tbuckley/cabot-search huggingface dataset:
Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy.
Authors: Byoung Chul Cho, Myung-Ju Ahn, Jong-Seok Lee, Dong-Wan Kim, Sang-We Kim, Tom John, Stephen Chuan-Hao Kao, Jonathan Wade Goldman, Wu-Chou Su, Ronald B. Natale, Jin Seok Ahn, HyeRyun Kim, Tae Min Kim, Chia-Chi Lin, Philip Overend, Zhenfan Yang, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2017)

2069 Background: AZD3759 is the first EGFR inhibitor primarily designed to effectively cross the blood brain barrier (BBB) to treat central nervous system (CNS) metastases. A phase I study is ongoing to assess AZD3759 in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other treatment (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Two dose levels of AZD3759, 200 mg and 300 mg BID, were assessed. Results: As of24 September, 2016,38 patients were recruited into the expansion cohorts of this phase I study. Of those, 18 were TKI pre-treated EGFRm NSCLC patients with LM. 10 and 8 patients were in the 300 and 200 mg BID cohorts, respectively. No DLTs were observed at either dose, while AZD3759 was better-tolerated at 200 than 300 mg BID during &gt; 2 month treatment. The longest duration on treatment was &gt; 9 months. Most common AEs included skin rash and diarrhea. 67% (12 out of 18) patients had drug-related dose interruption and/or reduction, however, there were no drug-related discontinuations.The C trough free plasma and CSF exposure were above pEGFR IC 90 at the two doses. 40% of patients (4 out of 10) had &gt; 50% inhibition of pEGFR in CSF tumor cells at C1D8, and 70% of patients (7 out of 10) had reduced EGFR copy numbers in CSF at C3D1. 53% of evaluable patients (9 out of 17) had confirmed improved/stable LM MRI imaging. 2 out of 3 patients with concomitant measurable BM lesions achieved confirmed/unconfirmed partial CNS response. Among 18 patients with measurable extracranial lesions, 6 (33%) had confirmed stable extracranial disease as best response. 3 patients achieved clearance of tumor cells in CSF by two consecutive assessments. After 6 months follow-up, 29% patients (5 out of 17 evaluable) were still surviving, plus 5 surviving patients with less than 6 months follow-up. Conclusions: AZD3759 was well-tolerated, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor activity in patients with LM who progressed after multiple lines of treatment. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
Abstract 043: Regulation of cardiac excitability by non-canonical Sonic Hedgehog signaling.
Authors: Lan Cheng, Manuel Covarrubias, Walter Koch, Natalia A Riobo
Journal: Circulation Research (2013)

Introduction: Induction of Sonic Hedgehog (Shh) in the myocardium post myocardial infarction promotes neovascularization and reduces infarct size. Shh signals through the 7-TM protein Smoothened (SMO), which we have found to couple to Gi proteins. Our goal is to investigate the effect of Shh on myocardial excitability and electrical remodeling and the role of SMO/Gi coupling. Methods and Results: We performed whole-cell patch clamp action potential and K+ currents measurements, biochemistry and volume-conducted ECG measurements in Langerdoff preparations using wild type and transgenic GiCT mice with inducible cardiomyocyte-specific impaired Gi protein signaling. In normal hearts and isolated cardiomyocytes, Shh reduced by 80% the isoproterenol-induced cAMP increase and protein kinase A (PKA) activation (p&lt;0.01). Shh also induced a 2-2.5 fold prolongation of the action potential duration (APD) (p&lt;0.001) and a reduction of the IK, slow (9.3±0.8 vs. 1.9±0.5 pA/pF; p&lt;0.05). In Langerdorff-perfused hearts, Shh agonists induced a ~30% increase of the QT interval (p&lt;0.01) and premature ventricular contractions (PVC) (0 out of 6 controls vs. 8 out of 8 Shh) and ventricular tachycardia (VT) (0 out of 6 controls vs. 7 out of 8 Shh), while pre-perfusion with KAAD-cyclopamine, a SMO inhibitor, reduced the arrhythmic episodes (PVC in 3 out of 8 and VT in 0 out 8). These effects we mediated by Gi proteins, as cAMP reduction, prolongation of the QT segment, and development of arrhythmias were abolished in hearts of GiCT mice. Conclusion: Our study demonstrates that acute Shh signaling in the heart leads to reshaping of the action potential (AP) and results in a dramatic increase of ventricular arrhythmias. Our data constitute the first evidence that acute, noncanonical Shh signaling may be implicated in the pathological electrical remodeling that sets the substrate for life-threatening arrhythmias in HF patients.
Final results of the EORTC Brain Tumor Group randomized phase II TAVAREC trial on temozolomide with or without bevacizumab in 1st recurrence grade II/III glioma without 1p/19q co-deletion.
Authors: Martin J. Van Den Bent, Martin Klein, Marion Smits, Jaap C. Reijneveld, Ahmed Idbaih, Paul Clement, Filip Yves Francine Leon De Vos, Wolfgang Wick, Paul James Mulholland, Martin J.B. Taphoorn, Joanne Lewis, Iris de Heer, Johan M Kros, Tina Verschuere, Vassilis Golfinopoulos, Thierry Gorlia, Pim French
Journal: Journal of Clinical Oncology (2017)

2009 Background: Although bevacizumab (BEV) is frequently used in recurrent grade II and III glioma without 1p/19q co-deletion, this use is without evidence from randomized trials. Methods: The TAVAREC trial (NCT01164189) is a randomized phase II study in locally diagnosed non-1p/19q co-deleted grade II or III glioma, with a first and contrast-enhancing recurrence after initial radiotherapy. Prior chemotherapy was allowed provided patients were at least 6 months off treatment. Patients were treated with either 200mg/m 2 temozolomide (TMZ) day 1-5 every 4 weeks for a maximum of twelve cycles, or with the same TMZ regimen in combination with BEV 10 mg/kg every 2 weeks until progression. Response, Quality of Life (QOL, using the EORTC QOL C30/BCM20 questionnaire) and neurocognitive function (NCF) using a standardized test battery with Hopkins Verbal Learning, Trail Making test A/B and Controlled Oral Word Association were evaluated every 3 months. Primary endpoint is the Overall Survival (OS) rate at 12 months (OS12). Tumor samples were centrally analyzed for MGMT status (Illumina methylation arrays) and IDH1/2 mutations ( IDHmt). Results: Between 8/2/2011 and 31/7/2015, 155 patients were randomized; median age was 44 years, 88 (70%) of 125 tested tumors showed an IDHmt, 27% of patients had received prior chemotherapy. OS12 was 61% in the TMZ arm and 55% in the TMZ+BEV arm, with overlapping OS and progression free survival (PFS) Kaplan Meier curves and similar response rates (TMZ: 42%; TMZ + BEV: 49%). Post-progression, 33% of the TMZ and 17% of the TMZ + BEV patients received BEV. OS was longer in IDHmt tumors compared to IDH wild type tumors (15 mo vs 10.7 mo, p = 0.001) but PFS was clinically similar (6.7 mo vs 5.1 mo, p = 0.056). IDH mutational status was not predictive for benefit to BEV. Compliance to NCF testing and QOL was above 60% in the 1 st year. At the group level, NCF was similar in the TMZ and in the TMZ+BEV patients. QOL and MGMTresults will be presented at the meeting. Conclusions: The addition of BEV to TMZ does not improve OS, PFS, or cognitive function in recurrent grade II and III 1p/19q intact gliomas; regardless of IDH mutational status. Clinical trial information: NCT01164189.
The internet, a simple and convenient tool in Chlamydia trachomatis screening of young people
Authors: D Novak, A C Edman, M. Jonsson, R B Karlsson
Journal: Eurosurveillance (2003)

The objective of this study was to evaluate a new C. trachomatis screening method based on a home sampling strategy and using the internet as a facility for the participants to obtain their test results. A population based screening study was designed in primary care setting in Umeå, Sweden. It included all males aged 22 years (n=1074), living in Umeå, a city with 100 000 inhabitants. The participation rate was 38.5%. In the study group, 1.1% were infected with C. trachomatis. Participants obtained their results on the internet and three quarters of males infected with C. trachomatis sought medical treatment independently. The number of times the internet was visited exceeded the number of urine samples tested. The internet C. trachomatis screening strategy achieved the highest male participation rate yet published, and also reached young males outside the high risk groups.
Abstract 2093: Myocardial Upregulation of mRNA Angiotensin II Receptor Subtype 1 (AGTR1) at One Year of Heart Transplantation is Associated with Worse Long-term Clinical Outcome Including Skin Cancer.
Authors: Mohamad H Yamani, Christinna Haire, David O Taylor, James B Young, Randall C Starling
Journal: Circulation (2007)

Background: We have previously shown that myocardial upregulation of mRNA gene expression of angiotensin II receptor subtype 1 (AGTR1) is associated with transplant vasculopathy evidenced by coronary intravascular ultrasound at one year following heart transplantation. Objectives: This study was undertaken to evaluate the long-term clinical outcome of heart transplant patients in relation to upregulation of mRNA AGTR1. Methods: A total of 45 heart transplant patients, mean age 55±12 years (78% male) had heart biopsy analysis for mRNA AGTR1 (Taqman PCR) at one year of transplantation. Dual Immunofluorescence staining for AGTR1 and vWF was also performed. Patients were divided into 2 groups according to the mRNA AGTR1 expression: Group I (n= 24), AGTR1 ≤2.0 and Group II (n=21), AGTR1 &gt; 2.0. Patients underwent annual coronary angiography and were followed up for a mean period of 7.6±2.1 years. Transplant coronary vasculopathy was defined as angiographic evidence of coronary obstruction greater than 30% in the absence of donor coronary artery disease. Results: The 2 groups had similar baseline characteristics. During follow up, Group II patients tended to have increased risk of diabetes mellitus (57.1% versus 29.2%, P= 0.058) and renal insufficiency (61.9% versus 33.3%, P= 0.055) defined by serum creatinine greater than 1.5 mg/dl. Group II patients had a worse survival (10 year K-M survival: 61% versus 86%, log-rank P= 0.061) and increased vasculopathy (10 year K-M freedom from vasculopathy: 19% versus 66%, log-rank P= 0.036). Since the renin-angiotensin system has been implicated in the development of various cancers, we also evaluated the clinical outcome of malignancy in relation to mRNA AGTR1. Interestingly, the 10 year K-M freedom from any malignancy tended to be worse in Group II patients (46% versus 77%, log-rank P= 0.063) and statistically significantly different in skin cancer (57% versus 86%, log-rank P= 0.034). Conclusions: Myocardial upregulation of mRNA AGTR1 at one year of heart transplantation is associated with worse clinical outcome including skin cancer. These findings may call for the need of prospective randomized trials to evaluate if the natural course of these patients could be altered with the use of angiotensin receptor blockers.
Hypoxia increases ursolic acid induced caspase-3/7 activation
Authors: Bikul Das, Risa Torkin, Sameera Rahman, Matthew Gee, Herman Yeger, Sylvain Baruchel
Journal: Cancer Research (2004)

4577  Background: Ursolic Acid is a triterpene saponin widely distributed in nature. Ursolic Acid has been found to induce apoptosis and caspase-3/7 activation in several malignant cell lines including lung, prostate, and leukemia cell lines. However, possible effect of hypoxia on UA-induced caspase-3 has not been studied. Earlier, we found that UA induces apoptosis in MYCN amplified neuroblastoma cell lines. We hyposthesize that UA induces apoptosis in neuroblastoma cells by activating caspase-3/7 and the activation is increased under hypoxia. Methods: SK-N-BE-2 cells were treated with UA for 24 hours under hypoxic and normoxic conditions. Treated cells were analysed for caspase-3 activity. The caspase-3 activity was measured using N-acetyl-DEVD-7-amino-4-methylcoumarin (DVED-AMC), a caspase-3/7 substrate. Result: 20uM UA increased caspase-3/7 activity by 3 fold (p=0.009), and 40uM UA increased caspase-3/7 activity by 7 fold (p=0.019). However, low dose UA (10-5uM) did not increase caspase-3/7 activity significantly. Compared to normoxic condition, hypoxia increased the caspase-3/7 activity at 40uM by 30% (p
Subcutaneous Implantable Cardioverter-Defibrillator Implantation Without Defibrillation Testing
Authors: Marc A. Miller, Chandrasekar Palaniswamy, Srinivas R. Dukkipati, Sujata Balulad, Jeffrey Smietana, Aaron Vigdor, Jacob S. Koruth, Subbarao Choudry, William Whang, Vivek Y. Reddy
Journal: Journal of the American College of Cardiology (2017)
Déterminants de l'observance du dépistage par coloscopie chez les frères et sœurs de patients atteints de cancer colorectal avant 60 ans
Authors: M Taouqi, I Ingrand, M Beauchant, V Migeot, P Ingrand
Journal: Endoscopy (2009)

Introduction: La France fait partie des pays à risque élevé de cancer colorectal. Un dépistage ciblé par coloscopie a été préconisé chez les apparentés au premier degré de sujets atteints par la maladie avant l'âge de 60 ans (HAS 2004). Les modèles psychosociaux de prévention ont fait la preuve de leur intérêt pour appréhender les comportements face au dépistage, mais n'ont pas encore étéétudiés en France dans ce contexte. L'objectif était de déterminer chez les frères et sœurs les facteurs associés à l'observance du dépistage, en intégrant ceux relatifs à l'individu, à la prise en charge médicale, à la famille et au réseau social.
Doses of Total Nucleated Cells and Activated T-Cells Transplanted Influence Survival and Graft Versus Host Disease Among AML and MDS Recipients of Reduced-Intensity Mobilized Peripheral Blood Allografts
Authors: Daniel R Richardson, Qiuhong Zhao, Rhonda Kitzler, Patrick Elder, Gerard Lozanski, Leslie A. Andritsos, Don M Benson, William Blum, Yvonne A Efebera, Samantha Jaglowski, Rebecca B Klisovic, Sam Penza, Sumithra Vasu, Steven M Devine
Journal: Blood (2016)
Characterising <i>cis</i>-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues
Authors: Mingfeng Zhang, Soren Lykke-Andersen, Bin Zhu, Wenming Xiao, Jason W Hoskins, Xijun Zhang, Lauren M Rost, Irene Collins, Martijn van de Bunt, Jinping Jia, Hemang Parikh, Tongwu Zhang, Lei Song, Ashley Jermusyk, Charles C Chung, Bin Zhu, Weiyin Zhou, Gail L Matters, Robert C Kurtz, Meredith Yeager, Torben Heick Jensen, Kevin M Brown, Halit Ongen, William R Bamlet, Bradley A Murray, Mark I McCarthy, Stephen J Chanock, Nilanjan Chatterjee, Brian M Wolpin, Jill P Smith, Sara H Olson, Gloria M Petersen, Jianxin Shi, Laufey Amundadottir
Journal: Gut (2017)

Objective To elucidate the genetic architecture of gene expression in pancreatic tissues. Design We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. Results We identified 38 615 cis -eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis -eQTL (in 237 genes) in tumour-derived tissues (false discovery rate &lt;0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis -eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis -eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10 −8 ) and tumour-derived (p=8.3×10 −5 ) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the ‘O’ mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. Conclusions We have identified cis -eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.
Controlled Observations on the Single Case
Authors: C M SMITH
Journal: JAMA (1963)

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
Identification of Lynch syndrome (LS) in patients (pts) without prior LS-associated cancer.
Authors: Matthew B. Yurgelun, Hajime Uno, Chinedu I. Ukaegbu, Ashley L. McFarland, Ewout W. Steyerberg, Fay Kastrinos, Sapna Syngal
Journal: Journal of Clinical Oncology (2016)

1521 Background: Identifying LS in pts without a prior history of an associated cancer (unaffected pts) relies exclusively on family history analysis and is thus inherently different from LS evaluation in cancer pts (affected pts) in whom tumor testing for mismatch repair deficiency is an effective screening strategy. Prediction models such as PREMM1,2,6 use clinical data to estimate an individual’s likelihood of having LS and thus may be useful for evaluating unaffected pts. Based on large studies of affected pts, NCCN guidelines recommend LS genetic testing for pts in whom prediction models estimate ≥ 5% likelihood of LS, but it is unknown if this threshold is effective at identifying LS in unaffected pts. Methods: PREMM1,2,6 scores were calculated for 51836 consecutive pts who underwent multigene LS genetic testing at a commercial laboratory from 2006-13. The ability of PREMM1,2,6 to discriminate LS mutation carriers from noncarriers in unaffected pts was evaluated using the area under the receiver operating curve (AUC), sensitivity, and specificity with comparison made to the performance of PREMM1,2,6 in affected pts. Results: 3869/51836 (7.5%; 95% CI 7.2-7.7%) pts carried a LS mutation, including 683/25138 (2.7%) unaffected pts and 3186/26698 (11.9%) affected pts. Median PREMM1,2,6 scores were 6.5% (IQR 2.8-14.0%) and 24.9% (IQR 10.9-51.8%; P < 0.001) for unaffected and affected mutation carriers, respectively. PREMM1,2,6 had significantly better discriminatory capacity for affected pts (AUC 0.80; 95% CI 0.79-0.81) than for unaffected pts (AUC 0.72; 95% CI 0.70-0.74; P < 0.001). At a ≥ 5% score cutoff, the sensitivity of PREMM1,2,6 was 58% and 93% (P < 0.001) for identifying unaffected and affected mutation carriers, respectively. A ≥ 2.5% score cutoff improved the sensitivity of PREMM1,2,6 to 79% for identifying unaffected mutation carriers, but at only 49% specificity. Conclusions: Roughly half of pts undergoing clinical LS testing lack a prior associated cancer. The ≥ 5% prediction model threshold endorsed by NCCN guidelines will fail to identify > 40% of such unaffected pts with LS. Adaptation of existing prediction models or use of a lower threshold may help identify unaffected pts who should undergo LS genetic testing.
Abstract 4653: Isolation Of Pulmonary Veins Using A Novel Decapolar Catheter For Mapping And Ablation
Authors: Stefan Weber, Sabine Fredersdorf, Clemens Jilek, Norbert Heinicke, Carsten Jungbauer, Oliver Husser, Andreas Jeron
Journal: Circulation (2008)

Background: Ablation of atrial fibrillation (AF) is one of the most time consuming procedures in interventional electrophysiology. Currently, the selection of catheters and ablation techniques is still a matter of debate. Due to the rapidly increasing demand of ablation procedures, technical advances would be helpful to reduce complexity and procedure time in AF ablation. Therefore we investigated the feasibility of a novel decapolar ablation catheter (PVAC) combined with a duty-cycled, low-power RF generator for pulmonary vein (PV) isolation. The system does not require 3D mapping and is the first to enable mapping, pacing and circular as well as segmental ablation with a single catheter. Methods: AF mapping and ablation was performed in 15 consecutive patients with intermittent AF (mean age 58±12 years, 6 males) using the PVAC- catheter. To visualize the pulmonary vein anatomy, CT or MRI scan was performed in addition to PV angiography before ablation procedure. Additionally all patients underwent transesophageal echocardiography to rule out left atrial (LA) thrombi. Ablation procedure was performed by introducing the PVAC to the LA via single transseptal puncture. An optimal and stable catheter position for mapping and ablation was achieved by using a steerable sheath and an over the wire technique. RF energy was typically delivered for 60s for circular and 30 to 60s for segmental ablations. Ablation success was defined by disappearance of PV signals and complete exit block obtained by PVAC stimulation. Results: Isolation of all four PVs could be achieved in 59/60 veins (98%). A very small and hypoplastic right inferior PV could not be reached. The median RF application time until all PV were isolated successfully was 23±7 min. First half of ablations were performed by circular RF application, second half with segmental applications until isolation. Procedure time for ablation was 81±14 min. Total fluoroscopy time was 31±9 min. There were no procedural complications. Conclusion: Mapping and ablation of pulmonary veins can be performed safe and fast, with low procedure times using a single catheter without 3D navigation or assisted steering. Thus this system may be of high interest not only for high volume but all centers performing AF ablation.
Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors
Authors: Jaeyop Lee, Yu Jerry Zhou, Wenji Ma, Wanwei Zhang, Arafat Aljoufi, Thomas Luh, Kimberly Lucero, Deguang Liang, Matthew Thomsen, Govind Bhagat, Yufeng Shen, Kang Liu
Journal: Nature Immunology (2017)
Revisiting the use of sPLA 2 -sensitive liposomes in cancer therapy
Authors: Houman Pourhassan, Gael Clergeaud, Anders E. Hansen, Ragnhild G. Østrem, Frederikke P. Fliedner, Fredrik Melander, Ole L. Nielsen, Ciara K. O'Sullivan, Andreas Kjær, Thomas L. Andresen
Journal: Journal of Controlled Release (2017)