tbuckley/cabot-search huggingface dataset:
Reducing Lung Cancer Progression With Immunotherapy
Authors: Rebecca Voelker
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Comparative pharmacokinetics and biodistributions of mebendazole from cosolvent and nanoemulsion formulations in nude athymic mice
Authors: Yulan Qi, Pranav Gupta, Diana Chow
Journal: Cancer Research (2007)

2259    Objective:  Mebendazole (Mbz), Methyl 5-benzoyl-2-benzimidazole carbamate, exerts growth inhibition in culture and tumor bearing nu/nu mice against NSCLC cell lines. The antineoplastic activity of MBZ is also evident in colorectal carcinoma and melanoma. A nanoemulsion (37 nm) formulation (PM1) of Mbz has been developed in our laboratory for potential parental delivery. This study was to comparatively characterize pharmacokinetics and biodistributions of Mbz from cosolvent formulation and PM1 in nude athymic mice.   Method:  Mbz was administrated by i.v. bolus to the mice (30-35 gm) at 5 mg/kg for cosolvent system and 2.5 mg/kg for PM1. Concentrations of Mbz in plasma and five organs (heart, lung, liver, spleen, and kidney) were monitored by HPLC assays up to 6 hours post dose. The pharmacokinetic and tissue distribution profiles were constructed and pharmacokinetic parameters were derived using the WinNonlin.   Results:  The plasma concentration-time profiles of Mbz from cosolvent and PM1 systems followed a two-compartment model with dose normalized AUCs of 2.46 and 2.38 μg·min/ml per μg dose, respectively. The clearance (CL) was 0.41 ml/min for cosolvent and 0.42 ml/min for PM1. The apparent volume distributions at steady-state (Vss) for cosolvent and PM1 were 42.8 ml and 38.8 ml, respectively. Different tissue distribution patterns between the two formulations were observed. For cosolvent, Mbz peak concentrations in different organs were reached in 5 minutes after injection. The highest peak concentration was 76.41 ng/g tissue/μg dose in liver, in contrast to 224.42 ng/g/μg in lung at 2 hr post dose for PM1. Mbz in cosolvent yielded the highest exposure in liver with AUC of 8.24 ug·min/g/ug dose, followed by kidney of 6.67 ug·min/g/ug. However, for PM1, AUC in lung (63.57 ug·min/g/ug) was the highest, which was about 20 folds of that from cosolvent (3.24 ug·min/g/ug), followed by those in liver (5.56 ug·min/g/ug) and kidney (5.22 ug·min/g/ug). For cosolvent, the elimination half-lives were 80, 72, 91, 84 and 98 min in heart, lung, liver, spleen, and kidney, respectively. For PM1, the elimination half-lives were substantially prolonged than those from cosolvent, 96, 172, 193, 123 and 131 min in heart, lung, liver, spleen, and kidney, respectively.        Conclusion:  Mbz in cosolvent and PM1 systems exhibit similar plasma pharmacokinetics, but distinct tissue distributions. PM1 yields higher Mbz concentrations and prolonged exposures in organs than cosolvent, especially in lung, which may have potential value for lung cancer therapy.
Practical Guide to Surgical Data Sets: National Cancer Database (NCDB)
Authors: Ryan P. Merkow, Alfred W. Rademaker, Karl Y. Bilimoria
Journal: JAMA Surgery (2018)

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 Surgery HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Surgery journal
Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia
Authors: Qingming Hou, Fei Liu, Anutosh Chakraborty, Yonghui Jia, Amit Prasad, Hongbo Yu, Li Zhao, Keqiang Ye, Solomon H. Snyder, Yuanfu Xu, Hongbo R. Luo
Journal: Science Translational Medicine (2018)

The significance of developing host-modulating personalized therapies to counteract the growing threat of antimicrobial resistance is well-recognized because such resistance cannot be overcome using microbe-centered strategies alone. Immune host defenses must be finely controlled during infection to balance pathogen clearance with unwanted inflammation-induced tissue damage. Thus, an ideal antimicrobial treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce tissue damage. We report that disrupting the inositol hexakisphosphate kinase 1 (Ip6k1) gene or pharmacologically inhibiting IP6K1 activity using the specific inhibitor TNP [N2-(m-(trifluoromethyl)benzyl) N6-(p-nitrobenzyl)purine] efficiently and effectively enhanced host bacterial killing but reduced pulmonary neutrophil accumulation, minimizing the lung damage caused by both Gram-positive and Gram-negative bacterial pneumonia. IP6K1-mediated inorganic polyphosphate (polyP) production by platelets was essential for infection-induced neutrophil-platelet aggregate (NPA) formation and facilitated neutrophil accumulation in alveolar spaces during bacterial pneumonia. IP6K1 inhibition reduced serum polyP levels, which regulated NPAs by triggering the bradykinin pathway and bradykinin-mediated neutrophil activation. Thus, we identified a mechanism that enhances host defenses while simultaneously suppressing neutrophil-mediated pulmonary damage in bacterial pneumonia. IP6K1 is, therefore, a legitimate therapeutic target for such disease.
Network Modeling of microRNA–mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN
Authors: Chi Yan Ooi, Daniel R. Carter, Bing Liu, Chelsea Mayoh, Anneleen Beckers, Amit Lalwani, Zsuzsanna Nagy, Sara De Brouwer, Bieke Decaesteker, Tzong-Tyng Hung, Murray D. Norris, Michelle Haber, Tao Liu, Katleen De Preter, Frank Speleman, Belamy B. Cheung, Glenn M. Marshall
Journal: Cancer Research (2018)

Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. On the basis of a Bayesian learning network model in which we compared pretumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.Significance: Network modeling of miRNA-mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN. Cancer Res; 78(12); 3122-34. ©2018 AACR.
Abstract P053: Cardiovascular Health is Associated With Incidence of Elevated C-Reactive Protein Over 18 Years of Follow-up: The Coronary Artery Risk Development in Young Adults Study
Authors: Jonathan J Ruiz-Ramie, Jacob L Barber, Donald M Lloyd-Jones, Abbi D Lane-Cordova, Myron Gross, Jamal S Rana, Stephen Sidney, David R Jacobs, Mark A Sarzynski
Journal: Circulation (2018)

Introduction: In 2010, the American Heart Association (AHA) established “Life’s Simple 7” a composite of metrics aimed at defining cardiovascular health (CVH). Seven positive health factors (blood cholesterol, blood pressure, and fasting plasma glucose) and behaviors (diet quality, physical activity, smoking, and body mass index) are emphasized within the construct, each being scored into ideal, intermediate, or poor categories. While multiple studies have explored the association between the individual components of CVH and markers of inflammation and atherogenesis, none have examined total CVH score as a predictor of elevated C-reactive protein (CRP) levels. Purpose: To assess the hypothesis that CVH score is inversely associated with future elevated CRP levels. Methods: Black and White men and women (N=1096) from the Coronary Artery Risk Development in young Adults (CARDIA) study were examined at 4 different examinations across 18 years (1992, 2000, 2005,2010). At each examination, CRP and the components of CVH were measured. A 14-point CVH score was determined by summing points for each CVH metric at ideal (2 points), intermediate (1 point), and poor (0 points) levels. Three categories of CVH score were created: low (0-7), moderate (8-11), and high (12-14). Multivariable Cox proportional hazards regression models were used to test the association of both categorical and continuous CVH score with incidence of elevated CRP (&gt;3.0 mg/L) over up to 18 years of follow-up. All models were adjusted for sex and race, and the following time-varying covariates: age, and current level of education. Results: Over the 18-year period, the incidence of elevated CRP was 33.6 per 1000 person years. Baseline CVH was associated with lower risk (hazard ratio (HR): 0.83; 95% CI: 0.80 to 0.86) of elevated CRP per 1point increment in CVH. When compared to the high CVH group at baseline, both low (HR: 2.80; 95% CI: 2.16 to 3.65) and moderate (HR: 1.63; 95%CI: 1.35 to 1.96) CVH groups had elevated risk of elevated CRP. Time-varying CVH was associated with a lower risk (HR: 0.88; 95% CI: 0.85 to 0.91) of elevated CRP per increment in CVH score. In models that entered CVH category as a time-varying covariate, both low (HR: 2.84; 95% CI: 2.08 to 3.87) and moderate (HR: 2.09; 95% CI: 1.56 to 2.79) CVH categories were associated with over twice the risk of elevated CRP compared to the optimal CVH group. Conclusions: Lower CVH is associated with elevated risk of elevated CRP during the transition from young adulthood to middle age.
Concerns Regarding Resource Use and Outcomes in Subsets of Clinicians
Authors: Romil Chadha, Preetham Talari, Alan M. Hall
Journal: JAMA Internal Medicine (2018)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Battery-free, wireless sensors for full-body pressure and temperature mapping
Authors: Seungyong Han, Jeonghyun Kim, Sang Min Won, Yinji Ma, Daeshik Kang, Zhaoqian Xie, Kyu-Tae Lee, Ha Uk Chung, Anthony Banks, Seunghwan Min, Seung Yun Heo, Charles R. Davies, Jung Woo Lee, Chi-Hwan Lee, Bong Hoon Kim, Kan Li, Yadong Zhou, Chen Wei, Xue Feng, Yonggang Huang, John A. Rogers
Journal: Science Translational Medicine (2018)

Battery-free, soft, skin-mounted wireless sensors enable continuous, full-body spatiotemporal mapping of pressure and temperature on human subjects.
Ethical Guidance for Selecting Clinical Trials to Receive Limited Space in an Immunotherapy Production Facility
Authors: Nancy S. Jecker, Aaron G. Wightman, Abby R. Rosenberg, Douglas S. Diekema
Journal: The American Journal of Bioethics (2018)

Our aims are to (1) set forth a multiprinciple system for selecting among clinical trials competing for limited space in an immunotherapy production facility that supplies products under investigation by scientific investigators; (2) defend this system by appealing to justice principles; and (3) illustrate our proposal by showing how it might be implemented. Our overarching aim is to assist manufacturers of immunotherapeutic products and other potentially breakthrough experimental therapies with the ethical task of prioritizing requests from scientific investigators when production capacity is limited.
Final toxicity results from a phase II study of 5-fluorouracil, oxaliplatin, and dasatinib (FOLFOX-D) in previously untreated metastatic pancreatic adenocarcinoma.
Authors: Thomas J. George, Jason Scott Starr, Hiral D. Parekh, Alison Marguerite Ivey, Long H. Dang, Karen Colleen Daily, Carmen Joseph Allegra, David L. DeRemer, Steven J. Hughes, Margaret A. McEwan, Jessica L Cioffi, Jose Gilberto Trevino
Journal: Journal of Clinical Oncology (2018)

504 Background: Systemic chemotherapy for pancreatic adenocarcinoma (PCa) improves survival but most targeted agents have consistently failed to demonstrate clinical benefits. Src is overexpressed in PCa and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the PCa phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This single arm phase II trial is to determine activity and toxicity of FOLFOX + D in previously untreated metastatic PCa. Pts must have at least 1 RECIST measurable target lesion, ECOG PS 0-2, normal QTc and adequate organ function. Treatment is standard q14d cycles of mFOLFOX6 with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints are PFS (primary), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those with durable disease control or exceptional response. Sample size is based on a 50% improved median PFS from 4 (historical) to 6 months. Results: Enrollment is now closed on this prospective phase II study with 42 of 42 evaluable pts. Baseline demographics are in Table 1. Toxicity and outcomes continue to be assessed. Conclusions: Final toxicity data will be presented at the meeting for this novel combination treatment in advanced PCa. Clinical trial information: NCT01652976. [Table: see text]
Association of immune markers and Immunoscore with survival of stage III colon carcinoma (CC) patients (pts) treated with adjuvant FOLFOX: NCCTG N0147 (Alliance).
Authors: Frank A. Sinicrope, Qian Shi, Fabienne Hermitte, Erica N Heying, Al Bowen Benson, Sharlene Gill, Richard M. Goldberg, Morton S. Kahlenberg, Suresh Nair, Anthony Frank Shields, Daniel J. Sargent, Jerome Galon, Steven R. Alberts
Journal: Journal of Clinical Oncology (2017)

3579 Background: Tumor infiltrating lymphocytes (TIL) indicate a host immune response that may influence survival. Immunoscore was developed using CD3 + and CD8 + density and location in primary CC pts with pooled stages, varying treatment and follow-up. We determined if individual immune markers and/or Immunoscore are prognostic in resected stage III CC pts (N=600). Methods: CD3 + and CD8 + T-cell or CD20 + B lymphocyte density in central tumor (CT) and invasive margin (IM) was evaluated by immunostaining and quantified by image analysis. Immunoscore was calculated on a scale of I0 to I4 with high densities of CD3 + and CD8 + in both CT and IM scored as I4; low densities scored as I0. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for covariates. Results: Data for CD3 + , CD8 + and CD20 + were generated (N=595). Higher density of CD3 + CT, CD3 + IM and CD8 + IM were associated with longer DFS adjusting for covariates (Table). CD3 + IM had the strongest association with DFS, and was stronger in left-sided (HR adj. =0.81, 95% CI, 0.70-0.94, p adj. = 0.0049) vs right-sided (HR adj. =0.93, 95% CI, 0.85-1.0 p adj. =0.52) tumors (p interaction =0.039). Higher density of CD3 + IM was associated with older age (p=0.034), T 1/2 (p&lt;.0001), N 1 (p=0.017), right-sided (p=0.013), high TILs (p=0.0008), and deficient MMR (p=0.0003). Using a prior Immunoscore risk stratification, higher scores were associated with better DFS (HR . =0.62, CI, 0.44-0.87, p=0.006) (Table). Conclusions: Densities of CD3 + and CD8 + , especially at IM, are individually prognostic in FOLFOX-treated pts. Association of CD3 + IM with prognosis differed by primary CC site. Immunoscore was strongly prognostic, and this result provides validation in a clinical trial cohort. [Table: see text]
Increased affluence, life history theory, and the decline of shamanism
Authors: Nicolas Baumard
Journal: Behavioral and Brain Sciences (2018)

Abstract I applaud Singh's proposition to use evolutionary psychology to explain the recurrence of shamanistic beliefs. Here, I suggest that evolutionary mechanisms (i.e., life history theory) also can explain the variability of the distribution of shamanism. When resources are abundant, individuals become more patient and more open minded to the point that science becomes cognitively attractive and may replace magic.
EYA4 inhibits hepatocellular carcinoma growth and invasion by suppressing NF‐κB‐dependent RAP1 transactivation
Authors: Shi‐Jing Mo, Xun Hou, Xiao‐Yi Hao, Jian‐Peng Cai, Xin Liu, Wei Chen, Dong Chen, Xiao‐Yu Yin
Journal: Cancer Communications (2018)

Abstract Background Our previous studies demonstrated that eyes absent homolog 4 (EYA4), a member of the eye development‐related EYA family in Drosophila , is frequently methylated and silenced in hepatocellular carcinoma (HCC) specimens and associated with shorter survival. The current work aimed to explore the mechanisms through which EYA4 functions as a tumor suppressor in HCC. Methods Stable EYA4‐expressing plasmid (pEYA4) transfectants of the human HCC cell lines Huh‐7 and PLC/PRF/5 (PLC) were established. Xenografts tumors were established via subcutaneous injection of the stable transfectants into BALB/c nude mice. Tissue samples were obtained from 75 pathologically diagnosed HCC patients. Quantitative real‐time polymerase chain reaction, Western blotting and immunohistochemistry were performed to determine the expression of EYA4 in cell lines, xenografts and clinical specimens. The cell proliferation, colony formation, invasiveness and tumor formation of stable transfectants were studied. A gene expression microarray was utilized to screen genes regulated by EYA4 expression. The effect of EYA4 on nuclear factor‐κB (NF‐κB)/RAS‐related protein 1 (RAP1) signaling was demonstrated through the co‐transfection of pEYA4 and Flag‐tagged RAS‐related protein 1A gene‐expressing plasmid (Flag‐RAP1A), functional studies, chromatin immunoprecipitation, immunofluorescence staining and cellular ubiquitination assay. Results The restoration of EYA4 expression in HCC cell lines suppressed cell proliferation, inhibited clonogenic outgrowth, reduced cell invasion and restrained xenograft tumor growth, and Flag‐RAP1A reversed the suppressive effects of pEYA4 in vitro. Activation of NF‐κB with tumor necrosis factor‐α (TNF‐α) increased the binding of p65 to the RAP1A gene promoter and up‐regulated RAP1 protein expression. The inhibition of NF‐κB with BAY 11‐7085 and p65 siRNA successfully blocked TNF‐α‐induced RAP1 up‐regulation. EYA4 antagonized the TNF‐α‐induced phosphorylation and ubiquitination of inhibitor of NF‐κBα (IκBα) as well as the nuclear translocation and transactivation of p65, resulting in repressed NF‐κB activity and RAP1 expression. Blocking the serine/threonine phosphatase activity of EYA4 with calyculin A notably abrogated its suppressive effect on NF‐κB activity. In addition, EYA4 expression was inversely correlated with IκBα/RAP1 activity in clinical HCC specimens. Conclusion Our findings provide a functional and mechanistic basis for identifying EYA4 as a bona fide tumor suppressor that disrupts aberrant activation of the NF‐κB/RAP1 signaling pathway and thus orchestrates a physiological impediment to HCC growth and invasion.