tbuckley/cabot-search huggingface dataset:
Multidrug Ebola Trial Underway in Democratic Republic of Congo
Authors: M.J. Friedrich
Journal: JAMA (2019)

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
Exercise Training Associated With Testosterone Replacement Decreases Muscle Sympathetic Nerve Activity in Heart Failure Patients With Hypogonadism
Authors: Marcelo R. dos Santos, Ana Luiza C. Sayegh, Marco A. Arap, Antonio Carlos P. Barretto, Holly Middlekauff, C. E. Negrão, d Alves Maria-Janieire
Journal: Circulation (2013)
A dose escalation study of nimotuzumab plus irinotecan as second-line treatment in metastatic colorectal cancer with wild-type K-ras.
Authors: Jun Zhou, Lin Shen, Jing Gao
Journal: Journal of Clinical Oncology (2012)

e14122 Background: Nimotuzumab is a humanized monoclonal antibody of EGFR. We assessed the safety/tolerability and the efficacy of nimotuzumab combined with Irinotecan as the second-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Methods: Patients with mCRC refractory to oxaliplatin, K-ras WT, signed informed consent, target lesion(s), performance status (PS) ≤2, adequate organ functions, were eligible for this open-labelled, single-armed trial (NCT00972465). Irinotecan was given as 180mg/m2 d1, Q2w until progression or AEs or maximum 6 cycles. Nimotzumab was given as 200, 400, 600 or 800mg weekly until progression or AEs. The primary end points were objective response rate and toxicity. The second end points are PFS and OS. Results: A total of 31 patients (M/F = 22/9; median age 55; range 29-77) have been enrolled from July 2009 to Nov 2011. 4/11/12/4 patients received nimotuzumab as the dose of 200/400/600/800mg respectively. Most common grade 3/4 toxicity are leukopenia (14.8%,) and neutrocytopenia 18.5%). For all the patients, no grade 3/4 toxicity relating with Nimotuzumab was observed. 2 and 3 patients developed skin rash (grade 1) in 400 and 600mg arm respectively. 2 patients developed skin rash grade 2 in 600/800mg arm. The maximum tolerated dose has not yet been reached. Three patients (400/600mg: 2/1) quitted the trial because of personal reason. In 600mg arm, PR was 33.3% (4/12), SD was 25% (3/12); in 400mg arm, PR was 9.l%(1/11), SD was 36.4%(4/11); in 200mg arm, SD was 50%(2/4), PD was 50% (2/4); in 800mg arm, PR was 25%(1/4), PD was 75%(3/4). The follow-up of overall survival is ongoing. Conclusions: Addition of Nimotuzumab with 600mg weekly plus Irinotecan is safe and first data suggest a promising activity. The maximum tolerated dose of Nimotuzumab has not been reached yet.
Half of GP premises are not fit for purpose, finds BMA survey
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Many general practice buildings in England are too small to meet patient demand, and half are deemed unfit for purpose, a large survey by the BMA has found.1

The association surveyed 1011 practices in England, asking GPs and practice managers to detail their experiences of property ownership, management, and leasing.

Only half of practices (489 of 979 respondents to this question) said that their premises were suitable for their patients’ present needs. And eight in 10 (783 of 1006 respondents to this question) said that their practice was not suitable to meet future needs or anticipated population growth.

Some 137 (83%) of 165 respondents who answered a question about leasing …
First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma
Authors: XiaoMin Wan, YuCong Zhang, ChongQing Tan, XiaoHui Zeng, LiuBao Peng
Journal: JAMA Oncology (2019)

Recently, new drugs have been approved for the first-line treatment of metastatic renal cell carcinoma (mRCC). Nivolumab plus ipilimumab significantly increases overall survival for intermediate- and poor-risk patients with mRCC. However, considering the high cost of nivolumab plus ipilimumab, there is a need to assess its value by considering both efficacy and cost.To evaluate the cost-effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line setting for intermediate- and poor-risk patients with mRCC from the US payer perspective.A Markov model was developed to compare the lifetime cost and effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line treatment of mRCC using outcomes data from the CheckMate 214 phase 3 randomized clinical trial, which included 1096 patients with mRCC (median age, 62 years) and compared nivolumab plus ipilimumab vs sunitinib as first-line treatment of mRCC. In the analysis, patients were modeled to receive sunitinib or nivolumab plus ipilimumab for 4 doses followed by nivolumab monotherapy.Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated, at a willingness-to-pay threshold of $100 000 to $150 000 per QALY. Univariable, 2-way, and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Additional subgroup analyses were performed.Nivolumab plus ipilimumab provided an additional 0.96 QALYs, at a cost of $108 363 per QALY. Sensitivity analyses found the results to be most sensitive to overall survival hazard ratio (0.63; 95% CI, 0.44-0.89) and mean patient weight (70 kg, range, 40-200 kg). Other variables, such as the cost of nivolumab plus ipilimumab (mean, $32 213.44; range, $25 770.75-$38 656.13), utility values for nivolumab plus ipilimumab (mean, 0.82; range, 0.65-0.98), and proportion receiving nivolumab in sunitinib arm (mean, 0.27; range, 0.22-0.32), had a moderate or minor influence on model results. Subgroup analyses demonstrated that nivolumab plus ipilimumab was most cost-effective for patients with programmed cell death 1 ligand 1 expression of at least 1% ($86 390 per QALY).In this model, nivolumab plus ipilimumab was estimated to be cost-effective compared with sunitinib for intermediate- and poor-risk patients with mRCC at a willingness-to-pay threshold from $100 000 to $150 000 per QALY.
Immunogenomic Landscape of Hematological Malignancies
Authors: Olli Dufva, Petri Pölönen, Oscar Brück, Mikko A Keränen, Juha Mehtonen, Sanna M. Siitonen, Suvi-Katri Leivonen, Leo Meriranta, Sirpa Leppa, Matti Nykter, Olli Lohi, Merja Heinäniemi, Satu Mustjoki
Journal: Blood (2018)
Update: influenza activity - United States, October 3-December 11, 2010.
Authors: L. Brammer, S. Epperson, K. Kniss, D. Mustaquim, A. Bishop, R. Dhara, M. Jhung, T. Wallis, L. Finelli, L. Gubareva, J. Bresee, A. Klimov, N. Cox
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
B7-H3 Expression in Merkel Cell Carcinoma–Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density
Authors: Phyu P. Aung, Edwin Roger Parra, Souptik Barua, Dawen Sui, Jing Ning, Barbara Mino, Debora Alejandra Ledesma, Jonathan L. Curry, Priyadharsini Nagarajan, Carlos A. Torres-Cabala, Eleni Efstathiou, Anh G. Hoang, Michael K. Wong, Jennifer A. Wargo, Alexander J. Lazar, Arvind Rao, Victor G. Prieto, Ignacio Wistuba, Michael T. Tetzlaff
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
Abstract IA17: Genome-epigenome interplay in medulloblastoma
Authors: Paul A. Northcott
Journal: Cancer Research (2015)

Abstract The recent application of genomics to large series of primary human medulloblastomas has dramatically improved our perspective of the genes, pathways, and molecular processes underpinning this highly malignant pediatric brain tumor. Transcriptionally defined molecular subgroups have emerged, changing the fundamental definition of medulloblastoma from a single histologically recognized entity, to four distinct subtypes: WNT, SHH, Group3, and Group4. These subgroups exhibit highly discriminatory genomic landscapes, patient demographics, and clinical phenotypes. Next-generation sequencing has identified and implicated recurrently altered somatic drivers, many of which are affected in a subgroup-restricted manner. In contrast, somatic variants affecting chromatin-modifying genes, including histone “writers,” “erasers,” and “readers” are prevalent in medulloblastoma and occur across subgroups, suggesting that deregulation of the epigenome is an essential step during medulloblastoma development. Integrative “omics”-based strategies have begun to dissect the fascinating genome-epigenome interplay underlying medulloblastoma, revealing previously undisclosed oncogenic mechanisms and drivers of disease. Furthermore, new insights into the biology and putative origins of the poorly understood Group3 and Group4 medulloblastomas have likewise been revealed. This talk will summarize these recent discoveries afforded through genomics and discuss their potential implications, both in the lab and in the clinic, going forward. Citation Format: Paul A. Northcott. Genome-epigenome interplay in medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA17.
Prevalence and Cellular Distribution of Novel Immune Checkpoint Targets Across Longitudinal Specimens in Treatment-naïve Melanoma Patients: Implications for Clinical Trials
Authors: Jarem Edwards, Annie Tasker, Inês Pires da Silva, Camelia Quek, Marcel Batten, Angela Ferguson, Ruth Allen, Benjamin Allanson, Robyn P.M. Saw, John F. Thompson, Alexander M. Menzies, Umaimainthan Palendira, James S. Wilmott, Georgina V. Long, Richard A. Scolyer
Journal: Clinical Cancer Research (2019)

Immunotherapies targeting costimulating and coinhibitory checkpoint receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known about the relative abundance, coexpression, and immune cells enriched for each specific drug target, limiting understanding of the biological basis of potential treatment outcomes and development of predictive biomarkers for personalized immunotherapy. We sought to assess the abundance of checkpoint receptors during melanoma disease progression and identify immune cells enriched for them.Experimental Design: Multiplex immunofluorescence staining for immune checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, VISTA) was performed on 96 melanoma biopsies from 41 treatment-naïve patients, including patient-matched primary tumors, nodal metastases, and distant metastases. Mass cytometry was conducted on tumor dissociates from 18 treatment-naïve melanoma metastases to explore immune subsets enriched for checkpoint receptors.A small subset of tumor-infiltrating leukocytes expressed checkpoint receptors at any stage of melanoma disease. GITR and OX40 were the least abundant checkpoint receptors, with <1% of intratumoral T cells expressing either marker. ICOS, PD-1, TIM-3, and VISTA were most abundant, with TIM-3 and VISTA mostly expressed on non-T cells, and TIM-3 enriched on dendritic cells. Tumor-resident T cells (CD69+/CD103+/CD8+) were enriched for TIGIT (>70%) and other coinhibitory but not costimulatory receptors. The proportion of GITR+ T cells decreased from primary melanoma (>5%) to lymph node (<1%, P = 0.04) and distant metastases (<1%, P = 0.0005).This study provides the first comprehensive assessment of immune checkpoint receptor expression in any cancer and provides important data for rational selection of targets for trials and predictive biomarker development.
Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury
Authors: Rita Manco, Laure-Alix Clerbaux, Stefaan Verhulst, Myriam Bou Nader, Christine Sempoux, Jerome Ambroise, Bertrand Bearzatto, Jean Luc Gala, Yves Horsmans, Leo van Grunsven, Chantal Desdouets, Isabelle Leclercq
Journal: Journal of Hepatology (2019)
Proteomic analysis of UKF-NB-4 cells reveals a stimulatory activity of MT-3 on cellular senescence and apoptosis
Authors: M.A. Merlos Rodrigo, H. Buchtelova, V. Strmiska, A. Jimenez Jimenez, I. Casal, V. Adam, Z. Heger
Journal: Annals of Oncology (2019)

Background: Metallothioneins (MTs) family is a intracellular and cysteine-rich proteins with a high affinity to metals. MT-3 could play important neuromodulatory and neuroprotective roles. MT-3 has been also found up-regulated in a number of cancers. Neuroblastoma (Nbl) is a cancer is the most common extra-cranial solid tumour of childhood. The main aim was to provide novel insights into the molecular mechanisms of hMT-3 up-regulation and to elucidate the effects beneath the MT-3 up-regulation in Nbl cells. Methods: To increase the expression of MT-3 Nbl (UKF-NB-4) cells were transiently transfected with a plasmid containing MT-3 gene (pcDNA3.1-GFP-hMT-3-TOPO). Separations of tryptic digests were carried out on an Easy-nLC 1000 nano system. MS analysis was performed using a Q-Exactive MS. The mass spectrum *.raw file was searched against the human SwissProt 57.15 database using MASCOT search engine (version 2.3, Matrix Science). Results: The efficiency of transfection analysed through a fluorescence of GFP tag expressed at the C-terminus of MT-3 showed more 70% transfection efficiency for both constructed plasmids (mock and MT-3). From the total of common proteins in dataset (hMT-3 vs. mock), 176, 20 and 1244 proteins were quantitatively identified with up-regulation, down-regulation, and no significant differences between hMT-3 and mock treatments. Noteworthy, the bioinformatical analyses revealed the exclusive expression (induced by MT-3) and up-regulation proteins of a number of proteins affecting biological pathways related to mitotic cell cycle, cellular responses to stress, positive regulation of proteolysis, negative regulation of cell cycle and programmed cell death. Conclusions: Our proteomic data shed some light on the proteins involved in inducing senescence and apoptosis in tested Nbl cells with up-regulated MT-3. Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. Cellular senescence and apoptosis are among those mechanisms. Further experiments will be performed to functionally verify these data to provide novel insights into the Nbl biology. These might be useful to develop novel therapeutic protocols utilizing MT-3 as prognostic biomarker or therapeutic target. Legal entity responsible for the study: Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ. Funding: European Research Council (ERC) under the European Uniońs Horizon 2020 Research and Innovation Programme (grant agreement No. 759585). Disclosure: All authors have declared no conflicts of interest.
Predictors of recurrence in stage I/II colorectal cancer: Analysis of a single Institution’s experience for over 14 years.
Authors: Narjust Duma, Daniel Pievsky, Arpita Gandhi, Abdullah Mohammad Khan, Larysa Jessica Sanchez, Donald A. McCain, Andrew Jennis, Zubin M. Bamboat, Martin Gutierrez
Journal: Journal of Clinical Oncology (2015)

e14542 Background: Surgical resection remains a mainstay of treatment for localized colorectal cancer (CRC). However, up to 35% of patients (pts) develop recurrence with a significant decrease in overall survival. The aim of this study was to evaluate clinical characteristics and specific predictors of recurrence for stage I/II CRC. Methods: We performed a retrospective analysis of 2310 pts diagnosed with stage I/II CRC at our institution between 1990 and 2013, with a minimum follow up of 24 months. Tumor characteristics and recurrence data were studied. Cox regression was used for statistical analysis. Results: Of the 2310 pts, recurrence was identified in 276 (12%) pts, of which 88 (32%) pts had early recurrence ( < 1year). Median time of recurrence was 625 days. 210 (76%) pts had local recurrence while 66 (24%) pts had distal recurrence, with liver being the main site of distant metastasis. Males had a higher recurrence rate than females (16% vs. 7%, p < 0.0001). When comparing recurrence pts (R) with non-recurrence (NR) pts, Hispanics were more prevalent in the R group (13% vs 8%, p < 0.01). R pts were more likely to have rectal and poorly differentiated tumors (33% vs. 13%, p < 0.0001; 23% vs. 14%, p < 0.0001, respectively). Mucinous adenocarcinomas were more prevalent in the R group (16% vs. 9%, p < 0.0005). In multivariate analysis: male sex (OR: 1.24, 95%CI: 1.21-1.56, p < 0.001), rectal tumors (OR: 4.2, 95%CI: 3.14-5.06, p < 0.001), tumor size (OR: 2.55, 95%CI: 1.31-4-51, p < 0.01), and positive margins (OR: 3.6, 95%CI: 2.13-5.21, p < 0.04) were independent predictors for recurrence. Kras (+) status was a predictor of recurrence by univariate analysis. Age, race, and histologic grade were not predictors of recurrence. Pts with early recurrence had a lower median overall survival compared to pts that developed recurrence after 1 year, 37 months (95%CI: 26.6-49.6) vs. 59 months (95%CI: 42.4-74.3), p < 0.04. Conclusions: Pts with recurrence were more likely to have rectal and poorly differentiated tumors. Poorer survival was observed in pts with early recurrence. These findings could serve as important prognostic information and may help identify the pts that would benefit from aggressive surveillance after treatment.
P081/O20 Lasp1 regulates cell-to-cell contact formations of fibroblast-like synoviocytes in RA
Authors: D Beckmann, A Krause, U Hansen, HP Kiener, T Kamradt, T Pap, A Korb-Pap
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) undergo a stable transformation resulting in an aggressive, tumour-like phenotype that mediates cartilage damage by increased levels of MMPs and adhesion molecules such as β1 integrins. In this context, the tumour-associated protein Lasp1 is of interest because it modulates actin organization and focal adhesion turnover. <h3>Objectives</h3> The effects of Lasp1 deficiency on RA-FLS cell-to-cell contact formations, the disease course and joint destruction have been investigated in this study. <h3>Methods</h3> Lasp-1 expression was analysed in RA synovial tissue and in murine models of arthritis (hTNFtg mice and G6PI mouse model). Hind paws were analysed by using WB analyses and immunofluorescence stainings, primary FLS were isolated and cultivated, respectively. Furthermore, Lasp1<sup>-/-</sup> mice were interbred with hTNFtg mice and offsprings were analysed for the progression of joint destruction by clinical evaluation and histopathology. Migration characteristics of FLS derived from wild type (wt), Lasp1<sup>-/-</sup>, hTNFtg and Lasp1<sup>-/-</sup>hTNFtg mice were analysed by live cell imaging. Additionally, we used an <i>in vitro</i> 3D organ culture system for functional analyses. <h3>Results</h3> Upregulated Lasp1 levels in RA synovial tissue and FLS were observed. In line with the human data, increased levels of Lasp1 were found in murine FLS derived from hTNFtg mice and the chronic G6PI model. Lasp1 was located in structures of cell-matrix as well as cell-to-cell contacts. The loss of Lasp1 led to clear alterations in adherens junction arrangement indicated by altered β-catenin pattern. <i>In vivo</i> evaluation of Lasp1<sup>-/-</sup>hTNFtg mice revealed a milder arthritis score, less cartilage degradation and reduced FLS attachment to articular cartilage compared to hTNFtg mice. <i>In vitro</i> migration assays using live cell imaging demonstrated alterations in spreading morphology and cell-to-cell contact turnovers and a significantly reduced migration rate of Lasp1<sup>-/-</sup> FLS and Lasp1<sup>-/-</sup>hTNFtg FLS compared to controls (−69.11% after 24 hour). Histological sections of the 3D matrices demonstrated that wt FLS formed an organised synovial structure comparable with healthy synovial tissue <i>in vivo,</i> whereas in matrices with hTNFtg FLS this synovial architecture absent. Interestingly, Lasp1 deletion in the hTNFtg background resulted in an organised cellular lining layer comparable with wt FLS matrices. <h3>Conclusions</h3> Lasp1 represents an interesting target involved in RA-caused joint destruction, because its loss resulted in significantly reduced cartilage destruction <i>in vivo</i> and RA-FLS interactions and migration rates <i>in vitro</i>. <h3>Disclosure of Interest</h3> None declared.
Case 7-2019: A 73-Year-Old Woman with Swelling of the Right Groin and Fever
Authors: Jacob D. Soumerai, Shahein H. Tajmir, Martin S. Hirsch, Lucas R. Massoth
Journal: New England Journal of Medicine (2019)

A 73-year-old woman with a history of chronic lymphocytic leukemia presented with right inguinal lymphadenopathy, fever, and night sweats. Results of core biopsy of the dominant lymph node were consistent with CLL without large-cell transformation. Additional diagnostic tests were performed.