tbuckley/cabot-search huggingface dataset:
Potent antibacterial activity of MSI-1 derived from the magainin 2 peptide against drug-resistant bacteria
Authors: Lingman Ma, Xin Xie, Hanhan Liu, Ya Huang, Haomin Wu, Meiling Jiang, Pengfei Xu, Xinyue Ye, Changlin Zhou
Journal: Theranostics (2020)

The structural modification of existing AMPs is an effective strategy to develop antimicrobial agents with high-efficiency, low-cost and low-toxicity antimicrobial agents. Methods: Here, we truncated 14-amino-acids at the N-terminus of MSI-78 to obtain MSI and further modified MSI to obtain four peptide analogs: MSI-1, MSI-2, MSI-3 and MSI-4. These peptide mutants were evaluated regarding their antibacterial activity against various sensitive or resistant bacteria; toxicity against mammalian cells or mice; and stability against violent pH, temperature variations and high NaCl concentrations. Finally, we also elucidated the possible mechanisms underlying its mode of action. Results: The results showed that MSI-1 and MSI-3 displayed activity that was superior to that of MSI-78 with MICs of 4-16 μg/ml and MBCs of 8-64 μg/ml, respectively, especially against drug-resistant bacteria, due to the increase in percent helicity and amphiphilicity. However, MSI-3, with higher hydrophobicity and antibacterial activity, had a relatively higher hemolysis rate and toxicity than MSI-1. MSI-1 exerted rapid bactericidal activity and effectively improved the survival rate and wound closure in penicillin-resistant E. coli-infected mice by eliminating bacterial counts in mouse organs or subeschar, further inhibiting the systemic dissemination of bacteria. Additionally, MSI-1 displayed perfect stability against violent pH, temperature variations and high NaCl concentrations and has the ability to circumvent the development of drug resistance. In terms of the mode of action, we found that at the super-MIC level, MSI-1 exhibited direct antimicrobial activity by disrupting the integrity of the bacterial cell membrane, while at the sub-MIC level, it bound to bacterial DNA to inhibit DNA replication and protein expression and ultimately disrupted bacterial biological function. Conclusions: This novel peptide MSI-1 could be a potential candidate for drug development against infection induced by drug-resistant bacteria.
Retrospective analysis of adjuvant chemotherapy for patients with soft tissue sarcomas at Washington University in St. Louis.
Authors: Aaron Schenone, Jingqin Luo, Luke Montgomery, Jessica C. Ley, Tanya Marya Wildes, Douglas Adkins, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2013)

e21501 Background: Adjuvant chemotherapy for soft tissue sarcomas (STS) is controversial. We undertook a retrospective analysis to validate the Memorial Sloan Kettering Predictive Nomogram (MSKPN). We then independently analyzed low and high risk patients, as defined by MSKPN 4-year post operative probability of death &gt; 30% for high grade patients to determine if high risk adjuvant chemotherapeutic patients had greater relapse free survival (RFS). Methods: A retrospective review was performed on all STS patients seen between 1/1/2000 and 5/1/10. Data collected included sex, age, race, city, stage, histology, primary lesion site and size, metastatic sites, response to therapy, radiologic response, and cause of death. The wilcoxon rank sum test was used to compare our predicted vs MSKPN predicted probability of death. Results: 170 subjects, 86 dead and 84 alive were assessed. 89 patients were classified as high risk, 17 treated by I/E, 2 by MAID, 3 by T&amp;G and 67 untreated. 35 patients were treated with I/E and 124 received no adjuvant. We validated the MSKPN as predicted by age, histology, site, grade, depth and tumor size with low risk patients having a greater RFS (log rank test p=0.005) vs high risk. High risk patients’ age was significantly lower I/E v. untreated (mean=46 vs. 60.15, p=0.0044). Overall, patients treated with I/E had greater RFS (p=0.01). High risk adjuvant showed greater RFS vs untreated (log rank test p=0.015). Low risk adjuvant treated patients did not show greater RFS (p=0.346). Independent subtype analysis revealed leiomyosarcoma had the greatest RFS vs all other sub-types (p=0.011). High risk patients, with age accounted for, untreated patients have a hazard ratio of 4.67 (95% CI 1.19~18.35, p=0.027) relative to chemotherapy, indicating chemotherapeutic benefit for high risk patients. Conclusions: Presently there is insufficient and conflicting data for adjuvant therapy in the treatment of STS. Our retrospective data, within the limits of a retrospective analysis, demonstrates that our patient population behaves as predicted by the MSKPN. High risk patients given I/E have an overall RFS advantage. We propose a prospective risk stratified adjuvant therapy trial is warranted.
The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma
Authors: Shuaishuai Zhang, Weiwei Gao, Juan Tang, Huaifang Zhang, Yuqi Zhou, Jie Liu, Kun Chen, Fangzhou Liu, Wengang Li, Sally K. Y. To, Alice Sze Tsai Wong, Xiao-kun Zhang, Hu Zhou, Jin-Zhang Zeng
Journal: Theranostics (2020)

Rationale: Glycogen synthase kinase-3β (GSK-3β) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3β can confer tumor growth. However, the expression and function of GSK-3β in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3β in HCC. Methods: We firstly clarified the expression of GSK-3β in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3β could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3β in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Results: We demonstrated that GSK-3β is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3β confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3β is correlated with reduced expression of retinoic acid receptor-β (RARβ), which is caused by GSK-3β-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARβ promoter. Overexpression of functional GSK-3β impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3β by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARβ by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARβ. Conclusions: Our findings demonstrate that GSK-3β is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3β may be a promising strategy for HCC treatment in clinic.
Coating biomimetic nanoparticles with chimeric antigen receptor T cell-membrane provides high specificity for hepatocellular carcinoma photothermal therapy treatment
Authors: Weijie Ma, Daoming Zhu, Jinghua Li, Xi Chen, Wei Xie, Xiang Jiang, Long Wu, Ganggang Wang, Yusha Xiao, Zhisu Liu, Fubing Wang, Andrew Li, Dan Shao, Wenfei Dong, Wei Liu, Yufeng Yuan
Journal: Theranostics (2020)

Rationale: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Apart from traditional surgical resection, radiotherapy, and chemotherapy, more recent techniques such as nano-photothermal therapy and biotherapy are gradually being adopted for the treatment of HCC. This project intends to combine the advantages of nanoscale drug delivery systems with the targeting ability of CAR-T cells. Method: Based on cell membrane-coated nanoparticles and cell membrane-targeting modifications, a novel nanomaterial was prepared by coating CAR-T cell membranes specifically recognizing GPC3+ HCC cells onto mesoporous silica containing IR780 nanoparticles. Subsequently, the physical properties were characterized, and the in vitro and in vivo targeting abilities of this nanoparticle were verified. Results: CAR-T cells were constructed which could recognize GPC3 expressed on the cell surface of HCC cells. Then the isolated CAR-T cell membrane was successfully coated on the IR780 loaded mesoporous silica materials, as verified by transmission electron microscopy. The superior targeting ability of CAR-T cell membrane coated nanoparticles compared to IR780 loaded mesoporous silica nanoparticles was verified, both in vitro and in vivo. Conclusion: This new nanomaterial exhibits photothermal antitumor abilities along with enhanced targeting abilities, suggesting a promising strategy for the treatment of HCC.
Star studded mental health film to be shown at 32 football games over weekend
Authors: Elisabeth Mahase
Journal: BMJ (2020)

A short film featuring famous footballers including Frank Lampard, Jesse Lingard, and Dele Alli will be shown at 32 games over the weekend of 4 January to encourage fans to think about their mental health and the actions they can take to improve it.

The one minute film, narrated by Prince William, the Duke of Cambridge, will play across stadiums, online, and on broadcast television, with the aim of reaching millions of football fans across England.

It forms part of Public Health England’s Every Mind Matters campaign which launched in October 2019 and includes a …
Massachusetts healthcare group to spend $100m to “rebrand” itself
Authors: Jeanne Lenzer
Journal: BMJ (2019)

Partners HealthCare, the largest healthcare provider in Massachusetts, has been criticised for spending an estimated $100m (£76m; €89m) to “rebrand” itself as Mass General Brigham.

The new title incorporates the names of Partners’ two founding hospitals, Massachusetts General Hospital and Brigham and Women’s Hospital, which are affiliated with Harvard University as teaching and research centres.

Partners HealthCare currently has 75 000 employees, 1.5 million patients, more than $14bn in annual revenues, and $2bn in annual research funding. The non-profit group said in …
A Novel Non-Covalent Modulator of Hemoglobin Improves Anemia and Reduces Sickling in a Mouse Model of Sickle Cell Disease
Authors: Kelly M. Knee, Reema Jasuja, Amey Barakat, Dharani Rao, Zane Wenzel, Parag Sahasrabudhe, Jatin Narula, Jay Jasti, Jeanne S. Chang, Kevin Beaumont, David W. Piotrowski, Jay M. Janz
Journal: Blood (2019)
ACTR-25. RETHINKING THE DOGMA: HOW IMPORTANT IS TREATMENT OF THE CSF IN PATIENTS WITH PRIMARY CNS LYMPHOMA (PCNSL)?
Authors: Dawit Aregawi, Agnieszka Korfel, Uwe Schlegel, Michael Glantz
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION PCNSL constitutes a small but important fraction of adult malignant primary brain tumors. These tumors frequently and often dramatically respond to high-dose methotrexate-containing regimens, but almost inevitably recur. Following initial treatment and at the time of recurrence, no widely accepted treatment paradigm exists. In particular, no consensus exists regarding the need to treat the CSF at the time of PCNSL diagnosis. METHODS We identified three independent cohorts of adults with PCNSL in which some patients received intra-CSF chemotherapy as part of their initial therapy, and others did not. All patients were comparable with respect to demographic and disease characteristics (study-level data). Data on CSF involvement, response, relapse, and survival were extracted and summary statistics were calculated from these three studies using the inverse variance method and random effects model. RESULTS The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/rituximab/vinca alkaloids/ifosfamide/cytarabine (group II) (n=48); or HD MTX/rituximab (group III). Intra-CSF chemotherapy consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=30); or liposomal cytarabine (group III, n=21). One- and two-year survivals were greater in the IT chemotherapy compared to the no-IT chemotherapy groups (RR 1.25 [1.16–1.34] and 1.20 [1.14–1.26] respectively, p&amp;lt; 0.001 for both). Relapse involving the CSF was greater in the non-IT chemotherapy group (RR 2.31 [2.03–2.62], p&amp;lt; 0.001). In one cohort, comparison of pre-treatment CSF cytology from ventricular vs lumbar sites was possible. CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p&amp;lt; 0.0001). CONCLUSIONS CSF involvement by tumor occurs in most patients with PCNSL. Including intra-CSF chemotherapy in the initial treatment regimen of these patients may improve overall survival and reduce the frequency of relapses involving the CSF. Well-designed prospective trials are warranted.
Prognostic Value of Pancreatic Fistula in Resected Patients With Pancreatic Cancer With Neoadjuvant Therapy
Authors: Si Shi, Jie Hua, Xianjun Yu
Journal: JAMA Surgery (2019)

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Letter to the Editor: Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Steatohepatitis Cirrhosis and Diabetes: Insufficient for Individual Management
Authors: Zhichao Feng, Pengfei Rong, Wei Wang
Journal: Hepatology (2020)

Supported by the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University, China (20160305; to P.R.). Potential conflict of interest: Nothing to report. To The Editor: We read with interest the article by Yang et al.1 The study demonstrated that diabetes is associated with an increased risk of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) cirrhosis and validated their findings in an external cohort. However, several important issues might affect the study results or clinical significance, which are proposed as follows. First, this study showed that there was no association between diabetic medications and HCC. According to the medication use recorded in Table 1 of Yang's study (note: belongs to Ref. 1), some diabetics had taken more than one kind of medication. This complex antidiabetic medication history, including medication changes or combinations, would affect subsequent risk analyses. Recent studies suggested that metformin was associated with a reduced risk of HCC in a dose‐response pattern in type 2 diabetes.2 Although without statistical significance, this study reported a hazard ratio of 1.93 (0.84‐4.41) for HCC development in metformin users. From our perspective, the cumulative duration of metformin therapy might be heterogeneous in ever‐users, which should be the major confounding factor resulting in the inconsistency. Also, hemoglobin A1c (HbA1c) of diabetics was reported as 7.6% ± 9.5%, varying over a wide range. HbA1c is an important indicator of long‐term glycemic control and predictive for developing diabetes‐related complications, even HCC.3 However, the influence of glycemic control on HCC risk was not investigated. These issues undoubtedly affected clinical management of patients with NASH cirrhosis and diabetes (e.g., course of metformin therapy, HbA1c target). Therefore, the conclusions would be more meaningful if the researchers could provide more details about diabetes, including diabetes duration, duration of medication use, and glycemic control. In addition, the Cox proportional hazard regression analysis, rather than competing risk analysis, was used to investigate the effect of diabetes on the risk of HCC. During the follow‐up period, 57 patients received liver transplants and 123 patients died in the Mayo Clinic cohort. HCC development, transplantation, and death were three competing events, given that transplantation or death impeded HCC occurrence. The Cox proportional hazard model assumes that competing events are censored; therefore, it may overestimate HCC risk.4 Propensity‐score matching analysis could be used to adjust for the baseline imbalance between groups in both cohorts.
Sleep Health: An Opportunity for Public Health to Address Health Equity
Authors: Lauren Hale, Wendy Troxel, Daniel J. Buysse
Journal: Annual Review of Public Health (2020)

The concept of sleep health provides a positive holistic framing of multiple sleep characteristics, including sleep duration, continuity, timing, alertness, and satisfaction. Sleep health promotion is an underrecognized public health opportunity with implications for a wide range of critical health outcomes, including cardiovascular disease, obesity, mental health, and neurodegenerative disease. Using a socioecological framework, we describe interacting domains of individual, social, and contextual influences on sleep health. To the extent that these determinants of sleep health are modifiable, sleep and public health researchers may benefit from taking a multilevel approach for addressing disparities in sleep health. For example, in addition to providing individual-level sleep behavioral recommendations, health promotion interventions need to occur at multiple contextual levels (e.g., family, schools, workplaces, media, and policy). Because sleep health, a key indicator of overall health, is unevenly distributed across the population, we consider improving sleep health a necessary step toward achieving health equity.
Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS
Authors: K. Park, J. Vansteenkiste, K.H. Lee, G. Pentheroudakis, C. Zhou, K. Prabhash, T. Seto, P.J. Voon, D.S.W. Tan, J.C.H. Yang, J. Wang, K. Govind Babu, Y. Nakayama, A. Alip, K.L.M. Chua, J.C.-H. Cheng, S. Senan, Y.C. Ahn, T.-Y. Kim, H.K. Ahn, S. Peters, T. Yoshino, J.-Y. Douillard
Journal: Annals of Oncology (2020)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries. The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.
Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609
Authors: Ahmad A. Tarhini, Sandra J. Lee, F. Stephen Hodi, Uma N. M. Rao, Gary I. Cohen, Omid Hamid, Laura F. Hutchins, Jeffrey A. Sosman, Harriett M. Kluger, Zeynep Eroglu, Henry B. Koon, Donald P. Lawrence, Kari L. Kendra, David R. Minor, Carrie B. Lee, Mark R. Albertini, Lawrence E. Flaherty, Teresa M. Petrella, Howard Streicher, Vernon K. Sondak, John M. Kirkwood
Journal: Journal of Clinical Oncology (2019)

PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti–programmed death 1 use in the HDI arm versus ipi3 and ipi10 ( P ≤ .001). CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.