tbuckley/cabot-search huggingface dataset:
Outcomes with CPX-351 versus 7+3 by baseline bone marrow (BM) blast percentage in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (sAML).
Authors: Ellen K. Ritchie, Tara L. Lin, Laura F. Newell, Robert K. Stuart, Scott R. Solomon, Richard M. Stone, Gary J. Schiller, Matthew Joseph Wieduwilt, Daniel H. Ryan, Robert J Ryan, Michael Chiarella, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2019)

7042 Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved as Vyxeos in the US and EU for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved OS and remission rates vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML. This post hoc analysis of phase 3 data assessed outcomes by baseline BM blast percentage. Methods: Pts diagnosed with AML per 2008 WHO criteria (≥20% blasts in peripheral blood or BM) were randomized 1:1 to receive ≤2 inductions of CPX-351 (100 units/m 2 [C 100 mg/m 2 + D 44 mg/m 2 ] on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m 2 /d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m 2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive ≤2 consolidations. Results: CPX-351 had longer median OS and higher remission rates vs 7+3 irrespective of baseline BM blast percentage; median OS was worse in higher blast groups for both treatments (Table). The incidence of grade ≥3 TEAEs was &gt;80% for both arms; febrile neutropenia was the most common. Conclusions: Improved outcomes were observed with CPX-351 vs 7+3 irrespective of baseline BM blast percentage in older adults with newly diagnosed high-risk/sAML. Clinical trial information: NCT01696084. [Table: see text]
Health-Related Quality of Life in Heart Failure With Preserved Ejection Fraction
Authors: Alvin Chandra, Muthiah Vaduganathan, Eldrin F. Lewis, Brian L. Claggett, Adel R. Rizkala, Wenyan Wang, Martin P. Lefkowitz, Victor C. Shi, Inder S. Anand, Junbo Ge, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Marc A. Pfeffer, Burkert Pieske, Margaret M. Redfield, Jean L. Rouleau, Dirk J. Van Veldhuisen, Faiez Zannad, Michael R. Zile, John J.V. McMurray, Scott D. Solomon
Journal: JACC Heart Failure (2019)
Serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) as prognostic factors in malignant pleural mesothelioma (MPM)
Authors: P. Betta, R. Filiberti, P. Marroni, M. Neri, S. Orecchia, R. Libener, G. Bottero, M. Paganuzzi, R. Puntoni
Journal: Journal of Clinical Oncology (2006)

10080 Background: MPM is an uncommon but extremely aggressive tumor of the serosal surfaces, which has been closely linked to asbestos exposure. Several in-vitro studies have demonstrated that HGF enhances MPM cell proliferation, migration, and invasiveness and the presence of EGF is closely related to the process of cell differentiation and the synthesis of glycosaminoglycans in MPM cells. Few studies have measured the blood levels of these growth factors in tumor patients and assessed their correlation with clinical outcome. This pilot study was designed to investigate the potential value of serum EGF and HGF measurements for the diagnosis and the prediction of survival in MPM patients. Methods: Baseline serum EGF and HGF levels (ng/ml) were determined using an ELISA method in 81 newly diagnosed MPM patients (mean age 67.5±11.0 years) and 48 patients with benign respiratory diseases (BRD; mean age 64.3±13.5 years). Results: HGF and EGF median concentrations in MPM (1.6 ng/ml and 0.5 ng/ml, respectively) were not statistically different from concentrations in BRD (1.2 ng/ml and 0.4 ng/ml). Median follow-up for MPM patients was 27 months, while overall median survival was 11.8 months. At univariate analysis, only high EGF serum levels were associated with an unfavorable survival outcome. Using a cut-off point for EGF of 0.5 ng/ml (corresponding to the median of marker concentration in MPM), the survival rate in patients with higher serum EGF was significantly worse than that in patients with lower levels (median 10.7 vs. 13.0 months, p=0.01). Multivariate analysis, after adjusting for age, sex, histology and platelet count, confirmed the independent predictive value of serum EGF concentration as a negative prognostic factor (p=0.01). Conclusions: High pre-treatment levels of serum EGF are associated with an adverse prognostic impact on survival in MPM patients. No significant financial relationships to disclose.
Increased Activated Protein C Response Rates Reduce the Thrombotic Risk of Factor V Leiden Carriers But Not of Prothrombin 20210G&gt;A Carriers
Authors: Heiko Rühl, Christina Berens, Franziska I. Winterhagen, Sara Reda, Jens Müller, Johannes Oldenburg, Bernd Pötzsch
Journal: Circulation Research (2019)

Rationale: Carriers of the most common prothrombotic mutations FVL (factor V Leiden) and FII (prothrombin) 20210G&gt;A show a highly variable clinical phenotype. Using standardized in vivo coagulation activation followed by activity pattern analysis we have recently shown, that the FVL mutation accelerates thrombin and APC (activated protein C) formation in carriers without a history of venous thromboembolism (VTE). Objective: The aim of this prospective cohort study was to investigate, if the FII 20210G&gt;A mutation induces a similar reaction pattern, and if the response rates differ in FVL and FII 20210G&gt;A mutation carriers with prior VTE (VTE+). Methods and Results: We comparatively analyzed 30 FVL carriers, 28 FII 20210G&gt;A carriers (thereof 13 VTE+ each) and 15 healthy controls. Changes in plasma levels of thrombin, prothrombin activation fragment 1+2 (F1+2), TAT (thrombin-antithrombin complex), APC, and D-dimer were monitored over 8 hours after infusion of recombinant factor VIIa (15 µg/kg). An increase of F1+2 and TAT levels was observed, that did neither differ between FVL and FII 20210G&gt;A carriers nor between asymptomatic and VTE+ carriers of these mutations. Median plasma levels of APC increased more ( P =0.008) in FVL carriers (from 1.39 to 7.79 pmol/L) than in FII 20210G&gt;A carriers (from 1.03 to 5.79 pmol/L), and more in FII 20210G&gt;A carriers ( P =2×10 –4 ) than in healthy controls (from 0.86 to 3.00 pmol/L). Most importantly, however, the APC response was greater ( P =0.015) in asymptomatic (n=13) than in VTE+ (n=12) heterozygous FVL carriers, with an increase of APC levels from 1.44 to 8.11 pmol/L versus 1.27 to 5.62 pmol/L. Conclusions: These in vivo data demonstrate that the FII 20210G&gt;A and FVL mutations share an intermediate phenotype that is characterized by increased thrombin formation after coagulation activation. Furthermore, our data support the conclusion that the APC activating capacity of FVL carriers modifies the thrombotic risk of this common prothrombotic mutation.
High-Resolution PET Cisternography With 64Cu-DOTA for CSF Leak Detection
Authors: Martin Freesmeyer, Matthias Schwab, Bianca Besteher, Sebastian Gröber, Albrecht Waschke, Robert Drescher
Journal: Clinical Nuclear Medicine (2019)

Abstract Intracranial hypotension may lead to chronic, debilitating symptoms, and severe complications. The underlying CSF leak may be difficult to localize. To establish a new diagnostic option for the detection of CSF leaks, 64 Cu-DOTA was developed as a tracer for PET imaging. PET/CT imaging was possible with high resolution and without complications. In one patient, the exact site of a dural tear was identified, enabling successful surgical treatment. PET cisternography with 64 Cu-DOTA appears to be safe and able to locate a CSF leak. It has the potential to be a problem-solving modality in cases with inconclusive CT, MR, and/or scintigraphic findings.
Ефективність ендоскопічного дослідження з високою роздільною здатністю, збільшенням, хромоскопією та NBI в діагностиці патології слизової органів езофагогастродуоденальної зони у хворих із гастроезофагеальною рефлюксною хворобою
Authors: O.O. Krylovа, L.N. Mosіichuk, І.V. Kushnіrenko, L.V. Demeshkіna
Journal: GASTROENTEROLOGY (2020)

У статті показані особливості стану слизової оболонки стравоходу, шлунка та дванадцятипалої кишки у хворих на гастроезофагеальну рефлюксну хворобу. Показано, що застосування вузькоспектрального дослідження та збільшення дозволяє виявляти метаплазований циліндричний епітелій у стравоході, атрофію та кишкову метаплазію слизової оболонки шлунка, тобто використання ендоскопії зі збільшенням, хромоскопії та вузькоспектральної ендоскопії значно покращує якість огляду, скорочує час дослідження й число виконуваних біопсій.
Weekly Dosing of Bortezomib in RVD Achieves Minimal Toxicity with No Reduction in Efficacy in a Diverse Cohort of Multiple Myeloma Patients
Authors: Syed Hussaini, Amitoj Gill, Rahul Gosain, Shesh Rai, Xiaoyong Wu, Jill Rhodes, Soumit K. Basu, Ju-Hsien Chao, William Tse, Geoffrey P. Herzig, Roger H. Herzig, Maxwell M. Krem
Journal: Blood (2017)
Evaluating Glomerular Filtration Rate Slope as a Surrogate End Point for ESKD in Clinical Trials: An Individual Participant Meta-Analysis of Observational Data
Authors: Morgan E. Grams, Yingying Sang, Shoshana H. Ballew, Kunihiro Matsushita, Brad C. Astor, Juan Jesus Carrero, Alex R. Chang, Lesley A. Inker, Timothy Kenealy, Csaba P. Kovesdy, Brian J. Lee, Adeera Levin, David Naimark, Michelle J. Pena, Jesse D. Schold, Varda Shalev, Jack F. M. Wetzels, Mark Woodward, Ron T. Gansevoort, Andrew S. Levey, Josef Coresh
Journal: Journal of the American Society of Nephrology (2019)

Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR.To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m2 and 122,664 participants with eGFR<60 ml/min per 1.73 m2 from 14 cohorts followed for an average of 4.2 years.Slower eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m2 (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m2 (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%.Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m2, but those with the highest risk would be expected to benefit the most.
Reply to Pablo Sierra's Letter to the Editor re: Felix Preisser, Felix K.H. Chun, Raisa S. Pompe, et al. Persistent Prostate-specific Antigen After Radical Prostatectomy and Its Impact on Oncologic Outcomes. Eur Urol 2019;76:106–14
Authors: Felix Preisser, Derya Tilki
Journal: European Urology (2019)
Stable enhancers are active in development, and fragile enhancers are associated with evolutionary adaptation
Authors: Shan Li, Evgeny Z Kvon, Axel Visel, Len A Pennacchio, Ivan Ovcharenko
Journal: Genome biology (2019)

Despite continual progress in the identification and characterization of trait- and disease-associated variants that disrupt transcription factor (TF)-DNA binding, little is known about the distribution of TF binding deactivating mutations (deMs) in enhancer sequences. Here, we focus on elucidating the mechanism underlying the different densities of deMs in human enhancers. We identify two classes of enhancers based on the density of nucleotides prone to deMs. Firstly, fragile enhancers with abundant deM nucleotides are associated with the immune system and regular cellular maintenance. Secondly, stable enhancers with only a few deM nucleotides are associated with the development and regulation of TFs and are evolutionarily conserved. These two classes of enhancers feature different regulatory programs: the binding sites of pioneer TFs of FOX family are specifically enriched in stable enhancers, while tissue-specific TFs are enriched in fragile enhancers. Moreover, stable enhancers are more tolerant of deMs due to their dominant employment of homotypic TF binding site (TFBS) clusters, as opposed to the larger-extent usage of heterotypic TFBS clusters in fragile enhancers. Notably, the sequence environment and chromatin context of the cognate motif, other than the motif itself, contribute more to the susceptibility to deMs of TF binding. This dichotomy of enhancer activity is conserved across different tissues, has a specific footprint in epigenetic profiles, and argues for a bimodal evolution of gene regulatory programs in vertebrates. Specifically encoded stable enhancers are evolutionarily conserved and associated with development, while differently encoded fragile enhancers are associated with the adaptation of species.
Results from the first-in-human study of mivebresib (ABBV-075), a pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory acute myeloid leukemia.
Authors: Olatoyosi Odenike, Johannes E. Wolff, Gautam Borthakur, Ibrahim Taha Aldoss, David Rizzieri, Thomas Prebet, Beibei Hu, Minh Dinh, Xiaotian Chen, Dimple Modi, Kevin J Freise, Brian Andrew Jonas
Journal: Journal of Clinical Oncology (2019)

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had &gt; 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.
A Phase I/II Study on the Anti-CD3/CD7 Immunotoxin Combination (T-GuardTM) for the Treatment of Steroid-Refractory Acute Gvhd
Authors: Christoph Groth, Lenneke F J Groningen, Manita E J Bremmers, Frank W M B Preijers, Harry Dolstra, Tiago R Matos, Christian Reicherts, Eric G van Hooren, Ypke V J M van Oosterhout, John E Levine, James L Ferrara, Nicole M A Blijlevens, Matthias Stelljes, Walter J F M van der Velden
Journal: Blood (2017)
Abstract P180: A Racial Comparison of Vascular Hemodynamics in Middle-aged Americans: The Jackson Heart Study
Authors: Floyd Washington, Solomon K Musani, Emelia J Benjamin, Gary F Mitchell, Ervin R Fox
Journal: Circulation (2016)

Background: Despite the higher rates of hypertension and cardiovascular disease (CVD) sequela due to hypertension in African Americans (AA), literature on the hemodynamic factors contributing to vascular stiffness is sparse in this high risk population. Objective: We investigated the hemodynamics of vascular stiffness and its components in a middle-aged cohort of AA using arterial tonometry and compared findings to what has been seen in a healthy cohort of non-Hispanic whites from Framingham. Methods: Noninvasive hemodynamic factors were measured in 1,750 Jackson Heart Study participants (68±11 years, 65% female). A healthy reference group from published work in Framingham was used to determine the prevalence of abnormals in the Jackson Heart Study sample. Reference group was defined in Framingham as those with: age (&lt;50 years), blood pressure (BP, 140/90 mmHg), total cholesterol (&lt;200 mg/dL), body mass index (&lt;30 kg/m2), no diabetes, not currently smoking, and no history of CVD. Abnormal hemodynamic factors were defined as measurements outside the 95th or 5th percentile of the reference group. Using comparison of proportions, we determined the difference in abnormal prevalence rates between middle-aged AA in the Jackson Heart Study and non-Hispanic whites in Framingham. Results: The prevalence rates of abnormal hemodynamic variables in a middle-aged group of AA was compared to that seen in middle-aged non-Hispanic whites in Framingham using a published reference sample of normals in Framingham. Compared to non-Hispanic whites in Framingham, the prevalence of abnormals found in Jackson Heart Study AA was higher for diastolic BP (p=0.009), peripheral resistance (p&lt;0.001), characteristic impedance (p=0.006), carotid-brachial pulse wave velocity (p=0.038) and cardiac output (p&lt;0.001). Conclusion: Abnormalities in pulsatile hemodynamic variables are much more common (and severe) in AA than European Americans, which may contribute to higher CVD risk in AA.
Abstract 18489: Predictors of Successful Chemical Cardioversion With Dofetilide in Patients With Persistent Atrial Fibrillation
Authors: Madhu Y Reddy, Pramod Janga, Hema Pamulapati, Ramchandur Bakhtiani, Namratha Reddy, Ajay Vallakati, Donita Atkins, Sudharani Bommana, Patricia Howard, Loren Berenbom, Dhanunjaya Lakkireddy
Journal: Circulation (2013)

Introduction: Dofetilide induced cardioversion in persistent atrial fibrillation (AF) patients is not well described. We intended to evaluate the incidence and predictors of chemical cardioversion after initiation of Dofetilide in patients with persistent AF. Methods: We performed a retrospective study including all patients with persistent AF who were admitted for initiation of Dofetilide in our center. Patients in sinus rhythm (SR) at the time of initiation were excluded. All patients were in the hospital for a minimum of 5 doses of the drug. If patients did not convert to SR spontaneously on the drug by the 4 th dose, they underwent electrical cardioversion (DCCV). Results: Of the 305 patients who underwent dofetilide initiation at our center, 195 (64%) persistent AF patients were in AF at the time of the first dose. Mean age of the population was 65 ±9 years with 61 (31%) females. Mean CHADS2 score was 1.7 ±1.0. Median duration of AF was 36 (IQ 12-84) months with a mean LA diameter of 4.6±0.8cm. Mean number of prior failed antiarrhythmic drugs (AAD) was 1.4 ±1.1. Spontaneous conversion to SR occurred in 91 (47%) patients. Patients who converted to SR were much more likely to be females (40% vs 24%; p = 0.020) and had smaller left atrial diameter (4.4 vs 4.7cm; p = 0.023). In multivariate analysis including age, gender, duration of AF, number of prior AADs, LA diameter, heart failure and LVED, the only independent predictor of successful chemical cardioversion was female gender (OR: 2.4; p = 0.022). Conclusion: In patients with persistent AF, female gender is independently associated with successful chemical cardioversion with dofetilide.
Single nucleotide polymorphisms analysis of BRAC and ERCC1 as predictor of recurrence after chemoradiation for cervical cancer patients.
Authors: Luis Roberto Féliz, Verónica Pereira, Mariano Monzo, Carmen Munoz, Pere Fuste, Pedro Gascon, A. Torrents, Laura Vidal Boixader
Journal: Journal of Clinical Oncology (2012)

e13540 Background: A number of patients with locally advanced cervical cancer will recur despite presenting initial response to chemoradiation. Single-nucleotide polymorphisms (SNP) of DNA repair genes have been found to be predictors of efficacy of chemotherapy and radiotherapy. Methods: We evaluated the presence of SNP in ERCC1, BRAC 1 and 2 genes. We analysed paraffin-embedded biopsies from patients who had relapsed after receiving treatment with chemoradiation, for SNP of the mentioned genes. The status of the alleles wild type (wt) or at least 1 SNP was compared with time to progression (TTP) and toxicity. Results: 90 patients who experience recurrence of their cervical cancer were included in the analysis. Of those, we only could obtain evaluable tumour from 43 patients. Median age: 52.5 yrs (31-81). Histology: 32 squamous cell, 8 adenocarcinoma, 3 adenosquamous. One SNP in BRAC1 (rs12516) was found to be significantly associated with better TTP for the mutant variant compared to the wild-type (124 m. vs. 14 m.). Furthermore, all six patients who presented with severe (grade 3-4) toxicity had this wild-type SNP (rs12516) in BRAC1 gene. Conclusions: We have identified a SNP which confers better outcome in patients with cervical cancer. Further analysis need to be done to determine its relation to radiation-induced toxicity in this group of patients.
Ephrin-B2 drives migration and invasion of glioma and predicts short term survival
Authors: Eric Anderson, Mitsutoshi Nakada, Tim Demuth, Satoko Nakada, Linsey Reavie, Kelsey Drake, Josh Niska, Michael Berens
Journal: Cancer Research (2007)

3940  Eph receptor tyrosine kinases mediate neurodevelopmental processes such as boundary formation, axon guidance, vasculogenesis, and cell migration. Eph ligands, termed ephrins, are also transmembrane proteins that bind to Eph receptors, the mutual activation of which causes repulsive effects in reciprocally contacting cells. We compared global gene expression of invasive versus tumor core cells collected by laser capture microdissection from 19 glioblastoma specimens; by pathway enrichment analysis, we show the Eph/ephrin pathway to be most tightly linked to glioma invasion. Expression profiles of the Eph/ephrin family members in various grades of 195 glial tumors showed high expression of ephrin-B2, especially in glioblastoma (p
Cardiovascular Biomarkers After Metabolic Surgery Versus Medical Therapy for Diabetes
Authors: Deepak L. Bhatt, Ali Aminian, Sangeeta R. Kashyap, John P. Kirwan, Kathy Wolski, Stacy A. Brethauer, Stanley L. Hazen, Steven E. Nissen, Philip R. Schauer
Journal: Journal of the American College of Cardiology (2019)
Preventing carbon monoxide poisoning
Authors: Sarah J Jones, Amber Horton, Huw Brunt, Giri Shankar
Journal: BMJ (2019)

By improving clinical awareness of the signs, symptoms, causes, and treatment of carbon monoxide (CO) poisoning,1 we can reduce this avoidable burden on health and health services.

CO poisoning is under-reported and under-recorded.2 In Wales, there were 1052 hospital admissions related to CO (ICD10 codes T58 and X47), requiring 5084 bed days, between 2005 and 2017. At 2013-14 estimates of £1542 (€1716; $1924) for …