tbuckley/cabot-search huggingface dataset:
Next-generation sequencing in <i>BRCA1/2</i>-negative breast and ovarian cancer families.
Authors: Jan Hauke, Andre Heimbach, Lisa Katharina Richters, Sandra Kroeber, Janine Altmüller, Holger Thiele, Peter Nuernberg, Barbara Wappenschmidt, Guido Neidhardt, Kerstin Rhiem, Rita K. Schmutzler, Eric Hahnen
Journal: Journal of Clinical Oncology (2016)

1533 Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic BRCA1/2 mutations. However, the mutation prevalence of non-BRCA1/2 genes associated with familial BC and/or BC/OC is largely unknown. Methods: Here, we present the first NGS data generated using the GC-HBOC-designed TruRisk gene panel. In this study a cohort of 737 high-risk, BRCA1/2 and CHEK2 c.1100delC negative index cases was analyzed which comprises 282 patients from BC families and 455 cases from BC/OC families. Sequencing was performed on the MiSeq or HiSeq 2000 system (Illumina) using customized SureSelect XT enrichment (Agilent). Data analysis was carried out using an in house bioinformatics pipeline (Cologne Center for Genomics, varpipe_v2.X). Results: By focusing on 22 BC/OC associated genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FAM175A, FANCM, MLH1, MRE11A, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RINT1, STK11, TP53, XRCC2), we identified 43 different deleterious variants in 58 unrelated mutation carriers derived from 737 high risk BC and BC/OC families (7.9%). 24 mutation carriers (8.5%) were identified in the BC only cases whereas 34 (7.5%) among the patients from BC/OC families. Interestingly, we identified a high prevalence of ATM mutations (n = 16, 2.2%) in the familial cases. Additionally mutations in PALB2 (n = 8), NBN (n = 6), CHEK2 (n = 5), BARD1 (n = 3), BRIP1 (n = 3), RAD51C (n = 3) were frequently observed and we confirmed FANCM (n = 4) as a novel BC/OC predisposing gene. No mutations in MLH1, MRE11A, PTEN, RAD51D, STK11 and XRCC2were identified in our collective. Conclusions: Due to the unexpectedly high mutation prevalence in familial cases, our study highlights the importance of these genes to be included in BC/OC routine diagnostics. In contrast we found low occurrence or absence of mutations for a subset of our gene selection which requires further investigation to optimize the gene panel for diagnostic purposes. Nevertheless this approach confirms the TruRisk gene panel as a reliable tool for this comprehensive analysis.
Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults
Authors: Maan Moualla, Clifford Qualls, Alexander Arynchyn, Bharat Thyagarajan, Ravi Kalhan, Lewis J Smith, John J Carr, David R Jacobs, Akshay Sood
Journal: Thorax (2017)

<h3>Rationale</h3> Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. <h3>Objective</h3> To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. <h3>Methods</h3> This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. <h3>Measurements</h3> In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV<sub>1</sub>) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. <h3>Results</h3> Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV<sub>1</sub> is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p&lt;0.001, and 1.56 (1.26, 1.94); p&lt;0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised β 0.09; p&lt;0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. <h3>Conclusions</h3> Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.
The role of RANK-signaling in breast cancer development and metastasis
Authors: Wei Tan, Weizhou Zhang, Li Tang, Zhijian Yang, Jun-Li Luo, Robert Hoffman, Michael Karin
Journal: Cancer Research (2008)

4200   RANK (Receptor Activator of NFκB) is a member of TNFα receptor super family. RANKL (RANK Ligand) activates RANK and its down-stream kinase IKKα, controlling osteoclast differentiation, mammary gland development as well as breast cancer tumorigenesis. Inhibition of RANK leads to reduction in tumor colonization and growth in bones in several mouse tumor metastasis models. However, the underlying mechanism underlying is still largely unknown. The purpose of the current study is to monitor and understand the influence of RANK-signaling on step-wise tumor development and metastasis. We used orthotopic tumor transplantation models with green fluorescent protein (GFP) and red fluorescent protein (DsRed2)-labeled Her2/neu transformed tumor cells which are under the control of RANK signaling. With the aid of real-time fluorescence imaging we can measure tumor growth, and monitor invasion, trafficking and colonization of tumor cells in real-time. To understand the mechanisms involved, we employed Western-blotting, RT-PCR, cell fractionation and transient transfection reporter assays. We found RANKL stimulation increased the nuclear accumulation of IKKα and expression of a group of genes involved in inflammation. However, genes which control the cell cycle and proliferation remained unchanged. This observation is consistent with that RANKL stimulation does not influence tumor-cell proliferation tumor growth. It is of great importance to analyze how blockage of RANK and RANK down-stream effectors, including IKKα and responsive genes affect tumor behavior and tumor-host interaction.
Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project
Authors: Louise K Mercer, Anne C Regierer, Xavier Mariette, William G Dixon, Eva Baecklund, Karin Hellgren, Lene Dreyer, Merete Lund Hetland, René Cordtz, Kimme Hyrich, Anja Strangfeld, Angela Zink, Helena Canhao, M Victoria Hernandez, Florence Tubach, Jacques-Eric Gottenberg, Jacques Morel, Jakub Zavada, Florenzo Iannone, Johan Askling, Joachim Listing
Journal: Annals of the Rheumatic Diseases (2017)

Background Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. Methods Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. Results Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. Conclusion This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.
Pediatric Surgery and Urology
Journal: JAMA (1999)

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
Radiation effects on tumour microcirculation assessed by high-frequency power doppler micro-ultrasound imaging in mice
Authors: Clinton Hupple, Anoja Giles, F. Foster, Peter Burns, Shun Wong, Gregory Czarnota
Journal: Cancer Research (2008)

5768   Recent evidence suggests that radiation may have very significant effects on tumour vasculature in addition to damaging the DNA inside tumour cells. We have previously demonstrated that with large doses (>8 Gy) that there can be large macroscopic areas of apoptotic death that develop in response to therapy. In this study we test the hypothesis that large doses of radiation (8Gy) have significant effects on blood flow and tumour microvasculature and that these effects can be detected and measured non-invasively by high-frequency power Doppler ultrasound vascular imaging.  Human PC3 prostate cancer xenograft-bearing SCID mice were exposed to 8 Gy irradiation with 160 kVp X-rays at a dose rate of 200 cGy/minute given in one fraction. Four animals were irradiated and four animals served as sham controls. Tumours were assessed before any treatment and 24 hours after the administration of radiation by high-frequency spectroscopic ultrasound imaging for cell death detection and then with power Doppler imaging at 20 MHz frequency to image blood flow. A VisualSonics VEVO-770 RF enabled high-frequency ultrasound device was used with a RMV-710B probe to acquire three-dimensional ultrasound data sets were collected. Ultrasound data sets were analyzed using custom written software and standard two-dimensional image processing tools. Tumours were subsequently removed after animal sacrifice for histological and immunohistochemistry-based analyses. Representative tumour sections were haematoxylin and eosin stained, TUNEL stained for apoptotic cell death and CD31 stained for endothelial distributions.  Three-dimensional power Doppler analyses indicated heterogeneous  distributions within tumours before and after treatment. Results with radiation treatments indicated significant changes between vascular imaging parameters before and after 8Gy radiation doses. Specifically, power Doppler estimated % vascularity dropped within 0.18 to 0.35 of original measurements. Analyses of vascular signals indicated that all detected vessel sizes were evenly affected by the radiation treatments. Additionally, within the tumours the number of power Doppler  signals dropped with radiation by 25 to 50%. Preliminary histological analyses indicate that radiation effects were linked to apoptotic perturbations of tumour vasculature endothelial cells. This is consistent with an approximate 10 dB increase in total ultrasound backscatter power at 20 MHz.  This work indicated that 8 Gy doses had significant effects on tumour vasculature as assessed by high-frequency power Doppler. Experimental evidence suggests that this vascular response may be linked to endothelial cell apoptosis ultimately leading to tumour cell death as demonstrated by histology and indicated by the increase in backscattered ultrasound power.
Clinical utility of expanded screening of the <i>KRAS</i> and <i>NRAS</i> genes for Metastatic Colorectal Cancer: Evaluation of the CRC RAScan tumor test as a companion diagnostic to determine efficacy of anti-EGFR therapies.
Authors: Katherine Anne Richardson, Stephanie Peterson, Jen Bevilacqua, Stephanie Veys, Vicki Rosendale, Benjamin L. Legendre, Keith Christopher Bible, Honey Reddi
Journal: Journal of Clinical Oncology (2015)

e12554 Background: RAS family genes affect signal transduction downstream of EGFR and play a critical role in determining response to EGFR-targeted therapies. Primary resistance to EGFR-specific Tyrosine Kinase Inhibitors (including cetuximab and panitumumab) in colon cancer is often due to the presence of RAS mutations. KRAS and NRAS mutations are found in ~25% of human tumors and lead to constitutive activation of Ras proteins. About 35-45% of colorectal tumors carry KRAS Exon 2 (codon 12 and 13) mutations which constitutively activate signaling downstream of EGFR. Presence of KRAS Exon 2 mutation status therefore predicts response to anti-EGFR therapy. However, ~10% of patient tumors that do not have a mutation in KRAS exon 2, have been found recently to harbor mutations in KRAS exons 3 or 4 or in NRAS exons 2, 3, or 4. Methods: The Transgenomic CRC RAScan test was developed to offer expanded screening of the KRAS and NRAS genes across exons 2, 3 and 4 respectively to better guide management decision making in metastatic CRC. Results: Using this approach, evaluation of 128 CRC cases tested in our facility in 2014 identified 29 cases (23%) with relevant mutations. Of these, 13 cases harbored a mutation in the canonical KRAS exon 2 at codons 12/13 (45%). The remaining 16 cases (55%) had mutations in KRAS exon 3 (1/16), KRAS exon 4 (7/16), NRAS exon 2 (5/16) and NRAS exon 3 (3/16). Evidence demonstrates that individuals with mutations in KRAS exon 3 and 4 as well as in NRAS exons 2, 3 and 4 also respond poorly to anti-EGFR treatments2, suggesting that screening for mutations in these gene regions is expected to play a an important role in personalized management of metastatic colorectal cancer. Conclusions: Our data demonstrates the clinical relevance of expanded screening of the KRAS and NRAS genes with the CRC RAScan test, which helps identify a sub-set of individuals who would be resistant to anti-EGFR therapies but would have otherwise been subjected to ineffective treatment strategies. Using the CRC RAScan test as a screen therefore ensures effective use of anti-EGFR therapies for individuals with metastatic CRC.
Sputum autoantibodies in patients with severe eosinophilic asthma
Authors: Manali Mukherjee, David C. Bulir, Katherine Radford, Melanie Kjarsgaard, Chynna Margaret Huang, Elizabeth A. Jacobsen, Sergei I. Ochkur, Ana Catuneanu, Hanah Lamothe-Kipnes, James Mahony, James J. Lee, Paige Lacy, Parameswaran K. Nair
Journal: Journal of Allergy and Clinical Immunology (2017)
Co-occurring genomic alterations and association with progression free survival in BRAFV600 mutated non-melanoma tumors treated with BRAF inhibitor.
Authors: Shiraj Sen, Arvind Rao, Filip Janku, David S. Hong, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, John Heymach, Lauren Averett Byers, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2016)

2546 Background: Vemurafenib, dabrafenib and tremetinib are FDA approved for treating BRAFV600-mutated melanoma. Vemurafenib has activity in non-melanoma BRAFV600-mutated tumors, as well. Unfortunately, most patients acquire resistance to BRAF monotherapy and mechanisms of resistance remain unknown. Methods: We analyzed CLIA certified clinical next generation sequencing data from BRAFV600E mutated non-melanoma tumors treated with BRAF inhibitor (BRAFi) from May 2012 to January 2016. We evaluated co-occurring genomic alterations and progression-free survival (PFS) of each patient. Results: Of the 30 patients treated with BRAFi monotherapy, 11 (37%) had NSCLC, 5 (17%) had colorectal cancer, 4 (13%) had cholangiocarcinoma, 3 (10%) had thyroid cancer, 3 (10%) had Erdheim Chester disease, and the remaining 4 (13%) had salivary gland carcinoma, glioblastoma, gliosarcoma, or unknown primary. Two of the 5 colorectal cancers were treated with BRAFi plus cetuximab. Three subsets of co-occurring genomic alterations were identified: 14 patients (47%) had no co-occuring alterations, 5 (17%) had PI3K/PTEN/mTOR pathway alterations, and 11 (37%) had other mutations: TP53 (n = 11), SMAD4 (n = 4), LKB1 (n = 2) and IDH (n = 2). Eight patients have ongoing response without progression on BRAFi monotherapy (PFS 222-805 days). Six of 8 responders (75%) have no co-occurring alterations, 2 of 8 (25%) have other mutations. All patients with co-alterations in the mTOR pathway progressed within 77 days. Tumors with mTOR pathway aberrations had a significantly lower median and mean PFS (mPFS, 53 days) compared to tumors with other co-occurring mutations (mPFS 206 days) and tumors without co-alterations (mPFS 276 days) (p = 1.03e-05). Conclusions: Co-occurring genomic alterations may help predict response to BRAFi therapy in BRAF-mutated tumors and PI3K/PTEN/mTOR pathway mutations may contribute to de novo resistance. Next generation sequencing is warranted on all BRAF mutated tumors as are further studies to address whether concurrently targeting co-occurring alterations will improve PFS. A trial combining BRAFi + mTOR inhibitor is underway (NCT01596140).
Abstract 322: Incubation With Histone Deacetylases 3 and 4 or p300/CREB Binding Protein Associated Factor Does Not Significantly Alter Cardiac Sarcomere Function
Authors: John S Walker, Xiaotao Li, Lori A Walker, Todd Horn, Timothy McKinsey, Peter Buttrick
Journal: Circulation Research (2012)

Recent studies have suggested that treatment of skinned cardiac trabeculae with a histone deacetylase (HDAC) inhibitor increases calcium sensitivity, measured as the calcium required for half maximal force development (pCa50). The proposed mechanism is the acetylation of sarcomeric proteins by an endogenous histone acetyl transferase, p300/CREB binding protein associated factor (pCAF). As a test of this proposed mechanism, we treated skinned cardiac myocytes from 8 rat left ventricles (LV) with supra-physiological concentrations of pCAF, with Acetyl COA as an acetyl group donor, and supra-physiological concentrations of constitutively active forms of HDACs 3 and 4, and examined the force-calcium relation. Myocytes were prepared from frozen rat LV samples by gentle homogenization in rigor solution (mM: 50 Tris, 1 EGTA, 100 KCl, 2 MgCl2, 2 DTT and a protease inhibitor cocktail) containing 0.1% Triton X-100. The myocyte homogenates were washed and resuspended in relaxing solution (mM: 5 MgATP, 10 Creatine phosphate, 40 K-Propionate and 10-6 Ca-EGTA) divided into four 300 µl aliquots, One was an untreated control and three were treated with either i) HDAC3/Ncor or HDAC4 , ii) pCAF + 1mM Acetyl CoA, or ii) 1mM Acetyl CoA. Force-calcium relationships were determined in mixtures of relaxing and activating solution (mM: 5 MgATP, 10 Creatine phosphate, 0.5 K-Propionate, 10-1.5 Ca-EGTA) to give 6 calcium concentrations between 10-9 and 10-3.5 mM. While HDAC 3 or 4 treatment tended to decrease calcium sensitivity, and pCAF+Acetyl COA, and Acetyl COA alone, tended to increase calcium sensitivity compared to controls, we found no statistically significant effects of HDAC3 or 4, or pCAF on the calcium sensitivity, maximum developed force or co-operativity of the myocytes (ANOVA, n=8, P&lt;0.05).
Abstract 15487: The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting With ST-Elevation Myocardial Infarction
Authors: Carine E Hamo, Igor Klem, Sunil V Rao, Vincent Songco, Samer S Najjar, Edward G Lakatta, Subha V Raman, Robert A Harrington, John F Heitner
Journal: Circulation (2015)

Background: Identification of the infarct-related artery (IRA) in patients with STEMI using angiography is often based on the ECG and can be challenging in some clinical situations. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR). Methods: Among patients enrolled in the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, 113 of 222 patients randomized who presented with a diagnosis of STEMI completed baseline CMR at 4 +/- 2 days post-PCI. Blinded reviewers interpreted the cardiac catheterization and the CMR, assigning acuity to the infarct region if microvascular obstruction or edema by T2-weighted imaging was present. For the determination of a match between the IRA by cardiac catheterization and the infarct territory on CMR, the segments affected by the IRA as coded according to the 17-segment model on angiography were compared to the segments of hyperenhancement noted on CMR. Results: A total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and angiography. In 4 of the 5 cases, there were multiple infarcts noted on CMR. In addition, 13 patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts. Conclusion: This study found that the identification of the IRA by angiography did not match the coronary artery territory of MI as determined by CMR in 4% of patients presenting with STEMI. These data suggest a role for more sophisticated imaging prior to PCI in selected STEMI patients.
Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex
Authors: Ruirui Zhao, Tao Li, Guirong Zheng, Kai Jiang, Lulu Fan, Jingwei Shao
Journal: Biomaterials (2017)
Comment on Niewczas et al. Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 2017;40:383–390
Authors: Kaiping Luo, Weidong Fang, Gaosi Xu
Journal: Diabetes Care (2017)

Niewczas et al. (1) reported the associations between metabolomic determinants and the risk of end-stage renal disease (ESRD) in participants with type 1 diabetes. The study concluded that patients with elevated circulating levels of certain modified metabolites experienced faster renal function decline than other participants. The research is exciting. However, we have several concerns about the study.

Niewczas et al. determined the estimated glomerular filtration rate (eGFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Concerns have been raised about the use of the CKD-EPI equation because of the high prevalence of ESRD that had been estimated in the elderly …