tbuckley/cabot-search huggingface dataset:
Gene-specific features (MLH1, MSH2, MSH6, PMS2) of mismatch repair (MMR) protein expression and somatic mutations (muts), microsatellite instability (MSI) and tumor mutational burden (TMB) in MSI-H and MMR-mutated tumor genomic profiles (TGPs).
Authors: Michael J. Hall, Joseph Nicholas Bodor, Joanne Xiu, Rebecca Feldman, Axel Grothey, Richard M. Goldberg, William Mills Worrilow, Jimmy J. Hwang, Edward S. Kim, Heinz-Josef Lenz, Derek Raghavan, Anthony Frank Shields, John Marshall, W. Michael Korn, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2019)

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p &lt; 0.001), was more commonly seen in EC vs CRC/OT (p &lt; 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]
Real World Analysis of the Incidence and Impact of Hypertension and Cardiac Toxicity Associated with Carfilzomib for Patients with Multiple Myeloma
Authors: Selina J Chavda, Rachael Pocock, Simon Cheesman, Emma Dowling, Puneet Verma, Malcolm Walker, Charalampia Kyriakou, Ashutosh D. Wechalekar, Neil K Rabin, Kwee Yong, Rakesh Popat
Journal: Blood (2018)
Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: A National Cancer Database (NCDB) analysis.
Authors: Shaakir Hasan, Paul Renz, Rodney E Wegner, Gene Grant Finley, Moses S. Raj, Dulabh K. Monga, James McCormick, Alexander V. Kirichenko
Journal: Journal of Clinical Oncology (2019)

616 Background: The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. We therefore utilized the national cancer database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. Methods: We analyzed 5,086 patients between 2010-2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4,450 MSI-negative(-) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional hazard ratios were used for survival. Results: All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher grade tumors (P &lt; 0.05). The overall pCR rate was 8.6%, including 8.9% for MSI(-) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (OR = 0.65, 95% CI 0.43 – 0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared to 73% without it (&lt; 0.001). Conclusions: Microsatellite instability was independently associated with a reduction in pathologic complete response for locally advanced rectal cancer following neoadjuvant chemoradiation in this NCDB-based analysis.[Table: see text]
Vascular Networks: Quantitative Label‐Free Imaging of 3D Vascular Networks Self‐Assembled in Synthetic Hydrogels (Adv. Healthcare Mater. 2/2019)
Authors: Gaurav Kaushik, Daniel A. Gil, Elizabeth Torr, Elizabeth S. Berge, Cheryl Soref, Peyton Uhl, Gianluca Fontana, Jessica Antosiewicz‐Bourget, Collin Edington, Michael P. Schwartz, Linda G. Griffith, James A. Thomson, Melissa C. Skala, William T. Daly, William L. Murphy
Journal: Advanced Healthcare Materials (2019)

Scanning electron microscopy (SEM) image of the vascular network represents pericytes that are wrapped around the apparent endothelial cell lumen. In article 1801186, William T. Daly, William L. Murphy, and co-workers, create three-dimensional vascular networks in a synthetic PEG hydrogel under the influence of dynamic flow conditions. Changes in the vascular network morphology is visualized and quantified by autofluorescence multiphoton microscopy.
Cell-Proliferation Imaging for Monitoring Response to CDK4/6 Inhibition Combined with Endocrine-Therapy in Breast Cancer: Comparison of [18F]FLT and [18F]ISO-1 PET/CT
Authors: Azadeh Elmi, Mehran Makvandi, Chi-Chang Weng, Catherine Hou, Amy S. Clark, Robert H. Mach, David A. Mankoff
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine-therapy have emerged as an important regimen of care for estrogen receptor (ER)-positive metastatic breast cancer, although identifying predictive biomarkers remains a challenge. We assessed the ability of two PET-proliferation tracers, [18F]FLT and [18F]ISO-1, for evaluating response to CDK4/6-inhibitor (palbociclib) and ER-antagonist (fulvestrant). Experimental Design: To determine the effect of CDK4/6 inhibition combined with estrogen-blockade, we assessed cell proliferation in six breast cancer cell lines after 1, 3, and 6 days of treatment with palbociclib and/or fulvestrant. These data were correlated to in vitro radiotracer assays and results were verified by longitudinal [18F]FLT and [18F]ISO-1 micro-PET imaging performed in MCF7 tumor-bearing mice. Results: All palbociclib-sensitive cell lines showed decreased [18F]FLT accumulation and S-phase depletion after treatment, with both measures augmented by combination therapy. In contrast, these cells showed changes in [18F]ISO-1 analogue-binding and G0 arrest only after prolonged treatment. MicroPET imaging of MCF7 xenografts showed a significant decrease in [18F]FLT but no changes in [18F]ISO-1 uptake in all treated mice on day 3. On day 14, however, mice treated with combination therapy showed a significant decrease in [18F]ISO-1, corresponding to G0 arrest, while maintaining reduced [18F]FLT uptake, which corresponded to S-phase depletion. Conclusions: Our data suggest complementary roles of [18F]FLT and [18F]ISO-1 PET in evaluating tumor-proliferation after combined CDK4/6 inhibitor and endocrine therapy in breast cancer. [18F]FLT is more sensitive to immediate changes in S-phase, whereas [18F]ISO-1 can assess more delayed changes related to cell-cycle arrest and transition to G0 quiescence from combination therapy. These data suggest a potential role for early prediction of long-term response using these imaging biomarkers.
Income Inequality and Outcomes in Heart Failure
Authors: Pooja Dewan, Rasmus Rørth, Pardeep S. Jhund, Joao Pedro Ferreira, Faiez Zannad, Li Shen, Lars Køber, William T. Abraham, Akshay S. Desai, Kenneth Dickstein, Milton Packer, Jean L. Rouleau, Scott D. Solomon, Karl Swedberg, Michael R. Zile, John J.V. McMurray
Journal: JACC Heart Failure (2019)

This study examined the relationship between income inequality and heart failure outcomes. The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes. This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density. Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively. Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes.
Radioembolization of Hepatocellular Carcinoma with Built-In Dosimetry: First <i>in vivo</i> Results with Uniformly-Sized, Biodegradable Microspheres Labeled with <sup>188</sup>Re
Authors: José Carlos De La Vega, Pedro Luis Esquinas, Cristina Rodríguez-Rodríguez, Mehrdad Bokharaei, Igor Moskalev, David Liu, Katayoun Saatchi, Urs O. Häfeli
Journal: Theranostics (2019)

A common form of treatment for patients with hepatocellular carcinoma (HCC) is transarterial radioembolization (TARE) with non-degradable glass or resin microspheres (MS) labeled with 90Y (90Y-MS). To further simplify the dosimetry calculations in the clinical setting, to have more control over the particle size and to change the permanent embolization to a temporary one, we developed uniformly-sized, biodegradable 188Re-labeled MS (188Re-MS) as a new and easily imageable TARE agent. Methods: MS made of poly(L-lactic acid) were produced in a flow focusing microchip. The MS were labeled with 188Re using a customized kit. An orthotopic HCC animal model was developed in male Sprague Dawley rats by injecting N1-S1 cells directly into the liver using ultrasound guidance. A suspension of 188Re-MS was administered via hepatic intra-arterial catheterization 2 weeks post-inoculation of the N1-S1 cells. The rats were imaged by SPECT 1, 24, 48, and 72 h post-radioembolization. Results: The spherical 188Re-MS had a diameter of 41.8 ± 6.0 µm (CV = 14.5%). The site and the depth of the injection of N1-S1 cells were controlled by visualization of the liver in sonograms. Single 0.5 g tumors were grown in all rats. 188Re-MS accumulated in the liver with no deposition in the lungs. 188Re decays to stable 188Os by emission of β¯ particles with similar energy to those emitted by 90Y while simultaneously emitting γ photons, which were imaged directly by single photon computed tomography (SPECT). Using Monte Carlo methods, the dose to the tumors was calculated to be 3-6 times larger than to the healthy liver tissue. Conclusions:188Re-MS have the potential to become the next generation of β¯-emitting MS for TARE. Future work revolves around the investigation of the therapeutic potential of 188Re-MS in a large-scale, long-term preclinical study as well as the evaluation of the clinical outcomes of using 188Re-MS with different sizes, from 20 to 50 µm.
Abstract 14634: Association Between Habitual Snoring and Metabolic Syndrome in Chinese Population: A Cross-Sectional Study
Authors: Yanjie Xia, Ying Li, Min Guo, Long Zhou, Huanhuan Liu, Yangfeng Wu, Liancheng Zhao
Journal: Circulation (2017)

Introduction: The metabolic syndrome (MS) is a predominant cardiovascular risk factor. Previous studies reported in western populations showed that habitual snoring was associated with hypertension...
Abstract 18479: The Level of Pre-discharge N-terminal Pro B-type Natriuretic Peptide and its Change During Hospitalization Can Predict Future Left Ventricular Functional Recovery in Acute De Novo Dilated Cardiomyopathy
Authors: Kye Hun Kim, Hyun Ju Yoon, Youngkeun Ahn, Myung Ho Jeong, Jeong Gwan Cho, Jong Chun Park, Jung Chaee Kang
Journal: Circulation (2012)

Background: To investigate the usefulness of N-terminal pro B-type natriuretic peptide (NT-proBNP) in the prediction of left ventricular (LV) functional recovery in acute de novo heart failure (HF) patients with dilated cardiomyopathy (DCMP). Methods: A total of 175 consecutive patients acute de novo DCMP and HF were divided into 2 groups; the recovered group (group 1, n=54, 54.3±18.5 years, 31 males) vs the non-recovered group (group 2, n=121, 60.5±15.1 years, 79 males). NT-proBNP was measured serially at admission, at discharge, at 3 months after discharge and compared. Results: NT-proBNP was 5465.2±5389.6 pg/mL at admission, and the level of NT-proBNP was significantly reduced after HF management (1805.1±2568.4 pg/mL at discharge, 1027.5±1394.9 pg/mL at 3 months after discharge, p&lt;0.001). The level of NT-proBNP at admission was not different between the groups (5251.7±4297.7 vs 5602.7±6013.4 pg/mL, p=ns). However, the level of NT-proBNP at discharge (844.3±630.6 vs 2459.5±3132.8 pg/mL, p&lt;0.001) and at 3 months after discharge (360.5±296.0 vs 1495.3±1652.2 pg/mL, p&lt;0.001) were significantly lower in group 1 than in group 2. The decrease of the level of NT-proBNP from admission to discharge was significantly greater in group 1 than in group 2 (4407.4±4115.6 vs 2817.0±4532.9 pg/mL, p=0.032). The area under the curve to predict LV functional recovery by Receiver Operating Characteristic curve analysis was 0.702 for NT-proBNP change at discharge, 0.247 for the level of NT-proBNP at discharge, and 0.137 for the level of NT-proBNP at 3 months after discharge. The decrease of NT-proBNP &gt; 1633.5 pg/mL from admission to discharge could significantly predict future LV functional recovery (sensitivity: 74.5%, specificity: 66.7%). Conclusion: The level of NT-proBNP at discharge, not at admission, and the changes of NT-proBNP at discharge were significant predictor of future LV functional recovery. The serial monitoring of NT-proBNP would be useful for predicting future outcomes in acute de novo HF patients with DCMP.
IgE Testing Can Predict Food Allergy Status in Patients with Moderate-Severe Atopic Dermatitis
Authors: Pamela A. Guerrerio, Marjohn Rasooly, Wenjuan Gu, Samara Levin, Rekha Jhamnani, Joshua D. Milner, Kelly D. Stone, Anthony L. Guerrerio, Joseph Jones, Magnus Borres, Erica Brittain
Journal: Journal of Allergy and Clinical Immunology (2019)
Further characterization and comparison of inducible nitric oxide synthase in mouse, rat, and human hepatocytes*1
Authors: A NUSSLER
Journal: Hepatology (1995)

Marked differences in induced nitric oxide (NO) synthesis occur between species. We have previously shown that both human and rat hepatocytes express an inducible NO synthase in response to cytokines and lipopolysaccharide. In this study, we compare the expression and regulation of cytokine-induced NO synthase in hepatocytes isolated from three species, human, rat, and mouse. On stimulation with tumor necrosis factor alpha (TNFα), interleukin-1β (IL-1β), interferon gamma (IFNγ), and lipopolysaccharide (LPS), it was found that hepatocytes from all three species produce high levels of NO with levels of production exhibiting the following hierarchy: rat hepatocytes > mouse hepatocytes > human hepatocytes. Whereas rat and mouse hepatocytes express inducible NO synthase messenger RNA (mRNA) in response to TNFα, IL-1β, or IFNγ as a single stimulus, human hepatocytes respond to LPS alone. Inhibition of NO generation through transforming growth factor (TGF-β1) was seen in mouse (77% ± 5.9) and rat hepatocytes (17% ± 2.6) whereas only about 10% was seen in human hepatocytes. Epidermal growth factor (EGF) was shown to inhibit NO synthesis in human and mouse hepatocytes but not rat. A marked NO-dependent inhibition of total protein synthesis was seen in rat and human hepatocytes, whereas mouse hepatocytes showed almost no inhibition in protein synthesis when stimulated. NO-dependent cyclic guanosine monophosphate (cGMP) release was found in all three species. Comparative studies on cytosol for inducible NO synthase enzyme activity showed that mouse and rat hepatocyte cytosol needed only l-arginine and reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) to exhibit NO formation, whereas cytosol from human hepatocytes required the addition of 5,6,7,8-tetrahydrobiopterin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) to exhibit maximal NO synthase activity. Our results show even though hepatocytes from all three species can express considerable inducible NO synthase activity, important differences exist in the characteristics and effects of the NO synthesis.
Evaluating Risks and Benefits of Evolving Systemic Treatments of Neuroendocrine Tumors
Authors: Jonathan Raphael Strosberg, Taymeyah Al-Toubah, Mauro Cives
Journal: JAMA Oncology (2019)

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Abstract 15986: Systematic Cardiac Magnetic Resonance Imaging in Patients With Angina-Like Symptoms and Elevated Troponin Levels Suggests Existing Protocols May Lead to Underdiagnosis of Myocarditis
Authors: Dimitri Patriki, Eva Gresser, Jan Berg, Nora Baltensperger, Kottwitz Jan, Marina Lovrinovic, Robert Manka, Maximilian Emmert, Thomas Lüscher, Bettina Heidecker
Journal: Circulation (2017)

Introduction: The wide range of reported incidence of myocarditis in literature reflects uncertainty of its epidemiologic impact. While cardiac magnetic resonance imaging (CMR) facilitates non-inva...
Genotypic resistance–guided and medication-guided therapies did not differ for eradicating refractory<i>H pylori</i>
Authors: Xavier Calvet
Journal: Annals of Internal Medicine (2019)

Source Citation Liou JM, Chen PY, Luo JC, et al; Taiwan Gastrointestinal Disease and Helicobacter Consortium. Efficacies of genotypic resistance-guided vs empirical therapy for refractory Helicobacter pylori infection. Gastroenterology. 2018;155:1109-19. 29964036
Abstract 18056: Incidence of Shock Therapies in Patients Implanted With CRT-D versus ICD: A NORDIC ICD Sub-Study
Authors: Hendrik Bonnemeier, Suling Anna, Felk Angelika, Tino Hauser, Karl Wegscheider, Dietmar Bänsch
Journal: Circulation (2017)

Introduction: The aim of the NORDIC ICD sub-study was to compare the incidence of implantable cardioverter-defibrillator (ICD) shocks and clinical outcome of a mixed population implanted with a Cardiac Resynchronization Therapy Defibrillator (CRT-D) or ICD. Methods: The NORDIC ICD study included 1077 patients randomized to ICD implantation with or without defibrillation testing. Based on current guidelines, 1067 were eventually implanted with an ICD for primary or secondary prevention. For the comparison of ICD shock incidence a mixed logistic regression model with center as random effect was used. For the comparison of mortality rates a shared frailty Cox-regression model with center as frailty term was applied. All models were adjusted for random group. Results: The sub-study included 356 patients with a CRT-D and 711 patients with an ICD. Patients with a CRT-D were significantly older (p<0.001), suffered more often from non-ischemic cardiomyopathy (p<0.001), had higher NYHA function class (p<0.001), ha...
A High Degree of Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies
Authors: Ioannis Politikos, Sean M Devlin, Molly Maloy, Christopher Mazis, Kristine Naputo, Aishat Olaide Afuye, Andromachi Scaradavou, Scott T Avecilla, Hugo R. Castro-Malaspina, Christina Cho, Parastoo B. Dahi, Sergio Giralt, Boglarka Gyurkocza, Ann A. Jakubowski, Esperanza B. Papadopoulos, Miguel-Angel Perales, Craig S. Sauter, Michael Scordo, Brian C. Shaffer, Gunjan L. Shah, Roni Tamari, Marcel R.M. van den Brink, James W. Young, Doris Ponce, Juliet Barker
Journal: Blood (2018)
Abstract 19744: The Role of Phosphate in Experimental Uraemia-induced Calcific Aortic Valve Disease
Authors: Mony Shuvy, Suzan Abedat, Ran ELiaz, Israa Abu-Rmeileh, Asmahan Abu-Snieneh, Chaim Lotan
Journal: Circulation (2017)

Introduction: High levels of phosphate are associated with uremia-induced calcific aortic valve disease (CAVD). However, it is not clear if hyperphosphatemia is required in all phases of process. O...
Abstract 14089: Significantly Worse Survival Despite Similar Rate of Progression of Aortic Stenosis in Patients With Radiation Heart Disease: A Matched Cohort Study
Authors: Eoin Donnellan, Brian P Griffin, Douglas R Johnston, Zoran B Popovic, Samir R Kapadia, Amar Krishnaswamy, Joseph F Sabik, Stephanie Mick, Lars G Svensson, Milind Y Desai
Journal: Circulation (2016)

Introduction: Aortic stenosis (AS) patients with radiation associated cardiac disease (RACD) have worse outcomes when compared to a matched cohort with a similar degree of AS without RACD. We sought to assess whether this was due to more rapid progression of AS in RACD patients. Methods: We included 81 RACD patients with at least moderate AS who had ≥ 2 surface echocardiograms at least 1 year apart and matched them in a 1:2 fashion based on age, gender and aortic valve area (AVA) with 162 patients without RACD. Serial AV gradients (AVG) and AVA were recorded. AV replacement (AVR) and mortality during follow-up were recorded. Results: Relevant characteristics of the two groups are shown in Figure 1. 100% of patients had one; 71% had two; and 39% of patients had three follow-up echocardiograms. Prior to AVR, over the course of follow-up echoes, peak and mean AVG and AVA were not significantly different between the RACD patients and the control patients (Figure 2a). At 6.6±4 years of follow-up, 60% underwent...