tbuckley/cabot-search huggingface dataset:
Synergistic effects between mTOR complex 1/2 and glycolysis inhibitors on non-small cell lung carcinoma metabolism.
Authors: Suhua Jiang1, Zhengzhi Zou2, Peipei Nie2, Yuanyuan Zhuang2, Juan He2, Jun Tang
Journal: Journal of Clinical Oncology (2014)

e22190 Background: Metabolism of cancer cells has recently attracted a lot of interest in cancer research. Cancer cell metabolism, characterized by enhanced glucose uptake, lactate production and anabolism, is considered a promising target for cancer therapeutic interventions. It has been shown that mammalian target of rapamycin (mTOR) is dysregulated in numerous cancers and growth factor signaling mediated by mTOR complex 1 (mTORC1) drives cancer metabolism. However, the function of mTORC2 in cancer metabolism is unclear. The objective of this study is to address the role of mTORC2 in regulating lung cancer metabolism. Methods: A549 and PC-9 cell lines of non-small cell lung carcinoma (NSCLC) were used. Cell viability was assayed by MTT and cell apoptosis assessed by using Apoptosis Detection Kit. The levels of proteins in cells were detected by Western blotting, and ATP content determined overtime by using ATP Bioluminescent Somatic Cell Assay Kit. siRNA oligonucleotides were synthesized and used for the gene-specific knockdown. Glucose uptake by cells was measured using Olympus AU5400 and lactate production in cells assayed using Lactate Assay Kit. Statistical analysis was conducted using student’s t test and p value < 0.05 was considered significant. Results: We found that the inhibition of mTORC1 by rapamycin and siRNA targeting Raptor (regulatory associated protein of mTORC1) attenuated cellular metabolism in NSCLC cells. Moreover, we first demonstrated that mTORC2 played a critical role in regulating cellular metabolism in lung cancer and this action of mTORC2 was associated with AKT pathway. Indeed, either depletion of mTORC2 by siRNA targeting Rictor (Raptor independent companion of mTORC2) or chemical inhibition of mTORC2 by a small molecule of AZD2014 significantly decreased the levels of glucose uptake, lactate and ATP production in the cancer cells. Lastly, the repression of glycolysis using 2-Deoxyglucose sensitized NSCLC cells to rapamycin- and AZD2014-induced apoptosis. Conclusions: This study reveals a novel effect of mTORC2 on cancer cell metabolism and provides a new insight into treatment of NSCLC by the inhibition of mTORC1/2 in combination with glycolysis inhibitors.
Abstract #2202: Sonic hedgehog-induced expression of mRNA translation machinery components leads to differential regulation of the eIF4E and S6 kinase branches of the mTOR pathway in proliferating neural progenitors
Authors: Lori Mainwaring, Anna Kenney
Journal: Cancer Research (2009)

Normal development of the cerebellum is required for proper movement coordination, balance, and posture. Cerebellar development takes place largely post-natally in mice and humans, and is marked by the rapid expansion of cerebellar granule neuron precursors (CGNPs), which proliferate in response to Sonic hedgehog (Shh) released from neighboring Purkinje neurons. These cells also require insulin-like growth factor (IGF) for their proliferation and survival. CGNPs have been proposed as cells-of-origin for certain classes of medulloblastoma, the most common solid pediatric malignancy. Aberrant activation of the Shh pathway and expression of its downstream components is implicated in medulloblastoma, and IGF pathway activity is also found in these tumors. We have investigated how the Shh pathway interacts with the mammalian Target of Rapamycin (mTOR) pathway, which induces new protein synthesis in response to IGF signaling. Phosphorylation by the kinase mTOR is understood to result in (a) inhibition of 4E-BP proteins, which results in activation of the mRNA cap-binding protein eIF4E, and (2) activation of S6 kinase, which is thought to play roles in cell size increase. We found that Shh induced increased levels and phosphorylation of 4E-BP2 in proliferating CGNPs, and increased levels of eIF4E, but decreased levels of S6 kinase activity. Further, we found that Shh up-regulated the mRNA and protein levels of almost all components of the mRNA cap-binding complex, many of which are mTOR substrates. Signals to induce CGNP cell cycle exit resulted in reduction in levels of these proteins, and restoration of S6 kinase activity. Our results are consistent with a model in which cap-binding components compete with S6 kinase for phosphorylation by mTOR, to promote proliferation-associated mRNA translation, while S6 kinase plays roles in cell cycle exit and differentiation, a process associated with CGNP cell size increase.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2202.
The road to assessing clinical trial-associated workload.
Authors: Marjorie J. Good, Patricia A. Hurley, Eden Mesfin
Journal: Journal of Clinical Oncology (2014)

e17587 Background: A 2011 ASCO survey of community-based oncology practices to assess for needs related to the conduct of clinical trials revealed a highly ranked request for a tool to assist in determining clinical trial (CT) associated workload. An online tool was developed for research programs that would be simple, reproducible and usable in the long-term. The tool accounted for the complexity of trials and the number of patients assigned to research staff. Community-based oncology research programs participated in a project to assess the utility and feasibility of the tool within their practices. Methods: Community-based oncology programs that accrue to industry and/or NCI-funded cooperative group trials were recruited via community-based research networks with a goal of obtaining 25-30 participants. Site-specific information was collected related to each research program’s structure, staffing, and portfolio of active trials. Participating sites assigned a score to each trial, based on its complexity, using a 4 point rating scale. Workload entries were made into the tool monthly for 6 consecutive months. Results: 100 sites indicated interest in the project and were sent recruitment information. Of those, 56 sites agreed to participate. At the end of the 6 month data collection period, 52 sites (93%) provided all or partial data; 48 sites (86%) had 6 months of data and 4 sites (7%) with less than 6 months of data. All participating sites were able to rate and assign a complexity score to each of their active trials. Variations were observed across sites, including how patients on trials were classified, how workload data were collected, and individualized staffing models. Overall feedback received from participating sites was positive, with the majority indicating that the tool would be useful for community-based research programs. Conclusions: The overwhelming interest in this project confirms the need to address workload issues within community-based research programs. This project demonstrates the utility and feasibility of compiling and entering CT-associated workload data into an online tool. Other primary endpoint findings for this project will be published and the tool will be made available to the public.
Salvage lrung resection after high-dose radiochemotherapy for lung cancer.
Authors: Kenji Suzuki, Takeshi Matsunaga, Kazuya Takamochi, Shiaki Oh
Journal: Journal of Clinical Oncology (2014)

e18513 Background: Concurrent chemoradiotherapy (CRT) is the standard for locally advanced stage III lung cancer. However, after treatment with definitive CRT, approximately 50% of patients experience local relapse. Additionally recent data from RTOG0617 suggested the inferior effect of 74Gy radiation (RT). Thus, for improving local control salvage lung resection (SLR) is theoretically necessary. Methods: Between February of 2008 and December of 2013, 1340 patients with lung cancer underwent surgical resection, which includes 32 (2.4%) SLR, including 20 pts after CRT and one after RT. The indication of SLR was as follows: 1) local relapse after definitive CRT or RT (n=19); 2) palliative surgery (n=2) for patients with fatal complication due to medical treatment including CRT, chemotherapy, or RT. SLR was completed except one exploratory thoracotomy. Twenty lung resections after high-dose RT were consisted with 13 (65%) lobectomies and 6 (30%) pneumonectomies. Bronchoplasty was performed in 9, including 2 sleeve pneumonectomies and 7 sleeve lobectomies. Double sleeve was done in 4, resection of the superior vena cava in 2. The dose of radiation was 45Gy in 1, 48Gy in 1, 50Gy in 1, 60Gy in 14 , 66Gy in 2, 70Gy or more in two (one is proton beam). Duration between radiotherapy and surgery ranged 1 to 120 months with a median of 7. Results: There were no overall surgical mortality. There were 6 (29%) postoperative morbidity including 3 empyema, 2 bronchopleural fistula (BPF), and one impaired venous return. Four (19%) underwent reoperation, including 2 fenestrations, 1 completion pneumonectomy and 1 completion lobectomy. BPF developed after right pneumonectomy after proton beam of 70Gy, and right sleeve lower lobectomy after 70Gy. Bronchial stenosis is one. Predictor for bronchial complications (BPF or stenosis) was preoperative irradiation of 70Gy or more (p=0.006). Conclusions: Salvage pulmonary resection following high dose radiation was feasible. While bronchoplasty was performed safely even after high-dose RT, 70Gy or more irradiation was a significant predictor for postoperative bronchial complications.
Statistical Code for Clinical Research Papers
Authors: Ravi Varadhan
Journal: Annals of Internal Medicine (2018)

Letters1 January 2019Statistical Code for Clinical Research PapersRavi Varadhan, PhD, PhDRavi Varadhan, PhD, PhDJohns Hopkins University, Baltimore, Maryland (R.V.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0612 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I welcome Assel and Vickers' suggestions and propose that major medical journals go 1 step further by requesting the data (under appropriate conditions of confidentiality) so that the analyses in papers can be reproduced. Merely looking at code is not sufficient to ensure reproducible results. Perhaps authors could instead produce an R Markdown document (RStudio) that displays the results of the paper when R software (R Foundation for Statistical Computing) is used in the analysis.I appreciate that the authors discussed the lack of training that students of statistics receive on the principles of coding and the ...Reference1. Assel M, Vickers AJ. Statistical code for clinical research papers in a high-impact specialist medical journal. Ann Intern Med. 2018;168:832-3. [PMID: 29404569]. doi:10.7326/M17-2863 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Johns Hopkins University, Baltimore, Maryland (R.V.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0612. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoStatistical Code for Clinical Research Papers in a High-Impact Specialist Medical Journal Melissa Assel and Andrew J. Vickers Statistical Code for Clinical Research Papers Gregory E. Simon , Rachel Richesson , Kevin Weinfurt , Adrian F. Hernandez , and Lesley H. Curtis Metrics Cited byThe 7 Habits of Highly Effective Cost-of-Care ConversationsCaroline E. Sloan, MD and Peter A. Ubel, MDTools to Help Overcome Barriers to Cost-of-Care ConversationsC. Jessica Dine, MD, MSHP, Domitilla Masi, MS, and Cynthia D. Smith, MD 1 January 2019Volume 170, Issue 1Page: 79-80KeywordsConflicts of interestDisclosureGraduate medical education ePublished: 1 January 2019 Issue Published: 1 January 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Angiogenic and procoagulant factors in plasma of brain tumor patients treated with bevacizumab.
Authors: Andrea Pace, Anna Antenucci, Chiara Mandoj, Veronica Villani, Carmine Maria Carapella, Alessandra Fabi, Laura Conti
Journal: Journal of Clinical Oncology (2014)

2085 Background: Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), a monoclonal antibody against VEGF, has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the possible predictive value of circulating VEGF, von Willebrand factor (vWF) and procoagulant factors in patients with recurrent GBM. Methods: We conducted a prospective analysis of recurrent malignant gliomas (MG) patients treated with BV alone or in combination with chemotherapy performing serial evaluations of plasma VEGF levels, vWF antigen and procoagulant factors such as thrombin-antithrombin complex (TAT), prothrombin fragment F1+2 (F1+2), Factor VIII and D-Dimer. Baseline, and post-treatment samples were collected at each administration of BV. Results: Forty-nine recurrent MGs (glioblastoma=26, astrocytoma=17, oligodendroglioma=6) who received BV at 10 mg/kg intravenously every 3 weeks, of whom 26 in association with chemotherapy were included in the study. Median age was 45 years (22-73), median Karnofsky performance status was 80 (60-100). Out of the 48 evaluable, 17 partial responses (35%), 7 stable disease (15%) and 24 disease progressions (50%) were observed. At baseline all patients presented with laboratory signs of coagulation activation (i.e. high TAT and FVIII levels). Circulating plasma levels of VEGF and vWF antigen significantly increased in all patients post-treatment of BV (p=0.0001 and 0.009 respectively). No responder patients showed significantly higher vWF antigen levels than responders (p=0.01) after second administration of BV. Conclusions: These preliminary data suggest that low vWF antigen levels might help predict response in recurrent MG patients treated with BV. This marker should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment.
Public’s perspective to disclosure of cancer-related bad news.
Authors: Jamal M Zekri, Mohamed Ezzat El Sayed, Youssef Nauf
Journal: Journal of Clinical Oncology (2014)

e17634 Background: The extent of disclosure of information about cancer diagnosis, treatment and prognosis to patients with cancer remains a controversial issue in the Middle East. This study investigates the public’s perspective in Saudi Arabia to disclosure of cancer related bad news if diagnosed with cancer. Methods: One hundred Saudi adult non-cancer patients presenting to the family medicine out-patient clinic were asked to respond to a written questionnaire composed of 9 closed ended questions. The questions reflect possible bad news from diagnosis until end of life and ask the respondents’ about their preference to be or not to be informed of the bad news if they were diagnosed with cancer. The preference is expressed by answering each question by “Yes” or “No”. Affirmative response to ≥7 questions was taken as a cut off indicating preference to be informed of large proportion (78%) of the bad news. Results: Fifty six (56%) were male and 44 (44%) were female. The median age was 32 years (18-75 years). Different questions were answered affirmatively by 76-99% of responders. Eighty three (83%) answered affirmativelyto ≥7 questions. There was no statistically significant difference between the rate of affirmative response to ≥7 questions and age,gender and employment status (Chi-square P value; 0.731, 0.427, and 0.148 respectively). There was a trend for more affirmative response by individuals with university and higher level education compared to those with school education (88% and 73% respectively, P=0.055) Conclusions: The results of this study shows that majority of Saudi Arabian public prefer to be informed of most health related bad news if diagnosed with cancer.These results should encourage physicians to keep cancer patients informed of their health related events unless patients indicate otherwise.
Helen Salisbury: Did you save any lives today?
Authors: Helen Salisbury
Journal: BMJ (2019)

Did you save any lives today? “Not obviously,” most doctors would usually answer. But a recent study on continuity of care found that maybe we did,1 just by being in the same outpatient clinic or GP surgery over time, seeing the same patients.

Sometimes I feel like a dinosaur, clinging to traditional general practice while the meteorite of new care models approaches. But what’s at stake here is not just the patient’s longevity but the quality of care and—dare I say it?—the possibility of enjoying my work and avoiding burnout.

I recently visited an elderly patient who is in the late stages of …
Maternity services to get more expert staff to improve safety
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Neonatal services are to be staffed with more specialists and expert nurses as part of a package of upgrades designed to make the NHS “one of the best places in the world to give birth.”

The health secretary for England, Matt Hancock, said that critically ill newborn babies would receive better accommodation and support from dedicated care coordinators from 2021-22.

The changes are designed to meet targets set by the government to save 4000 lives by 2025 by …
Avoiding Hospital Discharge Against Medical Advice
Authors: Eric W. Rudofker, Emily W. Gottenborg
Journal: JAMA Internal Medicine (2019)

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Separable and Replicable Neural Strategies During Social Brain Function in People With and Without Severe Mental Illness
Authors: Colin Hawco, Robert W. Buchanan, Navona Calarco, Benoit H. Mulsant, Joseph D. Viviano, Erin W. Dickie, Miklos Argyelan, James M. Gold, Marco Iacoboni, Pamela DeRosse, George Foussias, Anil K. Malhotra, Aristotle N. Voineskos
Journal: American Journal of Psychiatry (2019)

Case-control study design and disease heterogeneity may impede biomarker discovery in brain disorders, including serious mental illnesses. To identify biologically and/or behaviorally driven as opposed to diagnostically driven subgroups of individuals, the authors used hierarchical clustering to identify individuals with similar patterns of brain activity during a facial imitate/observe functional MRI task.Participants in the Social Processes Initiative in Neurobiology of the Schizophrenia(s) study (N=179; 109 with a schizophrenia spectrum disorder and 70 healthy control participants) underwent MRI scanning at three sites. Hierarchical clustering was used to identify new data-driven groups of participants; differences on social and neurocognitive tests completed outside the scanner were compared among the new groups.Three clusters with distinct patterns of neural activity were found. Cluster membership was not related to diagnosis or scan site. The largest cluster consisted of "typical activators," with activity in the canonical "simulation" circuit. The other clusters represented a "hyperactivating" group and a "deactivating" group. Between-participants Euclidean distances were smaller within clusters than within site or diagnostics groups. The deactivating group had the highest social cognitive and neurocognitive test scores. The hierarchical clustering analysis was repeated on a replication sample (N=108; 32 schizophrenia spectrum disorder, 37 euthymic bipolar disorder, and 39 healthy control participants), which exhibited the same three cluster patterns.The study findings demonstrate replicable differing patterns of neural activity among individuals during a socio-emotional task, independent of DSM diagnosis or scan site. The findings may provide objective neuroimaging endpoints (biomarkers) for subgroups of individuals in target engagement research aimed at enhancing cognitive performance independent of diagnostic category.
Surveillance after curative-intent ovarian cancer treatment: The impact of HMOs.
Authors: Frank E. Johnson, Robert J. Avino, Randall K. Gibb, David Gardner Mutch, Feng Gao, Katherine S. Virgo
Journal: Journal of Clinical Oncology (2014)

e16530 Background: Over 21,000 women are diagnosed with ovarian cancer in the US annually. Most patients receive curative-intent treatment. Post-treatment surveillance is commonly done. We have previously documented dramatic variation in surveillance intensity among members of the Society of Gynecologic Oncologists (SGO). Several large professional organizations have offered consensus-based surveillance guidelines. However, none are based on high quality-evidence. It is commonly believed that health maintenance organizations (HMOs) restrict test utilization. We sought to determine the effect of HMO penetration rate on the known variation in surveillance strategies. Methods: 943 SGO members and candidate members were surveyed regarding their surveillance practices. Members were asked to consider 4 idealized clinical vignettes and indicate their surveillance plan for each. A menu of 11 testing modalities was offered. Practice patterns were stratified by HMO penetration rate (0-29%, 30-40%, >40%) in each physician’s practice location. Repeated-measures ANOVA was employed for analysis. Results: Of the SGO members and candidate members surveyed, 323 responded; 283 were evaluable. The modalities most frequently recommended were office visit, pelvic exam, and serum CA-125 level. There was significant variation (p<0.05) for these most frequently recommended modalities, but in no other modalities. For example, in year 1, pelvic exam was recommended 4.4 ± 1.6 (mean ±SD) times for the 0-29% penetration rate cohort and 4.2 ± 1.2 times for the 30-40% cohort. Conclusions: We found little evidence that HMOs restrict test utilization. The HMO penetration rate in the clinician’s practice location cannot account for the overall variation we have documented previously.
A Five Fold Decrease in Admissions for Uncomplicated Vaso-Occlusive Crisis and Other Benefits from Care in Infusion Clinics: Results from the Escaped Trial
Authors: Sophie Lanzkron, Jane Little, Joshua J. Field, Carlton Haywood, Ravi Varadhan, Mustapha Saheed, Marc Proudford, Derek Robertson, Adrienne Kincaid, Lorri Burgess, Charles Green, Hang Wang, Rebecca Seufert, Jasmine Brooks, Allie Piehet, Brandi Griffin, Nicole Arnold, Steven Frymark, Chiung- Yu Huang, Marcus Wallace, Nebras Abu Al Hamayel, Jodi Segal
Journal: Blood (2018)