tbuckley/cabot-search huggingface dataset:
Patient-Derived Chimeric Antigen Receptor T-Cell Production Based on a Gammaretroviral Vector Platform Is Not Associated with Generation of CAR+ Leukemia Blasts
Authors: Concetta Quintarelli, Iolanda Boffa, Matilde Sinibaldi, Domenico Orlando, Marika Guercio, Stefano Di Cecca, Simona Caruso, Angela Pitisci, Valentina Bertaina, Francesca Del Bufalo, Pietro Merli, Mattia Algeri, Federica Galaverna, Luciana Vinti, Giuseppina Li Pira, Biagio De Angelis, Franco Locatelli
Journal: Blood (2018)
Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4- and HIF-1α-mediated regulation of apoptosis and autophagy
Authors: Xiaofei Zhang, Zihao Qi, Huijing Yin, Gong Yang
Journal: Theranostics (2019)

The interplay between p53 and RAS signaling regulates cancer chemoresistance, but the detailed mechanism is unclear. In this study, we investigated the interactive effects of p53 and RAS on ovarian cancer cisplatin resistance to explore the potential therapeutic targets. Methods: An inducible p53 and RAS mutants active in either MAPK/ERK (S35 and E38) or PI3K/AKT (C40) or both (V12) were sequentially introduced into a p53-null ovarian cancer cell line-SKOV3. Comparative microarray analysis was performed using Gene Chip Prime View Human Gene Expression arrays (Affymetrix). In vitro assays of autophagy and apoptosis and in vivo animal experiments were performed by p53 induction and/or cisplatin treatment using the established cell lines. The correlation between HDAC4 and HIF-1α or CREBZF and the association of HDAC4, HIF-1α, CREBZF, ERK, AKT, and p53 mRNA levels with patient survival in 523 serous ovarian cancer cases from TCGA was assessed. Results: We show that p53 and RAS mutants differentially control cellular apoptosis and autophagy to inhibit or to promote chemoresistance through dysregulation of Bax, Bcl2, ATG3, and ATG12. ERK and AKT active RAS mutants are mutually suppressive to confer or to deprive cisplatin resistance. Further studies demonstrate that p53 induces HIF-1α degradation and HDAC4 cytoplasmic translocation and phosphorylation. S35, E38, and V12 but not C40 promote HDAC4 phosphorylation and its cytoplasmic translocation along with HIF-1α. Wild-type p53 expression in RAS mutant cells enhances HIF-1α turnover in ovarian and lung cancer cells. Autophagy and anti-apoptotic processes can be promoted by the overexpression and cytoplasmic translocation of HDAC4 and HIF1-α. Moreover, the phosphorylation and cytoplasmic translocation of HDAC4 activate the transcription factor CREBZF to promote ATG3 transcription. High HDAC4 or CREBZF expression predicted poor overall survival (OS) and/or progression-free survival (PFS) in ovarian cancer patients, whereas high HIF-1α expression was statistically correlated with poor or good OS depending on p53 status. Conclusion: HIF-1α and HDAC4 may mediate the interaction between p53 and RAS signaling to actively control ovarian cancer cisplatin resistance through dysregulation of apoptosis and autophagy. Targeting HDAC4, HIF-1α and CREBZF may be considered in treatment of ovarian cancer with p53 and RAS mutations.
Resistance to SL-401 in AML and BPDCN Is Associated with Loss of the Diphthamide Synthesis Pathway Enzyme DPH1 and Is Reversible By Azacitidine
Authors: Jason Stephansky, Katsuhiro Togami, Mahmoud Ghandi, Joan Montero, Nick vonEgypt, Ross Lindsay, Christopher Brooks, Jon C. Aster, Cory Johannessen, Andrew A. Lane
Journal: Blood (2017)
Mebendazole Exerts Potent Anti-Leukemic Effects By Downregulating Protein Levels of Hedgehog Transcription Factors GLI1 and GLI2
Authors: Fabian Freisleben, Hauke Stamm, Jana Muschhammer, Alexander Krispien, Vanessa Thaden, Jasmin Wellbrock, Walter Fiedler
Journal: Blood (2018)
Abstract P2-13-05: Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting
Authors: O Calvillo-Argüelles, D Flores-Diaz, J-P Gonzalez-Serrano, A López-Rojas, L Mendoza-Galindo, J-A Matus-Santos, N Reynoso-Noverón, P Cabrera-Galeana, E Bargalló-Rocha, C Arce-Salinas
Journal: Cancer Research (2019)

Abstract Background: Trastuzumab treatment plus adjuvant or neoadjuvant chemotherapy is the standard of care for women with HER2 positive breast cancer. Despite relative low rates of cardiotoxicity observed in randomized clinical trials, trastuzumab interruption driven by LVEF reduction is a major concern in current clinical practice. Patients and methods: We retrospectively identified women with stage I-III HER2 positive breast cancer who received 12 months of trastuzumab treatment after adjuvant or neoadjuvant chemotherapy at Instituto Nacional de Cancerología (INCan, Mexico City), between 2006 and 2018. Patients were eligible if a pre-therapy MUGA scan and ≥2 subsequent follow-up scans were available. Cardiotoxicity was defined as a ≥10% LVEF reduction to a value &amp;lt; 50%, associated with trastuzumab interruption. Results: 910 patients were included, with a median age at diagnosis of 50 (24-85) years and a median follow up of 7 (2-11 ) years. Among the whole cohort, 10.3% of patients had diabetes, 15.4% had hypertension, 78% were obese/overweight, and 40% had positive estrogen and/or progesterone receptor status. Anthracycline-based therapy was used in 819 (90%) patients, with a median (doxorubicin equivalent) cumulative dose of 200 mg/m2 (IQR 180-240). The median baseline LVEF was 61.8% (50-88.9). In total, 94 (10.3%) patients developed cardiotoxicity, but symptomatic heart failure was observed in only 31 (3.4%) individuals. In univariable analyses, the development of cardiotoxicity was not associated significantly with cardiovascular risk factors. Conclusions: In this large single-center cohort, cardiotoxicity rates remain high, thus, interventions to minimize the risk of cardiotoxicity and trastuzumab treatment interruption should be considered. Citation Format: Calvillo-Argüelles O, Flores-Diaz D, Gonzalez-Serrano J-P, López-Rojas A, Mendoza-Galindo L, Matus-Santos J-A, Reynoso-Noverón N, Cabrera-Galeana P, Bargalló-Rocha E, Arce-Salinas C. Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-05.
Abstract P102: Epigenome-wide Association Study of Measures of Fasting Glucose, Fasting Insulin, and Hba1c in Non-diabetic Individuals of European, African, and Hispanic Ancestry in the Charge Consortium
Authors: Bertha A Hidalgo, Marie-France Hivert, Jennifer Wessel, Weihua Guan, Rahul B Gondalia, Elias L Salfati, Elena Montoro Carnero, Ann Z Moore, Jen Brody, Jennifer Kriebel, Jennifer Smith, Wei Zhao, Symen Ligthart, David Hill, James S Pankow, Audrey Y Chu
Journal: Circulation (2017)

Background: Fasting glucose, fasting insulin, and hemoglobin A1c are important glycemic biomarkers and elevated levels of these markers predict future glycemic dysfunction and type-2 diabetes. Several studies have identified DNA methylation sites associated with quantitative glycemic traits and T2D. However, these studies have generally been limited in size. In this project, we aim to identify blood cells methylation signatures associated with three quantitative glycemic traits - fasting glucose (FG), log-transformed fasting insulin (logFI) and hemoglobinA1c (HbA1c) through meta-analysis of DNA methylation data from participating CHARGE Epigenetics Working Group cohorts. Methods: We conducted a epigenome-wide meta-analysis of DNA methylation assessed with Illumina BeadChip 450K array on blood-based DNA samples, including 12,681 for FG, 11,224 for logFI, and 6358 for HbA1c, from non-diabetic participants of European, African, and Hispanic ancestry in 10 cohorts from the CHARGE Epigenetics Working Group. Mixed linear regression analyses were performed adjusting for age, sex, smoking status, cell composition, and and technical covariates, with and without adjustment for BMI. A Bonferroni corrected P value of 1.1 х 10 – 7 was considered significant. Results: In combined multiethnic analysis, methylation at a total of 208 cytosine guanine dinucleotides (CpGs) were significantly associated with FG, 761 CpGs with logFI, and 109 CpGs with HbA1c. Adjustment for BMI substantially reduced the number of DNA methylation loci that met epigenome-wide significance. Biologically putative genes include CPT1A and TXNIP (FG), ABCG1 and CPT1A (logFI),and ABCG1 and MAFG (HbA1C). Conclusion: Our findings suggest that methylation of CpG sites within multiple genes are cross-sectionally associated with glycemic biomarkers. Our results also confirm findings from prior and smaller studies, meriting further evaluation of these methylation sites and genes as novel disease risk markers.
Obesity and its impact on outcomes in stage III colon cancer (CC) patients receiving adjuvant chemotherapy (AC).
Authors: Qirui Ding, Geoff McKinnon, Yuan Xu, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2019)

627 Background: Obesity may complicate CC surgery, which can result in potential AC delays. We aimed to determine the effect of body mass index (BMI) and body surface area (BSA) on CC outcomes, accounting for variations in the time interval between surgery and AC. Methods: We analyzed a population-based cohort of patients from Alberta, Canada who were diagnosed with stage III CC from 2011 to 2016 and underwent AC. Patients were grouped based on their baseline BSA (underweight, &lt; 20 kg/m 2 ; normal, 20-24; overweight, 25-29; obese ≥ 30) and BMI (&lt; 2 m 2 vs ≥ 2 m 2 ). Logistic regression models were constructed to examine the effect of BMI/BSA on delays between surgery and AC. The Kaplan-Meier method was used to estimate overall (OS) and cancer-specific survival (CSS) and Cox proportional hazards models were developed to evaluate the impact of BMI/BSA on these outcomes, adjusting for confounders. Results: We examined 915 patients: median age was 64 years, 510 (56%) were men and 155 (17%) had a Charlson comorbidity index (CCI) ≥ 2. In this cohort, 126 (14%), 623 (68%) and 166 (18%) were stage IIIA, IIIB and IIIC, respectively. In total, 132 (14%) were underweight, 452 (49%) normal weight, 233 (26%) overweight and 98 (11%) obese. Based on the Mosteller formula, 527 (58%) patients had normal BSA and 368 (42%) had high BSA. Obese patients were more likely to be men (67% vs 56%, p &lt; 0.001) and had worse CCI (28% vs 17% with CCI ≥ 2, p = 0.03) when compared to non-obese patients. Neither BMI (p = 0.14) nor BSA (p = 0.44) correlated with AC delays after surgery. Similar OS and CSS were observed regardless of BMI and BSA (p = 0.76 and 0.80 for OS and p = 0.60 and 0.89 for CSS, respectively). In multivariate Cox models, only worse nodal stage was associated with inferior OS and CSS (HR 4.74, 95%CI 1.96-11.47, p &lt; 0.001 for OS; HR 4.92, 95%CI 1.42-17.00, p = 0.006 for CSS, comparing IIIC vs IIIA), but BMI and BSA were not (see Table). Conclusions: Obesity as measured by BMI and BSA did not correlate with AC delays or worse outcomes in stage III CC patients. [Table: see text]
Abstract 10895: The Association of Growth Patterns and Clinical Outcomes in Children With Dilated Cardiomyopathy: A Report From the Pediatric Cardiomyopathy Registry Study Group
Authors: Chesney Castleberry, John L Jefferies, Ling Shi, James D Wilkinson, Jeffrey A Towbin, Ryan W Harrison, Charles Canter, Joseph Rossano, Elfriede Pahl, Teresa Lee, Linda Addonizio, Paolo Rusconi, Justin Godown, Joseph Mahgerefteh, Steven D Colan, Paul F Kantor, Steven E Lipshultz, Tracie Miller
Journal: Circulation (2015)

Introduction: Although malnourishment is associated with mortality in adult dilated cardiomyopathy (DCM), a paradox exists where obesity is protective. We aim to look at the role of these risk factors in pediatric DCM. Hypothesis: We hypothesize malnourishment (MN) and obesity are risk factors for death or heart transplantation. Methods: The NHLBI- funded Pediatric Cardiomyopathy Registry (PCMR) database was used for this analysis of patients (age &lt; 18 years) with idiopathic or familial DCM and myocarditis. Patients were categorized by anthropological measurements: MN (defined as BMI &lt;5% for ≥2years or weight for length &lt;5% for &lt;2 years), obese (BMI&gt; 95% for ages ≥2years or weight for length &gt;95% for &lt;2 years), and normal. Results: Of 904 DCM patients, 23.7% (214) were MN, 13.3% (120) were obese, and 63.1% (570) were normal (Table). Obese patients were significantly older (p&lt;0.001) and more likely to have a family history of DCM (both p&lt;0.05). MN were more likely to have congestive heart failure, increased cardiac dimensions, and higher ventricular mass (p&lt;0.01). In a Kaplan Meier analysis, there was a difference in time to death or transplant by groups (Figure, p=0.0498). Adjusting for age and myocarditis, MN was associated with increased risk of death (HR: 1.857, 95%CI: 1.159-2.977, p=&lt;0.001), but obesity was not (HR: 1.362, 95%CI: 0.722, 2.566). Competing outcome analysis showed an increased risk of death for MN (p=0.026) but no difference between groups in transplant rate (p=0.159). Conclusion: Malnourishment is significantly associated with poor clinical outcomes. Unlike adult DCM where obesity is protective, obesity is not associated with improved survival in pediatric DCM.
Abstract 17450: Lineage Contribution of Adult c-Kit+ Cardiac Progenitor Cells in Embryonic and Neonatal Development
Authors: Bingyan J Wang, Alvin Muliono, Roberto Sacripanti, Roberto Alvarez, Mark A Sussman
Journal: Circulation (2017)

Introduction: Multipotent c-Kit+ cardiac progenitor cells (CPCs) are able to differentiate into three cardiac lineages: endothelial cells, smooth muscle cells, and cardiomyocytes. However, adult CPC differentiation and regeneration capacity seems to be hindered by poor long-term cell retention and engraftment following adoptive transfer, perhaps due to the infarct or ischemic recipient heart, which is continuously challenged by inflammation, cardiomyocyte death, and loss of ECM. Therefore, the undesirable recipient environment presents a continuous pathological challenge for CPCs to differentiate at their full potential. Developing heart hosts highly regulated spatiotemporal coordination that allows cell lineage diversification, hence providing the most permissive environment for CPCs to engage their maximum multipotent potential. Hypothesis: We hypothesize that the embryonic environment provides the optimal spatiotemporal conditions to promote CPCs commitment to their full multipotent potential. Methods:...
Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines
Authors: Mathias Vormehr, Özlem Türeci, Ugur Sahin
Journal: Annual Review of Medicine (2019)

T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing major histocompatibility complex-bound cancer-specific peptides. Accumulating evidence suggests that peptides associated with T cell-mediated tumor rejection arise predominantly from somatically mutated proteins and are unique to every patient's tumor. Knowledge of an individual's cancer mutanome (the entirety of cancer mutations) allows harnessing this enormous tumor cell-specific repertoire of highly immunogenic antigens for individualized cancer vaccines. This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.
Survival impact of the response at twelve weeks in patients with advanced gastric cancer received first-line chemotherapy.
Authors: Motoko Arakaki, Masahiko Aoki, Hiroshi Imazeki, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Atsuo Takashima, Ken Kato, Narikazu Boku
Journal: Journal of Clinical Oncology (2019)

103 Background: The continuation of first-line chemotherapy or the maintenance chemotherapy has been selected for advanced gastric cancer patients who have not progressed after 4 to 6 cycles of first-line chemotherapy. However, survival data about those patients remains unclear. We retrospectively assessed the impact of response at 12 weeks on survival for advanced gastric cancer who received first-line chemotherapy. Methods: Eligible patients had unresectable advanced gastric adenocarcinoma and treated for the combination chemotherapy with fluoropyrimidine and platinum from January 2010 to December 2017 in our hospital. Patients with HER2 positive were excluded. Patients were divided into three groups (PR, SD, or PD group) according to response at 12 weeks of first-line chemotherapy, and their overall survival and progression-free survival were assessed. Results: The total number of the subject was 249 whose median overall survival (mOS) and progression-free survival (mPFS) were 13.8 and 5.4 months. Among 152 patients with measurable lesions, 58, 42, and 52 patients achieved PR, SD, and PD at 12 weeks. mOS was 16.7 months in the PR group, 9.8 months in the SD group, and 5.7 months in the PD group. mPFS was 7.1 months in the PR group, 4.5 months in the SD group, and 1.7 months in the PD group. Among 97 patients without measurable lesions, 90 patients achieved nonCR/nonPD at 12 weeks of first-line chemotherapy whose mOS and mPFS were 17.9 months and 9.2 months while those were 9.6 months and 1.9 months in the remaining 7 patients with PD at 12 weeks. Conclusions: There were clear differences in survival among PR, SD, and PD at 12 weeks in patients with measurable lesions while patients without measurable lesions obtaining nonCR/nonPD at 12 weeks showed similar OS and PFS to those with measurable lesion obtaining PR in first-line chemotherapy for advanced gastric cancer. [Table: see text]
Whole Transcriptome RNA Sequencing As a Comprehensive Diagnostic Tool for Acute Myeloid Leukemia
Authors: Marieke Griffioen, Wibowo Arindrarto, Daniel M. Borras, Irene J. Locher, Saskia A.M.E. van Diessen, Rosalie van der Holst, Edith D. van der Meijden, M. Willy Honders, Rick H. de Leeuw, Inge Jedema, Wilma G.M. Kroes, Jeroen Knijnenburg, Joost Vermaat, Peter Valk, Bart Janssen, Peter de Knijff, Cornelis A.M. van Bergen, Erik B. van den Akker, Peter A.C. 't Hoen, Szymon M. Kielbasa, Jeroen F.J. Laros, Hendrik Veelken
Journal: Blood (2018)
Spatial Regulation of Thrombopoiesis in the Bone Marrow
Authors: David Stegner, Judith van Eeuwijk, Maximilian G Gorelashvili, Oguzhan Angay, Mike Friedrich, Jürgen Pinnecker, Patrick Schmithausen, Daniela Semeniak, Harald Schulze, Christian Brede, Andreas Beilhack, Bernhard Nieswandt, Katrin G Heinze
Journal: Blood (2018)
Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model
Authors: Angela M. Crist, Xingyan Zhou, Jone Garai, Amanda R. Lee, Janina Thoele, Christoph Ullmer, Christian Klein, Jovanny Zabaleta, Stryder M. Meadows
Journal: Circulation (2019)

Background: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFβ) pathway members, including the central transcriptional mediator of the TGFβ pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFβ downstream effectors responsible for hereditary hemorrhagic telangiectasia–associated AVM formation are currently unknown. Methods: To identify potential biological targets of the TGFβ pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation–sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4 -iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. Results: Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4 -iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4 -deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. Conclusions: Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFβ downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.
Bloodstream infections due to carbapenemase-producing Enterobacteriaceae in Italy: results from nationwide surveillance, 2014 to 2017
Authors: Simone Iacchini, Michela Sabbatucci, Carlo Gagliotti, Gian Maria Rossolini, Maria Luisa Moro, Stefania Iannazzo, Fortunato D’Ancona, Patrizio Pezzotti, Annalisa Pantosti
Journal: Eurosurveillance (2019)

Following the rapid increase of infections due to carbapenemase-producing Enterobacteriaceae (CPE) in Italy, the national surveillance of bloodstream infections (BSI) due to CPE (Klebsiella pneumoniae and Escherichia coli) was instituted in 2013. All CPE-BSI cases reported to the surveillance in the years 2014-17 were analysed in order to investigate incidence rate (IR), trend, main individual characteristics and enzymes involved in CPE resistance. Throughout this period, 7,632 CPE-BSI cases (IR: 3.14/100,000 inhabitants) were reported from all 21 regions and autonomous provinces in Italy, with an increasing number of reported cases (2014: 1,403; 2015: 1,838; 2016: 2,183; 2017: 2,208). CPE-BSI cases mainly occurred in subjects aged over 60 years (70.9%) and more frequently in males (62.7%) than in females. Most of the cases originated in hospitals (87.2%), mainly in intensive care units (38.0%), and were associated with central or peripheral venous catheter use (23.9%) or with urinary tract infections (21.1%). Almost all CPE-BSI (98.1%) were due to K. pneumoniae carrying the K. pneumoniae carbapenemase (KPC) enzyme (95.2%). These data show that carbapenemase-producing K. pneumoniae are endemic in our country, causing a high number of BSI and representing a threat to patient safety.
Partha Kar: Leadership without accountability benefits no one
Authors: Partha Kar
Journal: BMJ (2019)

In the NHS, the term “leadership” generates a huge range of emotions. Sometimes it’s ethereal and inspiring. At other times it prompts disdain or even derision. Leadership quangos abound, courses are drip fed into email inboxes, and conferences keep springing up.

Yet every analysis of the NHS’s failings tells us the same story—one of a “lack of leadership.” Why? Because we don’t have the right type of leader? Because we don’t have enough “completer-finishers”? Because “leadership” is now seen as a career opportunity? In my view, all of these have contributed to …
Acute kidney injury in trauma patients admitted to the ICU: a systematic review and meta-analysis
Authors: Signe Søvik, Marie Susanna Isachsen, Kine Marie Nordhuus, Christine Kooy Tveiten, Torsten Eken, Kjetil Sunde, Kjetil Gundro Brurberg, Sigrid Beitland
Journal: Intensive Care Medicine (2019)