tbuckley/cabot-search huggingface dataset:
Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials
Authors: C. Norman Coleman, Geoff S. Higgins, J. Martin Brown, Michael Baumann, David G. Kirsch, Henning Willers, Pataje G.S. Prasanna, Mark W. Dewhirst, Eric J. Bernhard, Mansoor M. Ahmed
Journal: Clinical Cancer Research (2016)

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR.
Heterogeneity in Tumors and Resistance to EGFR TKI Therapy—Letter
Authors: Kenichi Suda, Christopher J. Rivard, Tetsuya Mitsudomi, Fred R. Hirsch
Journal: Cancer Research (2016)

We read with great interest a recently published article in your journal, entitled "Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition," by Soucheray and colleagues (1). Lung cancer cell lines with EGFR mutations have "favorite" acquired resistance mechanisms to EGFR-TKIs (2, 3), including PC9 cells in which the EGFR T790M secondary mutation emerges directly, while HCC4006 cells often utilize epithelial-to-mesenchymal transition (EMT). In this article, Soucheray and colleagues showed that combined inhibition of EGFR and TGFβ receptor prevented the emergence of resistance via EMT in HCC4006 cells. HCC4006 cells, which acquired resistance to the combination therapy, instead, developed the T790M mutation. As the T790M mutation is a treatable resistance mechanism employing third-generation EGFR-TKIs (4), a reasonable treatment strategy would anticipate that lung cancer cells would eventually result in emergence of the T790M mutation (3).Translating these findings to the clinic, however, it is essential to identify biomarkers that predict acquired resistance mechanism(s) to EGFR-TKIs prior to treatment. Because some resistance mechanisms are believed to occur through the "selection" of preexistent minor resistant clones, it is reasonable to analyze pretreatment samples using high-throughput methods (5). In their study, however, Soucheray and colleagues failed to adequately explain the emergence of T790M mutation by analyzing the prevalence of T790M allele in parental cells (1), in which the number of HCC4006 cells (0.0738%) was greater than PC9 cells (0.0360%), which often develop acquired resistance via T790M mutation (2). We therefore suggest that at least two additional factors should be considered. First, EGFR gene copy number gain (CNG) should be assessed to make an estimate for the prevalence of preexisting minor clones with T790M mutation. Because it is probable that T790M mutation exists in a part of EGFR allele with an activating mutation, as shown in Fig. 1A, EGFR CNG can project an apparent lower T790M allele ratio. Second, balances between the potential resistance mechanisms should be important to predict upcoming resistance mechanisms (Fig. 1B). Therefore, a biomarker(s) that may predict the emergence of resistance via EMT, for example, preexisting EMT cells, should be identified. In clinical settings, the prediction of resistance mechanisms should be more difficult due to the effect of the microenvironment (5).EGFR-TKI has prolonged the survival of lung cancer patients with EGFR mutation. We believe that a rational upfront polytherapy that cotargets EGFR and resistance mechanism(s) is a reasonable strategy to evaluate in future studies to further improve their outcomes.See the Response, p. 3111No potential conflicts of interests were disclosed.
Abstract 1847: AR-V7 regulation during epithelial plasticity
Authors: Kathryn E. Ware, Daneen Schaeffer, Tian Zhang, Mariano A. Garcia-Blanco, Andrew J. Armstrong
Journal: Cancer Research (2015)

Abstract Background: The androgen receptor (AR) is a key gene involved in prostate cancer (PC) biology, including disease development, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. AR variants lacking the ligand-binding domain, such as AR-V7, have been observed and enriched in metastatic castration resistant prostate cancer. These variants contribute to resistance mechanisms against agents that target hormonal regulation of the AR, including anti-androgens, such as enzalutamide. In addition to AR variants, epithelial plasticity, including an epithelial-to-mesenchymal transition (EMT), has been implicated in PC metastatic dissemination during castration-resistance. In response to androgen deprivation therapy, PC xenografts have been found to display an acute and reversible up-regulation of both EMT phenotypic markers and AR variants. Methods: To explore the mechanism by which an EMT program may regulate AR variant expression and metastatic disease, we used pre- and post- EMT cells to compare AR expression, migration, invasion and enzalutamide resistance. To induce EMT, we stably transfected LNCaP95 PC cells with a plasmid encoding inducible Snail, a master regulator of EMT. In addition, LNCAP95 cells were serially passaged under increasing enzalutamide conditions and we assessed biomarkers of EMT and invasion/growth in resistant cells. Results: We found that Snail activation was sufficient to induce an EMT and increased expression of both AR-FL and AR-V7 as compared to pre-EMT cells. Nuclear localization of AR, migration and invasion were also increased in post-EMT cells. Importantly, cells were more resistant to enzalutamide treatment. Likewise, in a second model of acquired enzalutamide resistance, we found that Snail, AR-FL and AR-V7 were upregulated in enzalutamide resistant vs. sensitive cell lines. Conclusion: Our study suggests that Snail activation promotes both an aggressive and therapy resistant tumor cell through the induction of EP and both AR-FL and AR-V7 isoforms. Citation Format: Kathryn E. Ware, Daneen Schaeffer, Tian Zhang, Mariano A. Garcia-Blanco, Andrew J. Armstrong. AR-V7 regulation during epithelial plasticity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1847. doi:10.1158/1538-7445.AM2015-1847
The Internal Medicine Reporting Milestones: Cross-sectional Description of Initial Implementation in U.S. Residency Programs
Authors: Karen E. Hauer, Jerome Clauser, Rebecca S. Lipner, Eric S. Holmboe, Kelly Caverzagie, Stanley J. Hamstra, Sarah Hood, William Iobst, Eric Warm, Furman S. McDonald
Journal: Annals of Internal Medicine (2016)

Background: High-quality assessment of resident performance is needed to guide individual residents' development and ensure their preparedness to provide patient care. To facilitate this aim, reporting milestones are now required across all internal medicine (IM) residency programs. Objective: To describe initial milestone ratings for the population of IM residents by IM residency programs. Design: Cross-sectional study. Setting: IM residency programs. Participants: All IM residents whose residency program directors submitted milestone data at the end of the 2013–2014 academic year. Measurements: Ratings addressed 6 competencies and 22 subcompetencies. A rating of "not assessable" indicated insufficient information to evaluate the given subcompetency. Descriptive statistics were calculated to describe ratings across competencies and training years. Results: Data were available for all 21 774 U.S. IM residents from all 383 programs. Overall, 2889 residents (1621 in postgraduate year 1 [PGY-1], 902 in PGY-2, and 366 in PGY-3) had at least 1 subcompetency rated as not assessable. Summaries of average ratings by competency and training year showed higher ratings for PGY-3 residents in all competencies. Overall ratings for each of the 6 individual competencies showed that fewer than 1% of third-year residents were rated as "unsatisfactory" or "conditional on improvement." However, when subcompetency milestone ratings were used, 861 residents (12.8%) who successfully completed training had at least 1 competency with all corresponding subcompetencies graded below the threshold of "readiness for unsupervised practice." Limitation: Data were derived from a point in time in the first reporting period in which milestones were used. Conclusion: The initial milestone-based evaluations of IM residents nationally suggest that documenting developmental progression of competency is possible over training years. Subcompetencies may identify areas in which residents might benefit from additional feedback and experience. Future work is needed to explore how milestones are used to support residents' development and enhance residency curricula. Primary Funding Source: None.
Dengue Vaccine Performs Well in Small Clinical Trial
Authors: Tracy Hampton
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 139: Alterations to the Extracellular Matrix Composition Following Myocardial Infarction Impact Cardiac Progenitor Cell Fate In Vitro
Authors: Kelly E Sullivan, Sharada Sant, Laura Burns, Lauren D Black
Journal: Circulation Research (2014)

Limitations associated with cardiac progenitor cell (CPC) therapy of myocardial infarction (MI) including poor engraftment, cell death and incomplete cardiac differentiation have hindered the efficacy of treatment in pre-clinical trials. Given that the extracellular environment plays an important role in regulating cell function and that it is significantly remodeled following MI, it is critical to understand how these changes impact the therapeutic potential of CPCs. In this study, we investigated how the alterations to the extracellular matrix (ECM) following MI impacted the regenerative potential of CPCs in vitro. Hearts were decellularized with 1% SDS prior to MI and 1 and 4 weeks post-MI (Fig A) and the composition of the left ventricle or scar was characterized through LC-MS/MS. While Periostin and Collagen I increased post-MI, Laminin decreased (Fig B). c-kit+ CPCs isolated from rat hearts 1 week post-MI were cultured on tissue culture plastic (TCP) coated with pepsin-solubilized ECM. Our results demonstrated that the healthy matrix promoted the expression of pro-angiogenic growth factors, while maintaining the cells in an undifferentiated state (Fig D,E). Alternatively, 1 week ECM promoted cell adherence (Fig C) and the expression of pro-survival growth factors (Fig D) and GATA-4 (Fig E). Cells cultured on 4 week ECM demonstrated significant differentiation towards vascular lineages through their expression of smooth muscle (TAGLN) and endothelial (VWF) markers. By characterizing how the changing ECM composition following MI impacts CPC fate, we may be able to develop therapeutic strategies that modulate cell fate/ function in vivo following implantation.
Robust Therapeutic Expression of the Common Gamma Chain with the Human Pgk Promoter Using Foamy Virus in Vivo Gene Therapy in a Canine Model of Severe Combined Immunodeficiency
Authors: Christopher R Burtner, Olivier Humbert, Patricia O'Donnell, Nicholas Hubbard, Daniel Humphrys, Jennifer E Adair, Grant D Trobridge, Troy R Torgerson, Andrew M Scharenberg, David Rawlings, Peter J Felsburg, Hans-Peter Kiem
Journal: Blood (2014)
Exploring the relationship between anti-PEG IgM behaviors and PEGylated nanoparticles and its significance for accelerated blood clearance
Authors: Kouichi Shiraishi, Kumi Kawano, Yoshie Maitani, Taiki Aoshi, Ken J. Ishii, Yusuke Sanada, Shinichi Mochizuki, Kazuo Sakurai, Masayuki Yokoyama
Journal: Journal of Controlled Release (2016)
Body mass index and mortality: understanding the patterns and paradoxes
Authors: Sarah H Wild, Christopher D Byrne
Journal: BMJ (2016)

People who are lean for life have the lowest mortality

The optimal body mass index (BMI) associated with lowest risk of all cause mortality is not known. As excess adiposity increases risk of conditions such as diabetes that reduce life expectancy, one might expect increasing BMI to be associated with increasing mortality. However, compared with normal weight, underweight is associated with increased mortality and modestly elevated BMI is associated with lower mortality. The former pattern is only partly explained by confounding by smoking or comorbidity, and the second observation has been called the obesity paradox.1 In addition, the influence on mortality of different patterns of weight change throughout the life course is poorly understood. Two linked papers attempt to shed light on these important subjects.2 3

Aune and colleagues (doi:10.1136/bmj.i1256) report a meta-analysis of 230 prospective studies with more than 3.74 million deaths among more than 30.3 million participants, providing further evidence that adiposity (measured by BMI) increases the risk of premature death.2 Some increase in …
Role of endocervical curettage (ECC) in the preoperative staging of endometrial carcinoma
Authors: C. B. Bijen, G. H. de Bock, K. A. Ten Hoor, H. Hollema, M. J. Mourits
Journal: Journal of Clinical Oncology (2008)

16512 Background: Endometrial cancer patients with clinical stage I disease are treated by general gynecologist. However, clinical stage II patients are operated by a gynecologic oncologist including lymph node dissection. The purpose of this investigation is to evaluate the value of an endocervical curettage (ECC) in predicting cervical involvement in the uterine specimen and in predicting advanced FIGO stage. Methods: From 1978 till 2006, 300 patients with epithelial endometrial cancer were evaluated pre-operatively by endocervical curettage and treated at the University Medical Center Groningen. To evaluate the predictive value of ECC for cervical involvement and for advanced FIGO stage (FIGO stage ≥II), the negative and positive predictive values (NPV and PPV) and the percentage of misclassified patients (i.e false positive or false negative ECC) were calculated. Results: Amongst all ECC procedures, 245 (81.7%) were negative and 55 (18.3%) were positive for cervical involvement. Cervical involvement in the hysterectomy specimen was found in 21.7% (65/300) of all cases. The PPV and NPV of ECC were 73.1% and 90.4%, respectively. False negative ECC occurred in 9.8% (24/245) and false positive ECC occurred in 25.5% (14/55). With FIGO stage as the reference, in 23.3% (57/245) of all negative ECC procedures, FIGO stage was classified as advanced. Of all patients with negative ECC procedures, 16.3% (40/245) had extra uterine tumour spread. In this group, cervical involvement was absent in 75% (30/40) cases. In the positive ECC group, 14.5% (8/55) was classified as an early FIGO stage. Of the patients with a positive ECC procedure, 50.9% (28/55) had extra uterine tumour spread according to their FIGO stage, 82.1% (23/28) with and 17.9% (5/28) without cervical involvement. Conclusions: The value of ECC is suboptimal in excluding cervical involvement and may lead to undertreatment. In case of a negative ECC procedure, nearly 10% of the patients do have cervical involvement in the hysterectomy specimen (FIGO stage II) and 23.3% has an advanced FIGO stage. No significant financial relationships to disclose.
Dilute apple juice is good alternative to electrolyte fluids for children with gastroenteritis, study finds
Authors: Jacqui Wise
Journal: BMJ (2016)

Diluted apple juice may be an appropriate alternative to electrolyte maintenance fluids in children with mild gastroenteritis who have minimal dehydration, a study published in JAMA has found.1

Electrolyte maintenance solution is recommended for treating and preventing dehydration, but the evidence in minimally dehydrated children is unproved. It is also relatively expensive, and children may not like the taste.

The trial included 647 children aged 6-60 months with gastroenteritis and …
SURG-26COMPLICATION PROFILE: COMPARING CRANIECTOMY AND CRANIOTOMY FOR POSTERIOR FOSSA METASTASES
Authors: Amir Hadanny, Erez Nossek, Yuval Shapira, Ido Strauss, Andrew A Kanner, Uri Rozovski, Razi Sitt, Zvi Ram, Tal Shahar
Journal: Neuro-Oncology (2015)
Abstract 280: Thrombospondin-1 Carries CD55 like Domains: A Novel Target for E. coli Invasion into Human Heart Cells
Authors: Tanu Rana, Pius N Nde, Stella Nowicki, Aniekanabasi N Udoko, Rajbir Singh, Candice A Johnson, Andrey Dykan, Jack Lawler, Fernando Villata, Bogdan J Nowicki
Journal: Circulation Research (2014)

Introduction: E. coli septicemia with cardiovascular dysfunction is among most frequent causes of human mortality however, underlying molecular mechanisms remain unknown. We recently described a fatal case of uro-sepsis with E. coli, bearing invasion-ligand Dr-adhesin, resulting in myocardial necrosis. Here we investigated an unrecognized mechanism of pathogen mediated cardiac cell invasion as a contributing factor to cardiovascular pathology and patient mortality. Methods: The experiments on human cardiac fibroblasts (HCF) showed E. coli colonization and invasion. However, the primary cell receptor for Dr adhesin, CD55, was undetectable. Searching for an alternative receptor we focused on matrix protein TSP-1 which is elevated in heart during infection. We over-expressed TSP1 in HCF cells (HCF-TSP1) and challenged with Dr+ E. coli. Bacterial binding/invasion to HCF-TSP1 and wild-type (WT) HCF were compared and evaluated. To rule out the possibility of fibroblast invasion due to presence of CD55 we performed Western blotting with CD55 antibody. Analysis of TSP-1 and CD55 epitopes was done to look for bacteria binding domains. Results: A dose-dependent TSP-1-E. coli binding assay in triplicates showed bacteria-HCF specific interactions. HCF-TSP1 had 13±4 bacteria bound per cell and invasion level of 2000/well which was up to 2.5 fold higher compared to WT-HCF. Both immunostaining and immunoblotting showed presence of TSP1 and absence of CD55 in HCF-TSP1. The interaction between purified/recombinant TSP1 coated to microtiter plates showed dose-dependent attachment of E. coli which increased with TSP1 concentrations. Sequence analysis of TSP-1 and CD55-SCR-3 revealed multiple 12AA CD55-like sequences within TSP-1. CD55-like epitopes identified on TSP1 shared up to 80% identity with the CD55 functional epitopes required for complement inhibition, Dr+ E. coli binding and invasion. Conclusions: Here we identified cardiac fibroblasts as target for uro-septic E. coli invasion. We discovered TSP-1 as the receptor facilitating Dr+ E. coli invasion process and identified previously unrecognized CD55-like sequences within TSP-1 which in CD55 account for functional epitopes allowing E. coli attachment, invasion and complement inhibition.
Impacts of Progression Type on Overall Survival in Advanced Gastric Cancer: Randomized Piii Study of S-1 + Oxaliplatin Vs. S-1 + Cisplatin
Authors: K. Nishikawa, Y. Yamada, K. Higuchi, M. Gotoh, N. Fuse, N. Sugimoto, T. Nishina, K. Amagai, K. Chin, Y. Niwa, A. Tsuji, H. Imamura, M. Tsuda, H. Yasui, H. Fujii, K. Yamaguchi, H. Yasui, S. Hironaka, C. Hamada, I. Hyodo
Journal: Annals of Oncology (2014)
Systemic and In Situ Natural Killer Activity in C57BL/6N and CBA/N Mice Bearing Murine Sarcoma Virus-Induced Regressor Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: James M. Gerson, Howard T. Holden, Ronald B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1980)

Both systemic and in situ natural killer (NK) activity was assessed in young and old C57BL/6N and CBA/N mice bearing primary murine sarcoma virus-induced tumors. Splenic NK activity was depressed in tumor-bearing mice relative to normal age-matched controls. In situ NK activity was detected in young mice, and the level paralleled that found in the spleens of the same mice. In older mice, in situ NK activity was not detected. Furthermore, the depressed levels of activity in the spleens of tumor-bearing mice seemed to reflect systemic effects rather than migration of NK cells from the spleen to the tumor site.