tbuckley/cabot-search huggingface dataset:
Colorectal cancer lung metastasis treatment with polymer–drug nanoparticles
Authors: Piotr Rychahou, Younsoo Bae, Derek Reichel, Yekaterina Y. Zaytseva, Eun Y. Lee, Dana Napier, Heidi L. Weiss, Nick Roller, Heather Frohman, Anh-Thu Le, B. Mark Evers
Journal: Journal of Controlled Release (2018)

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States; the predominant cause for mortality is metastasis to distant organs (e.g., lung). A major problem limiting the success of chemotherapy in metastatic CRC is the inability to target tumor tissues selectively and avoid severe side effects to normal tissues and organs. Here, we demonstrate polymeric nanoparticles (PNPs) entrapping chemotherapeutic agents provide a new therapeutic option for treating CRC that has metastasized to the lung. PNPs assembled from FDA approved biocompatible block copolymer accumulated predominantly in lung tissue. PNPs showed negligible accumulation in liver, spleen and kidneys, which was confirmed by fluorescent nanoparticle imaging and analysis of PI3K inhibition in the organs. PNPs entrapping PI3K inhibitors (i.e., wortmannin and PX866) suppressed CRC lung metastasis growth, and SN-38-loaded PNPs completely eliminated CRC lung metastasis. Our results demonstrate that polymer-drug nanoparticles offer a new approach to reduce toxicity of cancer therapy and has the potential to improve outcomes for patients with lung metastasis.
PULMONARY DELIVERY OF THE CLASS IC ANTIARRHYTHMIC AGENT FLECAINIDE EXERTS A PREDOMINANT EFFECT ON ATRIAL COMPARED TO VENTRICULAR DEPOLARIZATION DURATION REVEALED BY INTRACARDIAC RECORDINGS
Authors: Victor Zandona De Antonio, Anderson Silva, Fernando G. Stocco, Narsi Rangachari, Luiz Belardinelli, Richard Verrier
Journal: Journal of the American College of Cardiology (2018)
Surgical education and training programme (STEP) foundation course
Authors: Mildrid Yeo
Journal: BMJ (2010)

The surgical education and training (STEP) programme of the Royal College of Surgeons of England is a distance learning programme that started in 1994. It is especially targeted at foundation year trainees with an interest in pursuing surgery as a career. All foundation year trainees would benefit from the course, however, because the course material can apply both to surgical and to medical disciplines.

I took this course as a foundation year 1 doctor while I was on my general surgery rotation.

I have always wanted to pursue a career in surgery and was looking for a course to provide me with a knowledge base to support the clinical training I was receiving during my foundation programme. The STEP foundation course not only addressed many of the practical competences required in the foundation curriculum, …
Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma
Authors: Yuan-Chung Tsai, Priya Vijayaraghavan, Wen-Hsuan Chiang, Hsin-Hung Chen, Te-I Liu, Ming-Yin Shen, Ayumu Omoto, Masao Kamimura, Kohei Soga, Hsin-Cheng Chiu
Journal: Theranostics (2018)

Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting.In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work.Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers.The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer.Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry.The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay.Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS).The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis.Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT.In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS.The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion:In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival.The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.
Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1
Authors: Karim Wahbi, Raphaël Porcher, Pascal Laforêt, Abdallah Fayssoil, Henri Marc Bécane, Arnaud Lazarus, Maximilien Sochala, Tanya Stojkovic, Anthony Béhin, Sarah Leonard-Louis, Pauline Arnaud, Denis Furling, Vincent Probst, Dominique Babuty, Sybille Pellieux, Nicolas Clementy, Guillaume Bassez, Yann Péréon, Bruno Eymard, Denis Duboc
Journal: JAMA Neurology (2018)

Life expectancy is greatly shortened in patients presenting with myotonic dystrophy type 1 (DM1), the most common neuromuscular disease. A reliable prediction of survival in patients with DM1 is critically important to plan personalized health supervision.To develop and validate a prognostic score to predict 10-year survival in patients with DM1.In this longitudinal cohort study, between January 2000 and November 2014, we enrolled 1296 adults referred to 4 tertiary neuromuscular centers in France for management of genetically proven DM1, including 1066 patients in the derivation cohort and 230 in the validation cohort. Data were analyzed from December 2016 to March 2017.Factors associated with survival by multiple variable Cox modeling, including 95% confidence intervals, and development of a predictive score validated internally and externally. Mean values are reported with their standard deviations.Of the 1296 included patients, 670 (51.7%) were women, and the mean (SD) age was 39.8 (13.7) years. Among the 1066 patients (82.3%) in the derivation cohort, 241 (22.6%) died over a median (interquartile range) follow-up of 11.7 (7.7-14.3) years. Age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. Simplified score points were attributed to each predictor, and adding these points yielded scores between 0 and 20, with 0 indicating the lowest and 20 the highest risk of death. The 10-year survival rate was 96.6% (95% CI, 94.4-98.9) in the group with 0 to 4 points, 92.2% (95% CI, 88.8-95.6) in the group with 5 to 7 points, 80.7% (95% CI, 75.4-86.1) in the group with 8 to 10 points, 57.9% (95% CI, 49.2-66.6) in the group with 11 to 13 points, and 19.4% (95% CI, 8.6-30.1) in the group with 14 points or more. In 230 patients (17.7%) included in the validation cohort, the 10-year survival rates for the groups with 0 to 4, 5 to 7, 8 to 10, 11 to 13, and 14 points or more were 99.3% (95% CI, 95.0-100), 80.6% (95% CI, 67.1-96.7), 79.3% (95% CI, 66.2-95.1), 43.2% (95% CI, 28.2-66.1), and 21.6% (95% CI, 10.0-46.8), respectively. The calibration curves did not deviate from the reference line. The C index was 0.753 (95% CI, 0.722-0.785) in the derivation cohort and 0.806 (95% CI, 0.758-0.855) in the validation cohort.The DM1 prognostic score is associated with long-term survival.
Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists
Authors: Martin A. Bewley, Richard C. Budd, Eilise Ryan, Joby Cole, Paul Collini, Jennifer Marshall, Umme Kolsum, Gussie Beech, Richard D. Emes, Irina Tcherniaeva, Guy A. M. Berbers, Sarah R. Walmsley, Gavin Donaldson, Jadwiga A. Wedzicha, Iain Kilty, William Rumsey, Yolanda Sanchez, Christopher E. Brightling, Louise E. Donnelly, Peter J. Barnes, Dave Singh, Moira K. B. Whyte, David H. Dockrell
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined.Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects.Methods: We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.Measurements and Main Results: COPD AMs and MDMs have impaired phagocytosis of Streptococcus pneumoniae. COPD AMs have a selective defect in uptake of opsonized bacteria, despite the presence of antipneumococcal antibodies in BAL, not observed in MDMs or healthy donor AMs. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria, and health-related quality-of-life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AMs was not reduced. COPD AMs have reduced transcriptional responses to opsonized bacteria, such as cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2 (nuclear factor erythroid 2–related factor 2)-regulated genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and compound 7) reverse defects in phagocytosis of S. pneumoniae and nontypeable Haemophilus influenzae by COPD AMs.Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
Pharmacological inhibition of caspase-8 suppresses inflammation-induced lymphangiogenesis and allograft rejection in the cornea
Authors: Wenru Su, Longhui Han, Xiaoqing Chen, Jianfeng Yu, Xiaokang Cheng, Jingwen Huang, Yichen Xiao, Yunzhe Tian, Nancy Olsen, Song Guo Zheng, Dan Liang
Journal: Journal of Allergy and Clinical Immunology (2018)
COMPLETE REVASCULARIZATION VERSUS CULPRIT VESSEL INTERVENTION-ONLY IN PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION AND MULTI VESSEL CORONARY DISEASE: STRATIFIED ANALYSES IN HIGH-RISK GROUPS FROM A PROSPECTIVE KOREA ACUTE MYOCARDIAL INFARCTION-NATIONAL INSTITUTES OF HEALTH REGISTRY
Authors: Sung Gyun Ahn, Dae Ryong Kang, Hye Sim Kim, Tae-Hwa Go, Min Heui Yu, Sangwook Park, Jung-Woo Son, Jun-Won Lee, Min-Soo Ahn, Young Jin Youn, Jang-Young Kim, Byung-Su Yoo, Seung-Hwan Lee, Junghan Yoon
Journal: Journal of the American College of Cardiology (2018)
A LEARNING CURVE FOR SHARED DECISION MAKING: THE IMPACT OF PHYSICIAN EXPERIENCE ON DECISION AID EFFICACY IN SEVERE AORTIC STENOSIS
Authors: Megan Coylewright, Elizabeth O'Neill, Ariel Sherman, Megan J. Gerling, Kaavya Adam, Keren Xu, Stuart W. Grande, Harold L. Dauerman, Glyn Elwyn
Journal: Journal of the American College of Cardiology (2018)
Dopamine Metabolism in Parkinson's Disease
Journal: JAMA (1963)

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Naps and breaks can build resilience in emergency clinicians, college says
Authors: Caroline White
Journal: BMJ (2013)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Naps and breaks can build resilience in emergency clinicians, college says Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Edinburgh international trauma instructional course
Authors: Kai Tsang
Journal: BMJ (2011)

Orthopaedic trauma surgery has been evolving at a fairly fast pace over the past few decades. Sometimes it is better to learn by exchanging ideas with other surgeons in a structured format, rather than reading books all the time.

The website says it is “education for surgeons in training, senior orthopaedic nurses and senior physiotherapists. It is also useful for experienced orthopaedic surgeons who wish to update their knowledge.” Junior doctors who are interested in orthopaedics would benefit …
DOSE ESCALATION AND THE SAFETY OF CELECOXIB, IBUPROFEN, AND NAPROXEN: ANALYSIS OF THE PRECISION TRIAL
Authors: Grant W. Reed, Mingyuan Shao, Kathy Wolski, Mouin Abdallah, Lisa Wisniewski, Neville Yeomans, Thomas F. Luscher, Jeffrey Borer, David Y. Graham, Elaine Husni, Daniel Solomon, Peter Libby, Venuy Menon, A. Lincoff, Steven Nissen
Journal: Journal of the American College of Cardiology (2018)
Evaluation of ability of OR51T1 expression to predict primary hormone therapy efficacy among men with hormone-naïve metastatic prostate cancer.
Authors: Taku Mochizuki, Yasuhide Miyoshi, Takashi Kawahara, Yumiko Yokomizo, Narihiko Hayashi, Masahiro Yao, Hiroshi Miyamoto, Hiroji Uemura
Journal: Journal of Clinical Oncology (2018)

317 Background: The olfactory receptor gene (OR) superfamily is the largest in the human genome. ORs are expressed not only in the neurons of the olfactory epithelium, but also in various other tissues in which their functions are largely unknown. We here investigated OR51T1 expression as a potential biomarker for predicting primary hormone therapy efficacy among men with metastatic hormone-naïve prostate cancer (mHNPC). Methods: Sixty-nine men with bone metastatic HNPC diagnosed from 2006 to 2015 were enrolled in this retrospective study. All patients had received hormone therapy as first-line treatment. Prostate cancer tissue obtained by needle biopsies before treatment were immunohistochemically stained for OR51T1. Correlations between the baseline clinical factors of age, PSA, Gleason score, T stage, N stage, extent of disease on bone scan (EOD), OR51T1 expression and primary hormone therapy efficacy (time to castration-resistant prostate cancer [CRPC]) were investigated by multivariate analysis using the Cox proportional hazard model. Continuous variables were classified as dichotomous. Results: Median age and PSA were 73.7 years and 263 ng/mL, respectively. Distribution of Gleason score of 9–10/6–8, T4/≤3, N1/0, and EOD 3–4/1–2 were 30 (43.5%)/39 (56.5%), 12 (17.4%)/57 (82.6%), 28 (40.6%)/41 (59.4%), and 26 (37.7%)/43 (62.3%), respectively. Median time to CRPC was 13.6 months. Patients with high OR51T1 expression had significantly shorter time to CRPC than those with low expression. Multivariate analysis showed that EOD (3–4 vs. 1–2, HR 3.1, 95% CI 1.6–6.2, p = 0.001) and OR51T1 expression (high vs. low; HR 2.3, 95%CI 1.2–4.4, p = 0.014) were significant biomarkers for predicting time to CRPC. Conclusions: OR51T1 expression could be a potential biomarker for predicting primary hormone therapy efficacy among men with mHNPC.
Abstract P3-05-18: The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy
Authors: MJ Bou-Dargham, Y Liu, Q-XA Sang, J Zhang
Journal: Cancer Research (2018)

Abstract Cancer immunotherapy activates the patient's immune system to recognize and kill cancer cells. The efficacy of immunotherapy in human breast cancer (BRCA) is hindered by the poor understanding of the immune system's anti-tumor response and tumor evasive mechanisms, and the lack of optimized treatment regimens for each BRCA patient. There are 6 known evasion mechanisms (M) by which tumors can escape immune surveillance. M1: immunosuppression via interleukin 10 (IL-10) and tumor growth factor beta (TGF-β); M2: induction of tolerance by cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands (PD-L1/PD-L2), and interferon gamma (IFN-γ); M3: apoptosis resistance via the expression of anti-apoptotic molecules, namely baculoviral IAP repeat-containing protein 3 (BIRC3), TNF receptor associated factor 1 (TRAF1), and TNF alpha induced protein 3 (TNFAIP3); M4: counterattack via decoy death receptors; M5: impaired antigen presentation by decreasing beta 2 microglobulin (B2M) and human leukocyte antigens A and B expression (HLA-A and HLA-B); and M6: ignorance caused by the absence of a danger signal or an antigen. Yet, which mechanisms or combination of mechanisms BRCA tumors utilize is unknown. Moreover, the currently used biomarkers for the choice of immunotherapy are not ideal, as for example, not all PD-L1+ patients respond to anti-PD-L1 treatment, and certain PD-L1- patients respond. Thus, there is a need for more precise biomarkers. Using the sequential biclustering method on the RNA-sequenced data of BRCA from The Cancer Genome Atlas (TCGA), eighty-one percent of BRCA patients were grouped into 7 different clusters (CL) of immune evasion subtypes. We found that the majority of breast cancer tumors utilize multiple immune evasion mechanisms. Tumors may use from 1 up to 4 combinatorial mechanisms simultaneously. We also identified classifier genes that would help sort patients based on their evasion mechanisms, and guide the choice of immunotherapy. This is especially important since the immune evasion molecules may not be the ideal biomarkers for the best choice of immunotherapy. Moreover, we showed that triple negative breast cancer (TNBC) patients were significantly associated with CL2 (M5). Citation Format: Bou-Dargham MJ, Liu Y, Sang Q-XA, Zhang J. The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-18.
Abstract ES6-3: Opportunities for immune therapy and prevention
Authors: RH Vonderheide
Journal: Cancer Research (2018)

Abstract The recent demonstration of modest single-agent activity of PD-L1 and PD-1 antibodies in patients with breast cancer has generated hope for advancing immunotherapy in this disease. Depending on the subtype of breast cancer, in both primary and metastatic disease, the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to non-immune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neo-epitopes – factors linked to response to checkpoint blockade in other malignancies – are all relatively modest in breast cancer, compared to melanoma or lung cancer. Thus, in breast cancer, combinations of immune agents with non-redundant mechanisms of action are the high-priority strategies. For most breast cancers that exhibit relatively modest T cell infiltration, major challenges include immune suppression in the tumor microenvironment as well as failed or suboptimal T cell priming. Agents that trigger de novo T cell responses may be critical for successful development of cancer immunotherapy and immune prevention in breast cancer. Success may also require reaching beyond nonsynonymous mutations as the T cell epitopes to target, especially as numerous unmutated proteins were validated as breast cancer associated antigens in the pre-checkpoint era. A deeper understanding of the immunobiology of breast cancer will be critical for immunotherapy to become broadly relevant in this disease. Citation Format: Vonderheide RH. Opportunities for immune therapy and prevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-3.
Clinical benefit of maintenance therapy for patients with advanced biliary tract cancer without progression on first-line gemcitabine plus cisplatin.
Authors: Jaewon Hyung, Changhoon Yoo, Kyu-Pyo Kim, Bum Jun Kim, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2018)

357 Background: Gemcitabine plus cisplatin (GP) is the standard first line chemotherapy for patients with advanced biliary tract cancer (BTC). In the pivotal ABC-02 study, patients received up to 24 weeks (6-8 cycles) of three-weekly GP. In daily practice setting, however, patients without progression often receive GP more than 6-8 cycles. It is uncertain whether maintenance treatment has clinical benefit in patients without progression on GP. Methods: Advanced BTC patients treated with GP between April 2010 and February 2015 in Asan Medical Center, Seoul, Korea, were retrospectively analyzed. Among the patients who did not progressed and stopped GP after 6-8 cycles, patients were stratified according to the further treatment; those with or without further cycles of GP (maintenance group vs observation group). Primary endpoint was overall survival (OS). Results: Among 740 patients, 231 patients (31.2%) were eligible for this analysis; 111 for observation group, 120 for maintenance group. In observation group, 76 patients (68.5%) stopped GP due to completion of scheduled chemotherapy and 27 patients (24.3%) due to the patients’ request or toxicity. There were no statistically significant differences in baseline characteristics between two groups. Median OS from the initiation of GP was 20.5 months [95% CI 15.4-25.6] and 22.4 months [95% CI 17.0-27.8] in the observation and maintenance group, respectively (p = 0.32). Median progression-free survival (PFS) was 10.4 months [95% CI 7.0-13.8] and 13.2 months [95% CI 11.3-15.2], respectively (p = 0.22). These were consistent in the multivariate analyses for OS and PFS after the adjustment of prognostic factors. Conclusions: In our analysis, maintenance therapy of GP was not associated with improved survival outcomes. Considering the potential disadvantages such as cumulative toxicities, maintenance therapy may not be beneficial in patients who did not progressed on 6-8 cycles of GP.