tbuckley/cabot-search huggingface dataset:
A phase I study of the BCR-ABL tyrosine kinase inhibitor nilotinib and cetuximab in patients with solid tumors that can be treated with cetuximab.
Authors: Brandon George Smaglo, Hongkun Wang, Kenneth Steadman, Joseph Murray, Michael Pishvaian, Aiwu Ruth He, Jimmy J. Hwang, Deepa Suresh Subramaniam, John F. Deeken, Louis M. Weiner
Journal: Journal of Clinical Oncology (2013)

TPS2624 Background: Therapeutic blockade of Epidermal Growth Factor Receptor (EGFR) signaling with the monoclonal antibody cetuximab is clinically effective in the treatment of patients with metastatic squamous cell carcinoma of the head and neck or KRAS wildtype colorectal cancer. However, these patients eventually become resistant to this therapy. An exploration of the EGFR signaling network using an EGFR network-focused small interfering RNA library identified potential regulators of resistance to EGFR-targeted therapies. The ABL1 gene was identified as a central node to target in this complex genomic pathway. In a preclinical EGFR-expressing cancer cell line model, targeting c-abl, the gene product of ABL1, using nilotinib was found to be highly synergistic in decreasing cell survival when combined with anti-EGFR targeted therapy. Methods: We have initiated an open-label Phase I study for patients who progressed after standard therapies for metastatic KRAS wildtype colorectal cancer or metastatic head and neck squamous cell carcinoma. Enrolled patients must have adequate performance status and organ function. Treatment consists of cetuximab 400 mg/m 2 on day 1, then 250 mg/m 2 once weekly, and nilotinib twice daily, starting on day 1, according to a traditional 3+3 dose escalation, from 200mg to 300mg BID. Patients are restaged every 2 cycles (every 8 weeks). The primary endpoint is the maximum tolerated dose (MTD) of nilotinib when used in conjunction with cetuximab. Secondary endpoints are clinical benefit rate (defined as rates of stable disease, partial response, and complete response) and response rate. Additionally, biopsies of metastases obtained prior to and after initiation of therapy will be used to establish primary tumor cell cultures using conditional cellular reprogramming to permit the dynamic study of signaling and drug sensitivity through an evaluation of evidence of a drug effect on EGFR signaling and on Antibody-Dependent Cell-Mediated Cytotoxicity. An additional 10 colorectal cancer patients will be treated as an expansion cohort at the MTD. This expansion cohort data may be used to plan a Phase II trial in the future.
An alternative interpretation of climate data: Intelligence
Authors: Robert J. Sternberg
Journal: Behavioral and Brain Sciences (2017)

Abstract The CLASH model proposed in the target article is plausible but less than parsimonious. I suggest that statistical analysis probably would find slower life history strategy, greater focus on the future, and greater self-control to be highly correlated and perhaps unifactorial, because they are all manifestations of a single underlying variable, namely, intelligence. I suggest how intelligence as a state variable plausibly could explain the differences observed by the authors.
Prognostic index for chronic- and smoldering-type adult T-cell leukemia-lymphoma
Authors: Hiroo Katsuya, Mototsugu Shimokawa, Kenji Ishitsuka, Kazuhiro Kawai, Masahiro Amano, Atae Utsunomiya, Ryosuke Hino, Shuichi Hanada, Tatsuro Jo, Kunihiro Tsukasaki, Yukiyoshi Moriuchi, Eisaburo Sueoka, Shinichiro Yoshida, Hitoshi Suzushima, Masaharu Miyahara, Kiyoshi Yamashita, Tetsuya Eto, Junji Suzumiya, Kazuo Tamura
Journal: Blood (2017)
The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase ε
Authors: Karolis Azukaitis, Eva Simkova, Mohammad Abdul Majid, Matthias Galiano, Kerstin Benz, Kerstin Amann, Clemens Bockmeyer, Radha Gajjar, Kevin E. Meyers, Hae Il Cheong, Bärbel Lange-Sperandio, Therese Jungraithmayr, Véronique Frémeaux-Bacchi, Carsten Bergmann, Csaba Bereczki, Monika Miklaszewska, Dorottya Csuka, Zoltán Prohászka, Patrick Gipson, Matthew G. Sampson, Mathieu Lemaire, Franz Schaefer
Journal: Journal of the American Society of Nephrology (2017)

The recent discovery of mutations in the gene encoding diacylglycerol kinase ε (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.
Hypercalcemia and adrenal insufficiency in a patient with myelofibrosis
Authors: Mark S. Hertzberg, Mark Wong
Journal: American Journal of Hematology (2000)

To the Editor: Semenzato et al. proposed new criteria for large granular lymphocyte (LGL) leukemia because patients with low levels of GL were similar to those with levels greater than 2,000 GL/l [1].LGL leukemia is a GL proliferative disease often accompanied by pure red cell aplasia (PRCA).T-cell LGL leukemia is a clonal disease, and the phenotype of leukemic cells is CD3 + 4 -8 + .PRCA with thymoma is often associated with peripheral T cell expansion.We previously reported a case of PRCA with thymoma in which the T-cell receptor ␤ of both the thymus and peripheral mononuclear cells was rearranged [2].Thymoma and PRCA may be caused by T-cell clonal expansion, leukemia.We examined four patients with PRCA and thymoma (Table I), one of which was previously reported.Three of the four showed CD3 + 4 -8 + lymphocytosis and two exhibited T-cell receptor ␤ rearrangement of peripheral mononuclear cells.Patient 2 showed low levels of lymphocytes and the mononuclear cell's CD4/8 ratio of patient 3 was greater than 1.Due to the low levels of abnormal cells and low sensitivity of Southern blot analysis, we could not confirm the clonality of these two cases.According to treatment of PRCA with thymoma, the response rate of thymectomy was 12% [3].This limited effectiveness of thymectomy indicated that thymoma did not play a causative role in PRCA.Loughran reported 129 patients with LGL leukemia [4] and Oshimi et al. examined 33 patients [5].Neither study noted a complication of thymoma.PRCA with thymoma had been considered a distinct clinical entity from LGL leukemia.The old diagnostic criteria for LGL leukemia was "greater than 2,000 GL/l."The normal value of GL is 223 ± 99 l [4].Three of the 4 patients with PRCA and thymoma demonstrated levels greater than the mean + 3 SD (Table I).However, it is unknown whether or not a distinction between 'PRCA with thymoma' and 'PRCA with LGL leukemia' exists.Patients with LGL leukemia showed an indolent clinical course, and immunosuppressive therapy with cyclosporin A or low-dose cyclophosphamide was effective for the clinical symptoms.In contrast, patients with PRCA with thymoma were treated with more aggressive therapy such as surgical resection, intensive chemotherapy, or radiation.As the effectiveness of surgical resection for PRCA with thymoma is limited, PRCA with thymoma should be initially treated with immunosuppressive therapy.
What, When, and How of Biomarker Testing in Non–Small Cell Lung Cancer
Authors: Gregory L. Riely
Journal: Journal of the National Comprehensive Cancer Network (2017)

Biomarker testing is recommended for all patients diagnosed with non–small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAFV600E mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy. In patients with EGFR-mutant lung cancer, when resistance develops, physicians should seek to identify the T790M mutation using plasma and tissue assays, because osimertinib therapy is available for this mutation.
Latex-Fixation Test in Rheumatoid Arthritis
Authors: Adalbert F. Schubart
Journal: New England Journal of Medicine (1959)

THE latex-fixation test of Singer and Plotz1 was designed as a diagnostic tool for the detection of rheumatoid arthritis. The positive reaction in this test depends upon the interaction of human gamma globulin with, presumably, various serum components, among which the rheumatoid factor is outstanding. The polystyrene latex particles act only as carriers for the gamma globulin and as indicators for the precipitin reaction that occurs on the surface of the biologically inert particle.The interaction of the rheumatoid factor and gamma globulin may be inhibited naturally in a given serum to the extent that aggregation of the particles no . . .
The IL-33/ST2 axis is crucial in type 2 airway responses induced by Staphylococcus aureus –derived serine protease–like protein D
Authors: Andrea R. Teufelberger, Maria Nordengrün, Harald Braun, Tania Maes, Katrien De Grove, Gabriele Holtappels, Clara O'Brien, Sharen Provoost, Hamida Hammad, Amanda Gonçalves, Rudi Beyaert, Wim Declercq, Peter Vandenabeele, Dmitri V. Krysko, Barbara M. Bröker, Claus Bachert, Olga Krysko
Journal: Journal of Allergy and Clinical Immunology (2017)
Response by Karam et al to Letter Regarding Article, “Identifying Patients at Risk for Prehospital Sudden Cardiac Arrest at the Early Phase of Myocardial Infarction: The e-MUST Study (Evaluation en Médecine d’Urgence des Stratégies Thérapeutiques des infarctus du myocarde)”
Authors: Nicole Karam, Sophie Bataille, Eloi Marijon, Muriel Tafflet, Frederic Lapostolle, Christian Spaulding, Xavier Jouven, Yves Lambert
Journal: Circulation (2017)
Evolving disparities in colorectal cancer control in Texas in the first decade of twenty-first century and implications for cancer control.
Authors: Davor Vugrin
Journal: Journal of Clinical Oncology (2013)

e14643 Background: Colorectal cancer (CRC) is the 2nd leading cause of cancer death among Texans although it is potentially one of the most preventable and curable cancers. In 2000, an intensive public education and screening was launched throughout Texas with goal by 2015 to increase up to 75% the number of 50 year and older individuals undergoing screening per the national guidelines, to reduce age-adjusted CRC incidence to 34.8/100,000 and mortality to 12.0/100,000. The purpose of this study is to identify disparities challenging meeting the 2015 objectives. Methods: The Texas Cancer Registry 2000 to 2009 data of the at risk population was queried for CRC cases diagnosed, number of deaths, age-adjusted incidence and mortality rates, and correlation with gender, race and anatomical location and evolving 10 year trend. Results: Incidence: of 91,260 CRC diagnosed 71.8% originated in colon (CoCa), 19.7 in rectum (ReCa) and 8.5 % in Rectosigmoid juction (RSJ). Age-adjusted rates (AAR) declined for CoCa by 6.6/100,000 (18%) and ReCa by 0.8 (8.6%). AAR for Non Hispanic White (NHW) declined by 10.0/100,000 (19.7%), Blacks (B) 9.8/ (15.3%) and Hispanics (H) 5.1/ (12.0%). Males AAR declined by 11.8/100,000 (19.7%) and women 18.1. 10 yr cumulative AAR for Black Males was 74.7/100,000, B female53.6/ with with lower AAR for other groups. Mortality: Of 32,929 death CoCa accounted for 83.5% and ReCa + RSJ for 16.5% cases. CoCa AAR mortality declined but for ReCa +RSJ was insignificant. Decline for NHW was –4.2 (22.0%), B – 5.6 (18.5%) and H – 1.5 (10.4%), males – 4.3 (18.5% and females – 3.7 (22.7%). AAR mortality rate in B males (35.0/100,000 and B females (23.2/) was higher than for other groups. Conclusions: Disparities in CRC control have been evolving over 10 yr study period based on anatomic site, gender, race/etnicity and their combination. Our targeted cancer control activities need to be adjusted to neutralize observed disparities in order to reach 2015 objective.
Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture
Authors: Takashi Miyamoto, Liana Stein, Reuben Thomas, Biljana Djukic, Praveen Taneja, Joseph Knox, Keith Vossel, Lennart Mucke
Journal: Molecular Neurodegeneration (2017)

Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear.We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau.We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt -/-) neurons. Reconstituting tau expression in Mapt -/- neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B-containing NMDA receptors, and do not require binding of Fyn to tau's major interacting PxxP motif or of tau to microtubules.Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx.
Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) in Elderly Patients with Comorbidities: Analysis of the CLL11 Study Population
Authors: Valentin Goede, Jasmin Bahlo, Nadine Kutsch, Kirsten Fischer, Anna Maria Fink, Guenter Fingerle-Rowson, Stephan Stilgenbauer, Manuela A. Bergmann, Barbara F. Eichhorst, Michael Hallek
Journal: Blood (2016)
Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.
Authors: Kohei Shitara, Satoshi Yuki, Daisuke Takahari, Michio Nakamura, Chihiro Kondo, Takashi Tsuda, Takayuki Kii, Yasushi Tsuji, Setsuo Utsunomiya, Daisuke Ichikawa, Ayumu Hosokawa, Atsushi Ishiguro, Daisuke Sakai, Shuichi Hironaka, Isao Oze, Keitaro Matsuo, Kei Muro
Journal: Journal of Clinical Oncology (2013)

4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m 2 , standard dose arm) or an escalated dose of wPTX (80 mg/m 2 on day 1, 100 mg/m 2 on day 8, and 120 mg/m 2 on day 15 unless severe toxicity nor neutropenia&lt;1.5 x 10 9 /L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.
Abstract 233: Metabolic Trapping Effects of ACS1 for Fatty Acid Uptake and Intracellular Trafficking are Different in Hearts of Males and Females
Authors: Joseph R Goldenberg, Xuerong Wang, Andrew N Carley, E. Douglas Lewandowski
Journal: Circulation Research (2015)

Disruption of cardiomyocyte lipid metabolism has been observed in the responses to both pathogenic and nutrient stresses in human patients and animal models, with distinct sex differences. This investigation examined cardiac acyl CoA synthetase-1 (ACS)-mediated, LCFA uptake and trafficking with hearts of male and female mice. Isolated mouse hearts with cardiac specific overexpression of ACS1 (MHC-ACS) and non-transgenic littermates (NTG) were perfused with buffer containing 13C palmitate, 10 mM glucose, and 1 mM lactate. Dynamic 13C NMR elucidated the two phases of LCFA incorporation into triacylglycerol (TAG). The time constant (τ) of the initial exponential phase, corresponding to LCFA trans-sarcolemmal uptake, was lower, indicating faster LCFA uptake and esterification in male ACS hearts compared to NTG males (ACS male τ = 1.59±0.67 min vs NTG male τ = 2.85±0.90 min, P&lt;0.05). Consistent with greater metabolic trapping, acyl CoA content was 470% higher in male ACS hearts (NTG male 57.5±9.4 vs ACS male 327.4±42 pmol/mg protein. P&lt;0.001). Despite no differences in ACS content, NTG females displayed faster uptake than NTG males at a rate similar to ACS males, which was reversed by ovariectomy (OVX) indicating an estrogen dependent response (NTG female τ = 1.56±0.46 min, P&lt;0.05 vs NTG OVX female τ = 3.02±0.77 min, P&lt;0.05). Despite prior reports of ACS localization distal from the sarcolemma, ACS level and female gender both independently accelerated LCFA uptake without affecting TAG content or turnover. The data are consistent with metabolic trapping to facilitate LCFA uptake due to ACS activity. ACS also leads to higher total ceramide in hearts, with specific elevation of C18 and C22 in both genders, C24 in males, and C20 in females (male P&lt;0.05; female P&lt;0.01). ACS overexpression induced lower content of the cardiac fatty acid transporter (FATP) isoform, FATP6, indicating cooperative regulation of LCFA uptake between membrane transport proteins and intracellular acyl chain activation (P&lt;0.05 male; P&lt;0.001 female and female OVX). These results demonstrate that perturbation of LCFA metabolism though facilitated metabolic trapping by ACS1 affects sarcolemma transporter expression and induces the conversion of the CoA activated LCFA to ceramide.
Lipoprotein-Associated Phospholipase A <sub>2</sub> Adds to Risk Prediction of Incident Coronary Events by C-Reactive Protein in Apparently Healthy Middle-Aged Men From the General Population
Authors: Wolfgang Koenig, Natalie Khuseyinova, Hannelore Löwel, Gerlinde Trischler, Christa Meisinger
Journal: Circulation (2004)

Chronic inflammation represents an essential feature of the atherosclerotic process. Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme mainly produced by monocytes/macrophages, generates potent proinflammatory products.Plasma concentrations of Lp-PLA2 were determined by ELISA in 934 apparently healthy men aged 45 to 64 years sampled from the general population in 1984 and followed up until 1998. During this period, 97 men experienced a coronary event diagnosed according to the MONICA (MONItoring of trends and determinants in CArdiovascular disease) protocol. Baseline levels of Lp-PLA2 were higher in subjects who experienced an event than in event-free subjects (295+/-113 versus 263+/-79 ng/mL, P<0.01). Lp-PLA2 was positively correlated with total cholesterol (R=0.30, P<0.0001) and age (R=0.12, P=0.001), was only slightly correlated with HDL cholesterol (R=0.09, P=0.005) and C-reactive protein R=0.06, P=0.06), but was not correlated with body mass index or blood pressure. In a Cox model, a 1-SD increase in Lp-PLA2 was associated with risk of future coronary events (hazard ratio [HR] 1.37, 95% CI 1.16 to 1.62). After controlling for potential confounders, the HR was attenuated but remained statistically significant (HR 1.23, 95% CI 1.02 to 1.47). Further inclusion of C-reactive protein in the model did not appreciably affect its predictive ability (HR 1.21, 95% CI 1.01 to 1.45).Elevated levels of Lp-PLA2 appeared to be predictive of future coronary events in apparently healthy middle-aged men with moderately elevated total cholesterol, independent of CRP. This suggests that Lp-PLA2 and CRP may be additive in their ability to predict risk of coronary heart disease.