tbuckley/cabot-search huggingface dataset:
DO NEIGHBORHOOD FACTORS AFFECT PARTICIPATION IN CARDIAC REHABILITATION IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION?
Authors: Andrew Lutz, Emily Guhl, Julia P. Holber, Kwonho Jeong, Kaleab Abebe, Amy Anderson, Jared Magnani, Daniel Forman, Bruce Rollman
Journal: Journal of the American College of Cardiology (2020)
A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors.
Authors: Cristina Saura, Suzanne Jones, Joaquin Mateo, Antoine Hollebecque, James M. Cleary, Desamparados Roda Perez, Jin Zhu, Luna C. Musib, Premal H. Patel, Andres Cervantes-Ruiperez, Steven J. Isakoff, Jean-Charles Soria, L Rhoda Molife, Josep Tabernero, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2012)

3021 Background: Activation of the Akt pathway is observed in multiple tumors and may contribute to chemoresistance. GDC-0068 is an ATP-competitive small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7days off) and pharmacodynamic down-regulation of Akt signaling in tumors at doses ≥100 mg. In vitro, GDC-0068 shows synergism with cytotoxic agents. This phase Ib study defines the dose limiting toxicities (DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination with D and F. Methods: Using a 3+3 designeligible patients (pt) with advanced/metastatic solid tumors were treated with either D, 75 mg/m 2 day 1 and GDC-0068 daily on days 2-15 of a 21 day cycle (Arm A); or F, bolus 5FU 400mg/m 2 , leucovorin 400 mg/m 2 , oxaliplatin 85 mg/m 2 all day 1, and infusional 5FU 2400mg/m 2 for 46 hours and GDC-0068 daily on days 1-7 of a 14 day cycle (Arm B). PK sampling was performed in Cycles 1 and 2. Results: 23 pts have enrolled; Arm A (GDC-0068, mg): 100 (n=3), 200 (n=4), and 400 (n=5); Arm B:100 (n=6) and 200 (n=5). Median prior therapies = 3. GDC-0068-related adverse events in ≥ 10% of pts were diarrhea, nausea, vomiting, fatigue, and decreased appetite. All GDC-0068-related AEs were grade 1 or 2, except one grade 4 neutropenia in Arm A. No DLTs have been reported to date. Preliminary data show no alteration in the PK of GDC-0068, D or F compared to phase Ia or historical data. Two heavily pretreated pts with cervical and PTEN-loss colon cancers treated in Arm B demonstrated both RECIST partial response and tumor marker decrease by first CT evaluation. Conclusions: The combination of GDC-0068 with D or F is well-tolerated and shows early signs of anti-tumor activity. Dose-escalations continue.
Abstract 17421: Use of a Novel Septal Occluder Device for Left Atrial Appendage Closure in Patients With Post-Surgical and Post-Lariat Leaks or Anatomies Unsuitable for Conventional Percutaneous Occlusion
Authors: Domenico G Della Rocca, Rodney Horton, Nicola Tarantino, Luigi Di Biase, Carola Gianni, CHINTAN G TRIVEDI, Mohamed Bassiouny, G Joseph Gallinghouse, Amin Al-Ahmad, Javier Sanchez, Sanghamitra Mohanty, Andrea Natale
Journal: Circulation (2020)

Introduction: Interventional therapies aiming at excluding the left atrial appendage (LAA) from systemic circulation have been established as a valid alternative to oral anticoagulation (OAC) in patients at high thromboembolic (TE) risk. However, their efficacy on stroke prophylaxis may be compromised owing to incomplete LAA closure. Additionally, the need for an alternative TE prevention may remain unmet in patients with contraindications to OAC whose appendage anatomy is unsuitable for some conventional devices commercially available. Hypothesis: We aimed at evaluating the feasibility of LAA closure with the novel Gore® Cardioform Septal Occluder (CSO) in patients with incomplete appendage ligation or anatomical features which do not meet the manufacturer’s requirements for Watchman deployment. Methods: Twenty-one consecutive patients (mean age: 72±6 years; 85.7% males; CHA 2 DS 2 -VASc: 4.5±1.4; HAS-BLED: 3.6±1.0) were included. Trans-esophageal echocardiography (TEE) was performed within 2 months to assess for residual LAA patency. Results: Fourteen patients had incomplete LAA closure following surgical (n=6) or Lariat ligation (n=8). In 7 patients with an appendage anatomy unsuitable for Watchman deployment, the mean maximal landing zone size and LAA depth were 14.4±1.3mm and 18.6±2.8mm. Successful CSO deployment was achieved in all patients. No peri-procedural complications were documented.Procedure and fluoroscopy times were 46±13min and 14±5min. Follow-up TEE after 58±9 days revealed complete LAA closure in all patients. Conclusions: Transcatheter LAA closure via a CSO device might be a valid alternative in patients with residual leaks following failed appendage ligation or whose LAA anatomy does not meet the minimal anatomical criteria to accommodate a Watchman device.
OPTIMIZATION OF DIURETIC THERAPY IN THE ACUTELY DECOMPENSATED HEART FAILURE PATIENT
Authors: Megan E. Barber, Nicholas Malchione, Ateet Kosaraju, Brandon Pelletier, Manouchkathe Casagnol, Ofek Hai, Amgad Makaryus, Roman Zeltser
Journal: Journal of the American College of Cardiology (2020)
Noninvasive respiratory support in the hypoxaemic peri-operative/periprocedural patient: a joint ESA/ESICM guideline
Authors: Marc Leone, Sharon Einav, Davide Chiumello, Jean-Michel Constantin, Edoardo De Robertis, Marcelo Gama De Abreu, Cesare Gregoretti, Samir Jaber, Salvatore Maurizio Maggiore, Paolo Pelosi, Massimiliano Sorbello, Arash Afshari
Journal: Intensive Care Medicine (2020)
Rampant Misexpression in a Mimulus (Monkeyflower) Introgression Line Caused by Hybrid Sterility, Not Regulatory Divergence
Authors: Rachel E Kerwin, Andrea L Sweigart
Journal: Molecular Biology and Evolution (2020)

Abstract Divergence in gene expression regulation is common between closely related species and may give rise to incompatibilities in their hybrid progeny. In this study, we investigated the relationship between regulatory evolution within species and reproductive isolation between species. We focused on a well-studied case of hybrid sterility between two closely related yellow monkeyflower species, Mimulus guttatus and Mimulus nasutus, that is caused by two epistatic loci, hybrid male sterility 1 (hms1) and hybrid male sterility 2 (hms2). We compared genome-wide transcript abundance across male and female reproductive tissues (i.e., stamens and carpels) from four genotypes: M. guttatus, M. nasutus, and sterile and fertile progeny from an advanced M. nasutus–M. guttatus introgression line carrying the hms1–hms2 incompatibility. We observed substantial variation in transcript abundance between M. guttatus and M. nasutus, including distinct but overlapping patterns of tissue-biased expression, providing evidence for regulatory divergence between these species. We also found rampant genome-wide misexpression, but only in the affected tissues (i.e., stamens) of sterile introgression hybrids carrying incompatible alleles at hms1 and hms2. Examining patterns of allele-specific expression in sterile and fertile introgression hybrids, we found evidence for interspecific divergence in cis- and trans-regulation, including compensatory cis–trans mutations likely to be driven by stabilizing selection. Nevertheless, species divergence in gene regulatory networks cannot explain the vast majority of the gene misexpression we observe in Mimulus introgression hybrids, which instead likely manifests as a downstream consequence of sterility itself.
IMPACT OF CARDIOVASCULAR AND NON-CARDIOVASCULAR HOSPITALIZATION ON QUALITY OF LIFE IN PATIENTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION
Authors: Carisi Anne Polanczyk, Brian Claggett, Milton Packer, Michael Zile, John McMurray, Jean L. Rouleau, Karl Swedberg, Martin Lefkowitz, Victor Shi, Akshay S. Desai, Scott D. Solomon, Eldrin Lewis
Journal: Journal of the American College of Cardiology (2020)
PREDICTION OF LEFT MAIN DISEASE USING CLINICAL AND STRESS TEST PARAMETERS
Authors: Roxy Senior, Harmony Reynolds, James Min, Daniel S. Berman, Michael Picard, Bernard Chaitman, Leslee J. Shaw, Courtney B. Page, Sajeev Govindan, Jose Lopez-Sendon, Jesus Peteiro, Gurpreet Singh Wander, Jaroslaw Drozdz, Jose Marin-Neto, Joseph Brindaban Selvanayagam, Jonathan D. Newman, Christophe Thuaire, James Jang, Sripal Bangalore, Gregg W. Stone, Sean O'Brien, Jerome Fleg, William E. Boden, David Joel Maron, Judith S. Hochman
Journal: Journal of the American College of Cardiology (2020)
An analysis of adjuvant temozolomide plus radiotherapy vs radiotherapy alone in a single academic institution
Authors: S. Hopkins, S. Gertler, G. Nicholas
Journal: Journal of Clinical Oncology (2006)

1575 Background: The NCIC CE.3/EORTC 22981/26981 was open during the time period of August 2000 to March 2002. When the study closed, there existed a gap in care that did not address the ongoing management of patients (pts) with glioblastoma multiforme (GBM) that had been surgically excised. As a result of this gap, it was decided that the adjuvant use of temozolomide (TMZ) was to become the standard of care at our centre due to its lack of perceived toxicities and early evidence for its activity. Methods: An analysis was performed of all pts with GBM that were seen at the centre from 1998 to the summer of 2005. In total, 240 pts were identified across multiple medical and radiation oncologists. 75 pts were treated with radiotherapy (RAD) alone post surgery, 86 pts were treated with RAD + TMZ post surgery, 18 pts only had surgery and the remaining pts were unresectable. Average age was 59.7 years for pts treated only with RAD, and 54.6 years for those treated with TMZ + RAD (p = 0.028). 59% of pts treated with RAD were male, while 62% treated with RAD + TMZ were male. Median follow-up was 11.3 months for RAD and 15.7 months for TMZ + RAD (p = 0.0001816). Preliminary survival analysis demonstrates a 56% reduction in the risk of death for pts treated with TMZ + RAD when compared to RAD (log rank p = 9.6 × 10 −6 ). Median survival was 12.7 months for pts treated with RAD and 27 months for pts treated with TMZ + RAD (see table ). A further analysis including recursive partitioning analysis (RPA) and duration of therapy post RAD will be attempted to confirm the similarities between the two groups. Conclusion: Adjuvant TMZ + RAD has increased overall survival by 14.3 months in our institution. Further analysis is necessary to determine the impact on duration of therapy of TMZ. [Table: see text] [Table: see text]
Docetaxel (T), cisplatin (P), and TP 5-fluorouracil (F) with or without cetuximab in head and neck squamous cell carcinoma (HNSCC): Simulation of ex vivo results in the FLAVINO-assay.
Authors: Andreas Dietz, Andreas Boehm, Dietger Niederwieser, Gunnar Wichmann
Journal: Journal of Clinical Oncology (2012)

e16016 Background: Individual response evaluation in head and neck squamous cell carcinomas (HNSCC) would be welcome for better biology-based decision making since therapy strategies like concurrent radio-chemo and induction-chemo (IC) compete with surgery e.g. of resectable advanced HNSCC. However, inter-individual differences in response to mixtures of chemotherapeutics and biologicals are not exactly known even in guideline-conform treatments. The purpose was to analyze combined effects of T, P, F, and cetuximab (E) on colony formation (CF) of HNSCC in the FLAVINO assay and the comparison with the clinical response to IC. Methods: Before starting IC, biopsies were taken, collagenase-digested and exposed to T and/or P at quarter, half, and exact their tolerable plasma (TPL) levels (6.6 and 0.55 µM) in presence or absence of F (1.5 µM)±E, and controls. To facilitate counting of colonies formed within 72h, epithelial cells were stained by Cy2-labeled pan-cytokeratin antibodies. The 28-d response to the first cycle of IC (reduction in surface and volume of the primary) was compared with CF. Results: Poorest response to IC was observed in patients with HNSCC unable to form epithelial colonies (13/36). Of the 63.9% ex vivo growing HNSCC, 34.8% (8/23) and 8.7% (2/27) responded to C and T in concentrations ≤TPL with completely inhibited CF. This rate was increased in presence of E. 22/23 (95.6%) HNSCC formed &gt;4 epithelial colonies and allowed for IC 50 calculation. TP+E and TPF+E proved to be more effective than binary combinations. Combined with increasing doses of P, the IC 50 of T decreased and indicated superiority compared to treatment with T in binary combination with F. We found a high correlation of ex vivo and in vivo response of HNSCC. Conclusions: Complete suppression of CF and failure to form colonies ex vivo best predicted responsiveness or resistance to IC. Despite mostly additive or synergistic effects of TP and TPF ex vivo, identification of HNSCC probably failing to benefit from IC prior to starting therapy could reduce the risk of choosing inappropriate treatment modalities for HNSCC.
Telecommunicator Cardiopulmonary Resuscitation: A Policy Statement From the American Heart Association
Authors: Michael Christopher Kurz, Bentley J. Bobrow, Julie Buckingham, Jose G. Cabanas, Mickey Eisenberg, Peter Fromm, Micah J. Panczyk, Tom Rea, Kevin Seaman, Christian Vaillancourt
Journal: Circulation (2020)

Every year in the United States, &gt;350 000 people have sudden cardiac arrest outside of a hospital environment. Sudden cardiac arrest is the unexpected loss of heart function, breathing, and consciousness and is commonly the result of an electric disturbance in the heart. Unfortunately, only ≈1 in 10 victims survives this dramatic event. Early access to 9-1-1 and early cardiopulmonary resuscitation (CPR) are the first 2 links in the chain of survival for out-of-hospital cardiac arrest. Although 9-1-1 is frequently accessed, in the majority of cases, individuals with out-of-hospital cardiac arrest do not receive lay rescuer CPR and wait for the arrival of professional emergency rescuers. Telecommunicators are the true first responders and a critical link in the cardiac arrest chain of survival. In partnership with the 9-1-1 caller, telecommunicators have the first opportunity to identify a patient in cardiac arrest and provide initial care by delivering CPR instructions while quickly dispatching emergency medical services. The telecommunicator and the caller form a unique team in which the expertise of the telecommunicator is provided just in time to a willing caller, transforming the caller into a lay rescuer delivering CPR. The telecommunicator CPR (T-CPR) process, also previously described as dispatch CPR, dispatch-assisted CPR, or telephone CPR, represents an important opportunity to improve survival from sudden cardiac arrest. Conversely, failure to provide T-CPR in this manner results in preventable harm. This statement describes the public health impact of out-of-hospital cardiac arrest, provides guidance and resources to construct and maintain a T-CPR program, outlines the minimal acceptable standards for timely and high-quality delivery of T-CPR instructions, and identifies strategies to overcome common implementation barriers to T-CPR.
Urinary tract infection and bladder cancer risk in Los Angeles
Authors: Xuejuan Jiang, Jose Castelao, Ronald Ross, Manuela Gago-Dominguez
Journal: Cancer Research (2007)

1756  Background: Urinary tract infection (UTI) is the most common kidney and urologic disease in the United States and far more common in women than in men. Approximately 50% of women have ≥1 symptomatic UTI during their lifetime and many have recurrent episodes; while UTIs in men are uncommon until after age 50 years, when increasing prostatic hypertrophy may obstruct urinary flow. About 80-85% of UTIs are caused by Escherichia coli. In two prior studies, UTIs have been found to be associated with increased risk of bladder cancer, especially squamous cell carcinoma.  Methods: A population-based case-control study of bladder cancer was conducted in Los Angeles County from 1987-99. A total of 1586 age-, gender-, race- matched cases and neighborhood controls were included in the analyses. Participants were asked if they were told by a doctor that they had kidney infection, bladder infection, or other type of UTI. If the answer was yes, the year of first and last diagnosis, and total number of diagnosis were also requested.  Results: Bladder infection was more frequent in women than in men in our study (48% vs. 8%, respectively). A history of bladder infection significantly reduced the risk of bladder cancer (multivariate odds ratio - OR, 0.77; 95% confidence interval - 95% CI, 0.60-0.99), particularly in women (OR, 0.63, 95% CI, 0.43-0.91). Among them, frequency of bladder infection was statistically significantly associated with reduced risk of bladder cancer [ORs (95% CI) for 1, 2-3, and >3 diagnoses of bladder infection were 0.87 (0.47-1.59), 0.59 (0.33, 1.03), and 0.53 (0.32-0.89), respectively (P trend = 0.006)]. Among men, the association was less consistent. Relative to men that did not have a history of bladder infection, those with a history of 1 bladder infection had a 34% reduction in risk (OR, 0.66; 95% CI, 0.43-1.01), while those with a history of >3 bladder infections had two times higher risk (OR, 2.05; 95% CI, 0.89-4.71), although recurrent infections (>3) among men were very rare ( 3 kidney or other UTIs, especially among those diagnosed within 5 years of the diagnosis of cancer.  Conclusion: Our results suggest that a history bladder infection is associated with a reduced risk of bladder cancer. Cytotoxicity against bladder cancer cells from antibiotics commonly used to treat bladder infections is proposed as one possible mechanism to explain this association.
Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers.
Authors: Greg Coffey, Aradhana Rani, Andreas Betz, Yvonne Pak, Anjali Pandey, Stanley Hollenbach, Daniel D. Gretler, Tim Mant, Stipo Jurcevic, Uma Sinha
Journal: Journal of Clinical Oncology (2013)

8574 Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as FcεRI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a T max of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC 50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC 50 of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of FcεRI-mediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.
Patients with breast and ovarian cancer generate immune responses to the folate receptor alpha
Authors: K. L. Knutson, K. R. Kalli, C. J. Krco, K. Goodman, L. E. Kelemen, P. S. Low, L. C. Hartmann
Journal: Journal of Clinical Oncology (2006)

20043 Background: Studies have demonstrated that the generation of endogenous immunity to specific tumor antigens is associated with improved prognosis for many cancers. Thus, there has been increased efforts to identify tumor-associated antigens to which there is immunity, as these may be tumor rejection antigens. A candidate antigen is the folate receptor alpha (FRα) which is overexpressed in malignancies, especially breast and ovarian cancer. Prior studies involving ovarian and breast cancer patients have demonstrated the presence of FRα-specific cytotoxic T cells in the tumor-associated lymphocyte population. Methods: Using the RANKPEP CD4 T cell epitope prediction algorithm, we predicted promiscuous immunogenic regions of FRα, and tested for immunity in 30 breast or ovarian cancer patients and 18 healthy volunteer donors in order to attain a better understanding of the levels and extent of the endogenous FRα immune response. Immunity was examined using IFN-γ ELIspot analysis and IgG ELISAs. Results: Fourteen peptides were predicted as potential epitopes to which T cells may respond, seven each from the carboxy- and amino-terminus halves of the protein. Greater than 70% of patients demonstrated T cell immunity to at least one of the fourteen peptides. Patients responded to an average of 3 ± 0.7 peptides while healthy donors responded to only 1 ± 0.5 peptides (p = 0.02). Five peptides were recognized by &gt;25% of patients. Responses to three of these peptides were higher (p &gt; 0.05) in the patients than in healthy donors, suggesting that patients generated immunity upon cancer development. Compared to healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor, suggesting natural epitope spreading (p = 0.03). There was no difference between patients and healthy donors in the immune responses to either non-specific stimuli (p = 0.2) or viral peptides (p = 0.5). Patients had detectable FRα-specific IgG antibody consistent with active FRα-specific helper T cell immunity. Conclusions: These findings demonstrate that the FRα is a target of the immune system in patients with breast or ovarian cancer. Understanding the antigens that are naturally targeted by the immune system may be important for diagnosis, prognosis, and immune-based therapies. No significant financial relationships to disclose.