 % per cycle at 1.0 A g−1. Furthermore, the Cu 7.2 S 4 nanotube cathode can also exhibit a large specific capacity of 314 mAh g−1 at 0.1 A g−1 as well as an excellent rate capability of 91.7 mAh g−1 at 1.0 A g−1. The present electrochemical performances greatly surpass those of Cu 7.2 S 4 nanowire, Cu 7.2 S 4 nanoparticle, and conventional phase CuS nanotubes and at least are comparable to the conversion-type cathode materials reported so far. The generated lattice defect combined with the optimized robust nanotube structure can effectively buffer lattice strain and mechanical stress to provide a favorable diffusion kinetic. Our designed microwave-induced selective etching system demonstrates significant superiority in morphology, phase, and defect engineering of Cu 7.2 S 4 nanotubes to accommodate reversible Mg2+ storage for high-performance rechargeable magnesium batteries. [ABSTRACT FROM AUTHOR]

Dark carbon fixation (DCF), conducted mainly by chemoautotrophs, contributes greatly to primary production and the global carbon budget. Understanding the response of DCF process to climate warming in coastal wetlands is of great significance for model optimization and climate change prediction. Here, based on a four-year field warming experiment (average annual temperature increase of 1.5°C), DCF rates were observed to be significantly inhibited by warming in coastal wetlands (average annual DCF decline of 21.6%, and estimated annual loss of 0.08-1.5 Tg C yr-1 in global coastal marshes), thus causing a positive climate feedback. Under climate warming, chemoautotrophic microbial abundance and biodiversity, which were jointly affected by environmental changes such as soil organic carbon and water content, were recognized as significant drivers directly affecting DCF rates. Metagenomic analysis further revealed that climate warming may alter the pattern of DCF carbon sequestration pathways in coastal wetlands, increasing the relative importance of the 3HP/4HB cycle, whereas the relative importance of the dominant chemoautotrophic carbon fixation pathways (CBB cycle and W-L pathway) may decrease due to warming stress. Collectively, our work uncovers the feedback mechanism of microbially mediated DCF to climate warming in coastal wetlands, and emphasizes a decrease in carbon sequestration through DCF activities in this globally important ecosystem under a warming climate., (© The Author(s) [2024]. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Introduction: Patient comfort is an important quality indicator of healthcare. According to Kolcaba's comfort theory, enhanced comfort is achieved by meeting the needs in four contexts: physical, psychospiritual, sociocultural and environmental. An enhanced patient comfort (EPC) programme based on this theory has been designed for elective neurosurgical patients. This study aims to assess its feasibility, effectiveness and safety., Methods and Analysis: The EPC programme patients will be evaluated in a single institutional randomised controlled trial. A total of 110 patients admitted for elective neurosurgery (including craniotomy, endoscopic trans-sphenoidal surgery and spine surgery) will be randomised in a 1:1 ratio to two groups. Patients in the EPC group are managed under the newly developed EPC programme, which aims to enhance patient experience and includes care coordination since admission (such as appointment of a care support coordinator, personalised setting, and cultural and spiritual support), preoperative management (such as lifestyle intervention, potential psychological and sleep intervention, and prerehabilitation), intraoperative and anaesthetic management (such as nurse coaching, music playing, and pre-emptive warming), postoperative management (such as early extubation, early diet advancement, mood and sleep management, and early ambulation) and optimised discharge planning; while those in the control group receive conventional perioperative care. The primary outcome is patient satisfaction and comfort measured by the Chinese Surgical Inpatient Satisfaction and Comfort Questionnaire. The secondary outcomes include postoperative morbidity and mortality, postoperative pain score, postoperative nausea and vomiting, functional recovery status (Karnofsky performance status and Quality of Recovery-15 score), mental status (anxiety and depression), nutritional status, health-related quality of life, hospital length of stay, reoperation and readmission rates, overall cost and patient experience., Ethics and Dissemination: Ethical approval to conduct the study has been obtained from Institutional Review Board of Xi'an International Medical Center (No. 202028). The results will be presented at scientific meetings and published in peer-reviewed journals., Trial Registration Number: Chinese clinical trial registry ChiCTR2000039983., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry-based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies., Significance: GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer., (©2022 American Association for Cancer Research.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo . Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Purpose: Thyroid disease is a frequent comorbidity in women with breast cancer, and many require thyroid hormone replacement therapy (THRT). We postulated that THRT has a deleterious clinical effect mechanistically through hormonal interactions, nuclear receptor cross-talk, and upregulation of high-risk breast cancer genes., Experimental Design: Observational studies of patients with lymph node-negative (LN - ) breast cancer ( n = 820 and n = 160) were performed to test interactions between THRT and clinical, histologic, outcome, and treatment variables. Differences between the two cohorts include but are not limited to patient numbers, decades of treatment, duration of follow-up/treatment, tumor sizes, incidence, and type and dose/regimen of antihormonal and/or chemotherapeutic agents. In vivo and vitro models, in silico databases, and molecular methods were used to study interactions and define mechanisms underlying THRT effects., Results: THRT significantly and independently reduced disease-free and breast cancer-specific overall survival of only the steroid receptor (SR)-positive (as compared with SR-negative) node-negative patients in both long-term observational studies. Patients with SR + LN - breast cancer who received THRT and tamoxifen experienced the shortest survival of all treatment groups. A less potent interaction between THRT and aromatase inhibitors was noted in the second patient cohort. Using in vivo and in vitro models, TH administration enhanced estrogen and TH-associated gene expression and proliferation, nuclear colocalization of estrogen receptor and thyroid hormone receptor, and activation of genes used clinically to predict tumor aggression in SR + breast cancer, including the IGF-IR , WNT , and TGFβ pathways., Conclusions: We show clinically significant adverse interactions between THRT, estrogenic, and oncogenic signaling in patients with SR + LN - breast cancer., (©2020 American Association for Cancer Research.)

Objective: To prospectively evaluate the efficacy of a neurosurgical enhanced recovery after surgery (ERAS) protocol on the management of postoperative pain after elective craniotomies. Methods: This randomized controlled trial was conducted in the neurosurgical center of Tangdu Hospital (Fourth Military Medical University, Xi'an, China). A total of 129 patients undergoing craniotomies between October 2016 and July 2017 were enrolled in a randomized clinical trial comparing an ERAS protocol to a conventional postoperative care regimen. The primary outcome was the postoperative pain score assessed by a verbal numerical rating scale (NRS). Results: Patients in the ERAS group had a significant reduction in their postoperative pain scores on POD 1 compared to patients in the control group (p < 0.05). More patients (n = 44, 68.8%) in the ERAS group experienced mild pain (NRS: 1 to 3) on POD1 compared with patients (n = 23, 35.4%) in the control group (p < 0.05). A further reduction in pain scores was also observed on POD 2 and maintained on POD 3 in the ERAS group compared with that in the control group. In addition, the median postoperative length of hospital stay was significantly decreased with the incorporation of the ERAS protocol compared to controls (ERAS: 4 days, control: 7 days, P<0.001). Conclusion: The implementation of a neurosurgical ERAS protocol for elective craniotomy patients has significant benefits in alleviating postoperative pain and enhancing recovery leading to early discharge after surgery compared to conventional care. Further evaluation of this protocol in larger, multi-center studies is warranted., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Approximately 20% of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2 (HER2/ErbB2). Of these, some also express steroid receptors (the so-called Luminal B subtype), whereas others do not (the HER2 subtype). HER2 abnormal breast cancers are associated with a worse prognosis, chemotherapy resistance, and sensitivity to selected anti-HER2 targeted therapeutics. Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic; rather, the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells. Most notably, this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors, particularly the androgen receptor. We discuss members of the HER receptor tyrosine kinase family, heterodimer formation, and downstream signaling, with a focus on HER2 associated pathology in breast carcinogenesis. The development and application of anti-HER2 drugs, including selected clinical trials, are discussed. In light of the many excellent reviews in the clinical literature, our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance. These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors, targeting crosstalk between HER2 and other nuclear receptors, lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation, and metformin, a broadly inhibitory drug. We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+ invasive breast cancer patients., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2020.)

Objective: To evaluate patient satisfaction and associated predictors at discharge, as well as patient experience at 30-day follow-up, in a neurosurgical enhanced recovery after surgery (ERAS) programme., Design: A single-centre, prospective, randomised controlled study., Setting: A tertiary hospital in China., Participants: A total of 140 neurosurgical patients aged 18-65 years old who had a single intracranial lesion and were admitted for elective craniotomy between October 2016 and July 2017 were included., Interventions: Patients were randomised into two groups: 70 patients received care according to a novel neurosurgical ERAS protocol (ERAS group) and 70 patients received conventional perioperative care (control group)., Outcome Measures: Patient satisfaction at discharge was evaluated using a multimodal questionnaire. A secondary analysis of patient experience regarding participation in the ERAS programme was conducted using a semistructured qualitative interview via telephone at 30-day follow-up., Results: The mean patient satisfaction was significantly higher in the ERAS group than in the control group at discharge (92.2±4.3 vs 86.8±7.4, p=0.0001). The most important predictors of patient satisfaction included age (OR=6.934), postoperative nausea and vomiting (PONV) Visual Analogue Scale (VAS) score (OR=0.184), absorbable skin suture (OR=0.007) and postoperative length of stay (LOS) (OR=0.765). Analysis on patient experience revealed five themes: information transfer, professional support, shared responsibility and active participation, readiness for discharge, and follow-up, all of which are closely related and represent positive and negative aspects., Conclusions: Measures that include decreasing PONV VAS score, incorporating absorbable skin suture and shortening LOS seem to increase patient satisfaction in a neurosurgical ERAS programme. Analysis of data on patient experience highlights several aspects to achieve patient-centred and high-quality care. Further studies are warranted to standardise the assessment of patient satisfaction and experience in planning, employing and appraising the ERAS programme., Trial Registration Number: ChiCTR-INR-16009662., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction The Journal of Neurosurgery (JNS) published its first volume in 1944 and has evolved into the top cited journal in the field of neurosurgery. The aim of this study was to determine and characterize the 100 most cited (based on the total number of citations) vs. most relevant (based on the number of citations per year) articles originating in JNS. Methods The top 100 most cited articles in JNS were determined by searching the Web of Science database. Citations per year were additionally calculated for the top 1000 articles by total citations to rank the 100 most relevant articles. Results The median number of total citations for the 100 most cited articles in JNS was 505 (range 383-2200), and the median number of citations per year for the 100 most relevant articles was 21.88 (range 17.31-82.61). The median year of publication for the 100 most cited and most relevant articles was 1990 and 1999, respectively (P < 0.0001). Most articles originated in the United States in both categories (72% and 71%, respectively). The most common topic of study was cerebrovascular on both lists, followed by trauma on the most cited list vs. tumor on the most relevant list. The most relevant list also contained considerably more articles with a higher level of evidence such as systemic reviews/meta-analyses and prospective studies. Conclusions This study highlights the key contributing factors to the growth and flourishing of JNS. It also reveals several discrepancies between the most cited and most relevant articles, with the latter including more recently published articles, more studies addressing tumor, and more level I/1 (NHMRC/CEBM) evidence. Bibliometric analysis serves as a useful tool for clinicians and researchers to appraise published literature and understand the scientific foundation of modern neurosurgery., Competing Interests: The authors have declared that no competing interests exist.

Although ErbB2-targeted therapeutics have significantly improved ErbB2 + breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2 + cancers. Nevertheless, the anti-cancer efficacy and clinical application of ganetespib for ErbB2 + breast cancer is largely unknown. In our study, we examined the anti-cancer effects of ganetespib on ErbB2 + BT474 and SKBR3 breast cancer cells, and isogenic paired cancer cell lines with lentivirus-mediated ErbB2 overexpression. Ganetespib potently inhibited cell proliferation, cell cycle progression, survival, and activation/phosphorylation of ErbB2 and key downstream effectors in ErbB2 + breast cancer cells. Moreover, ganetespib decreased the total protein levels of HSP90 client proteins and reduced ErbB2 protein half-life. ErbB2-overexpressing cancer cells were also more sensitive to ganetespib-mediated growth inhibition than parental cells. Ganetespib also strikingly potentiated the inhibitory effects of lapatinib in BT474 and SKBR3 cells. Ultimately, our results support the application of ganetespib-mediated HSP90 inhibition as a promising therapeutic strategy for ErbB2 + breast cancer.

Background/aim: ESE-1/Elf3 controls transformation properties in mammary epithelial cells, and is most clinically relevant in HER2 + breast cancer. Herein we showed that ESE-1 knockdown inhibits tumorigenic growth in HER2 + , trastuzumab-resistant HR20 (derived from HER2 + ER + BT474) and Pool2 (derived from HER2 + ER- SKBR3 cells) cell lines., Materials and Methods: We used cell proliferation, clonogenicity, viability, and soft agar assays to measure the effects of ESE-1 knockdown in cell lines., Results: ESE-1 knockdown in the resistant cell lines inhibited HER2 and other downstream effectors in a cell-type specific manner, but caused down-regulation of pAkt and cyclin D1 in both sublines. In parental BT474 and SKBR3 ESE-1 silencing revealed a potent anti-proliferative effect that mimics the trastuzumab-mediated growth inhibition but did not enhance trastuzumab sensitivity in the resistant sublines., Conclusion: This study provides rationale to study ESE-1 as a novel mean to treat HER2 + patients who show resistance to anti-HER2 therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells. We found that lapatinib concurrently downregulated CIP2A and receptor tyrosine kinase signaling in ErbB2-overexpressing SKBR3 and 78617 cells; however, these effects were attenuated in lapatinib-resistant (LR) cells. CIP2A overexpression rendered SKBR3 and 78617 cells resistant to lapatinib-induced apoptosis and growth inhibition. Conversely, CIP2A knockdown via lentiviral shRNA enhanced cell sensitivity to lapatinib-induced growth inhibition and apoptosis. Results also suggested that lapatinib downregulated CIP2A through regulation of protein stability. We further demonstrated that lapatinib-induced CIP2A downregulation can be recapitulated by LY294002, suggesting that Akt mediates CIP2A upregulation. Importantly, lapatinib induced differential CIP2A downregulation between parental BT474 and BT474/LR cell lines. Moreover, CIP2A shRNA knockdown significantly sensitized the BT474/LR cells to lapatinib. Collectively, our results demonstrate that CIP2A is a molecular target and resistance factor of lapatinib with a critical role in lapatinib-induced cellular responses, including the inhibition of the CIP2A-Akt feedback loop. Further investigation of lapatinib-mediated CIP2A regulation will advance our understanding of lapatinib-associated anti-tumor activities and drug resistance., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicting interests to declare.