tbuckley/cabot-search huggingface dataset:
Looking backwards: is it time to assess veno-atrial interactions in pulmonary arterial hypertension?
Authors: Steven Pugliese, Rebecca R. Vanderpool
Journal: European Respiratory Journal (2019)

Right ventricular (RV) function is the major determinant of mortality in patients with pulmonary arterial hypertension (PAH). As a result, much of recent research has focused on right ventricular–pulmonary arterial coupling and, specifically, RV systolic function. As research on diastolic RV and right atrial function is beginning to emerge, the effect of the venous system on right ventricular function has been largely ignored. While observations regarding the effect of right ventricular function on venous return date to Aristotle ( circa 380 BC), one of the earliest pathological descriptions came in 1873 when Kussmaul described a paradoxical rise in jugular venous pressure during inspiration in constrictive pericarditis [1–3]. This phenomenon can be explained by venous backflow in the setting of an elevated right atrial pressure and a noncompliant RV. To this day the determinants of venous backflow have yet to be worked out, but there is a strong clinical relevance, including the effects on RV workload and venous congestion mediated hepatic and renal dysfunction [4, 5]. Vena cava backflow measured using CMR imaging is a novel marker to assess veno-atrial interactions in patients with pulmonary arterial hypertension <http://bit.ly/2TU4d9V>
Predictors of delays in initiation of oral tyrosine kinase inhibitors (TKIs) in EGFR and ALK positive advanced non-small cell lung cancer (NSCLC).
Authors: Bernardo H. L. Goulart, Shasank Chennupati, Kathryn Egan, Catherine R. Fedorenko, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

134 Background: Molecular testing practices and cost-sharing policies may result in delayed initiation of TKI therapy. We assessed predictors of delayed initiation of TKIs in metastatic EGFR+ or ALK+ NSCLC. Methods: We identified patients with EGFR+ and ALK+ NSCLC diagnosed between 01/01/2010 and 12/31/2016 in the Washington State SEER registry using validated natural language processing methods. We linked registry records to commercial and Medicare (including part D) claims. Eligible patients had stage IV NSCLC, sensitizing EGFR mutations or ALK+ by FISH, ≥ 1 pharmacy claims for EGFR or ALK TKIs, and ≥12 months of insurance enrollment post-diagnosis. Potential predictors included age, sex, race, Census-level median household income, urban status, insurance type, comorbidity, histology, mutation type, and receipt of chemotherapy prior to first TKI claim (pre-TKI chemo). We defined time to TKI initiation as the interval from diagnosis to first pharmacy claim for EGFR or ALK TKIs. We fitted Cox regression models to identify predictors of delays in TKI initiation, defining covariates with a P &lt; 0.05 in a final multivariate model as independently associated with delays. Results: For 122 patients (median age 70; 65% female; 74% White; median income $66,580; 98% metropolitan; 35% Medicare; 80% EGFR+; 12% using pre-TKI chemo), the median time to TKI initiation was 6.7 weeks (IQR = 3.9 to 14.0). Independent predictors of TKI delays included male sex (HR = 0.51; 95%CI = 0.34; 0.76); Medicare insurance (HR = 0.32; 95% CI = 0.20; 0.53) and pre-TKI chemo (HR = 0.37; 95% CI = 0.20; 0.66). Median time to TKI initiation was 9.7 vs. 5.8; 7.8 vs. 4.1; and 16.0 vs. 6.3 weeks in male vs. female, Medicare vs. commercial insurance, and pre-TKI chemo (yes vs no), respectively. Conclusions: Male sex, Medicare insurance, and chemotherapy prior to TKI are associated with delays in TKI initiation for EGFR+ and ALK+ stage IV NSCLC patients. Possible explanations include higher prevalence of smoking in males resulting in lower priority for molecular testing, high cost-sharing policies for TKIs in Medicare patients, and prolonged time to obtain molecular test results leading patients to start chemotherapy first.
Cost implications of potentially avoidable hospitalizations among Oncology Care Model patients with prostate cancer.
Authors: William H. Smith, Anish B Parikh, Lihua Li, Mark Sanderson, Mark Liu, Madhu Mazumdar, Luis M. Isola, Kavita Vyas Dharmarajan
Journal: Journal of Clinical Oncology (2019)

114 Background: Hospital-based care remains a major contributor to cost in oncology and thus represents an important cost-saving opportunity. We previously developed a rigorous two-stage consensus driven review process to identify potentially avoidable hospitalizations (PAHs) among oncology care model (OCM) patients with prostate cancer and reported a 28% rate of PAHs between 1/2012-6/2015. Our current objective was to estimate the magnitude of any expected cost savings generated if inpatient care from these PAHs were shifted to an acute care model in the outpatient setting. Methods: Costs for ambulatory acute care management among a separate but characteristically similar cohort of cancer patients were obtained from our institution’s recently established Oncology Care Unit (OCU), where acute clinical issues are managed in an enhanced ambulatory setting. We used an exact-matching algorithm to match previously identified PAHs to OCU visits based on strata of age (≤ 70 years vs. &gt; 70 years), categorically defined chief complaint (infusion/transfusion, lab abnormalities, symptom control, and diagnostic work-up), and the presence of “systemic disease” (metastatic disease or hematologic malignancy). PAH costs obtained from OCM data were compared to costs from these matched OCU encounters. Results: We identified 89 acute care OCU visits occurring from 5/2017-12/2018, of which 48 were fully evaluable based on documentation. Twenty-five of our initial 28 PAHs (89%) matched to 29 OCU acute care visits. The mean inpatient cost among matched PAHs was $15,879 compared to $975 for matched OCU visits. Boot strapping within each match produced a mean estimated cost savings of $15,120 (95% CI $13,682 to $16,557) per PAH. We estimate this per event savings to yield an overall spending decrement of 5.7% for OCM prostate cancer episodes. Conclusions: PAHs contribute substantially to costs of care in oncology. Investment in specialized ambulatory acute care services for oncology patients could lead to meaningful cost savings by shifting avoidable inpatient care to the outpatient setting.
Three Novel α-Globin Variants: Hb Itapira [α30(B11) Glu→Val (α1)], Hb Bom Jesus Da Lapa [α30(B11) Glu→Ala (α1)] and Hb Boa Esperança [α16(A14) Lis→Thr (α2)].
Authors: Maria F. Sonati, Elza M. Kimura, Dulcineia M. Albuquerque, Denise M. Oliveira, Fernando F. Costa
Journal: Blood (2004)
Decreased Erythrocyte Binding Capability for Neutrophil Siglec-9 Is a Source of Oxidative Stress in Sickle Cell Disease
Authors: Zachary Monroe Kiser, Greta L Becker, Julia Nguyen, Anel Lizcano, John D Belcher, Ajit P. Varki, Gregory M. Vercellotti
Journal: Blood (2018)
Abstract 892: Ablation of MiR-144 Increases Vimentin Expression and Atherosclerotic Plaque Formation
Authors: Quan He, Fangfei Wang, Takashi Honda, Kenneth D Greis, Andrew N Redington
Journal: Circulation Research (2019)

Objective: It has been suggested that miR-144 is pro-atherosclerotic via effects on reverse cholesterol transportation targeting the ATP binding cassette protein 1 (ABCA1). This study used proteomic analysis to identify additional cardiovascular targets of miR-144, and subsequently examined the role of a newly identified regulator of atherosclerotic burden in miR-144 KO mice receiving a high fat diet (HFD). Approach and Results: To identify affected secretory proteins, miR-144 treated endothelial cell culture medium was subjected to proteomic analysis including two-dimensional gel separation and nanospray liquid chromatography coupled to tandem mass spectrometry. We identified 5 gel spots representing 19 proteins that changed consistently across the biological replicates. One of these spots, was identified as vimentin. Atherosclerosis was induced in miR-144 KO mice by HFD and vascular lesions were quantified by Oil Red-O staining of the serial sectioned aortic root and from en-face views of the aortic tree. Unexpectedly, HFD induced extensive atherosclerosis in miR-144 KO mice in aortic root (WT 100% ± 22.71 vs miR-144 KO 256.88% ± 58.19, p &lt; 0.05, n = 10) and arch areas (WT 100% ± 29.67 vs miR-144 KO 371.74% ± 73.48, p &lt; 0.01, n = 10), and was accompanied by severe fatty liver disease compared with wild type littermates (WT). Vimentin levels were reduced by miR-144 and increased by antagomiR-144 in cultured cardiac endothelial cells without affecting vimentin mRNA levels. Compared with WT, ablation of the miR-144/451 cluster significantly increased plasma vimentin, while vimentin levels were decreased in control mice injected with synthetic miR-144 as double confirmed with Western blot and ELISA assays. Furthermore, increased vimentin expression was seen in the commissural regions of the aortic root (WT 100% ± 10.02 vs 164.19 ± 13.90, p &lt; 0.01, n = 10) and collocated with other areas of aortic atherosclerosis. In contrast, neither liver ABCA1 nor circulating cholesterol levels were different between WT and miR-144/451 KO mice. Conclusion: We conclude that miR-144 is a potential regulator of the development of atherosclerosis via changes in vimentin signaling and both miR-144 and vimentin are potential therapeutic targets for atherosclerosis.
Significant Changes in Inducible Cytokine Synthesis by Activated Peripheral Blood Leukocytes of Multiple Myeloma Patients Receiving Standard Dose Autologous Stem Cell Transplantation
Authors: Bang-Ning Lee, Nina Shah, Sergio Giralt, Hui Gao, Evan N Cohen, Lori Williams, Ibrahima Gning, Tito R Mendoza, Jane O Brown, Valen E Johnson, Richard Champlin, Charles S Cleeland, James M Reuben
Journal: Blood (2011)
Abstract 456: Fundamental New Clinical Insight From Excitation-contraction Coupling Studies of the Cardiovascular System via Integrated ECG And Photoplethysmography (PPG) Analyses During Sleep
Authors: Daniel R Wendelken, Neha Sanagala, Ginger A Conway, Steven R Jones, Deeptankar DeMazumder
Journal: Circulation Research (2019)

Introduction: The surface ECG provides critical insights into cardiac excitation. The ECG waveform dynamics inform clinical decisions beyond heart rate and QT measures. Likewise, the PPG waveforms contain physiologically rich information about a person’s health, but it’s clinical use is limited to peripheral oxygen saturation. Importantly, the complexity of ECG and PPG dynamics reflect multi-directional interconnected networks of cellular signaling pathways, tissues, organs and organ system interactions that regulate homeostatic function under changing conditions. While integrated dynamic analysis of ECG and PPG is rooted in fundamental principles of electromechanical coupling and systems biology, this has been unexplored for identifying subclinical illness. Hypothesis: Integrated dynamic analysis of ECG and PPG waveforms during sleep identify subclinical cardiovascular illness in a multicenter study of asymptomatic community subjects. Methods &amp; Results: We studied polysomnography recordings from 137 adults in a substudy of the multi-ethnic study of atherosclerosis (MESA-5). The cohort had mean age of 69±10 years, 43% women, 11% African Americans, 48% diabetes mellitus (DM) of which 33% received insulin therapy (DM-RxI), 21% prior myocardial infarction (MI), and 16% ostensibly healthy (i.e., unremarkable findings on history, physical exam, lab, etc). Dynamic analysis of PPG waveforms were performed for each sleep stage: (1) Awake before onset of sleep; (2) Non-REM sleep; (3) REM sleep; (4) Arousals during sleep; (5) Awake after completing sleep. In a multivariate model, the odds ratio (5th compared to 1st quintile) for MI for sleep stage 1 was 7.5 (2.1-27), for DM sleep stage 5 was 0.057 (0.0040-0.82), and for DM-RxI for sleep stage 5 was 0.23 (0.057-0.91), with corresponding ROC curve areas ranging between 0.65-0.90 (p &lt; 0.05). Conclusions: Integrated dynamic analysis of ECG and PPG waveforms provide fundamental new insight for identifying an individual’s health status, including MI, DM and treatment for DM. This novel strategy has potential for broad clinical application and warrants prospective validation.
Abstract 490: Sex-Specific Inflammatory Gene Expression in the Hypertrophied and Failing Human Heart
Authors: Georgios Kararigas, Daniel Lehmann, Christoph Knosalla, Lea Gaignebet
Journal: Circulation Research (2019)

Heart failure (HF) is a devastating syndrome with poor prognosis that is most often preceded by a left ventricular (LV) pressure overload (PO) disorder, such as aortic stenosis (AS). As pressure inside the LV increases, LV hypertrophy (LVH) develops. Persistent inflammation is known to be detrimental to the heart, which might promote HF. LVH manifests differently between men and women and there are pronounced sex differences in disease progression and outcome. However, the mechanisms that cause these differences are poorly understood. Hypothesizing significant sex differences, we aimed at studying the expression of inflammatory and remodeling genes in cardiomyocytes (CMs) isolated from the LV septum of AS patients ( n = 34; 50% men; 67.5 ± 9.6 years old) undergoing aortic valve replacement. Echocardiography was performed 1 week before surgery and 20.06 ± 9.7 days after surgery. Ethics committee approval and patient consent were obtained. There was no significant difference between men and women in age, body mass index, systolic and diastolic blood pressure, co-morbidities and medication. Posterior wall thickness ( P = 0.02), LV end diastolic diameter ( P = 0.007) and mass index ( P = 0.03) were higher in men than women. Preoperative ejection fraction (EF) was significantly lower in men than women ( P = 0.01). Postoperative EF levels improved in men reaching those of women. Compared to female CMs, male CMs had significantly higher levels of CTGF ( P = 0.03) and NFKB1 ( P = 0.01), as well as ACTC1 ( P = 0.03), GATA4 ( P = 0.03), GJA1 ( P = 0.03), MYH6 ( P = 0.02), MYL4 ( P = 0.03), NPPA ( P = 0.03) and NPPB ( P = 0.05). We found a negative association between gene expression and postoperative EF in men only for GATA4 ( r = -0.77, P = 0.01), GJA1 ( r = -0.69, P = 0.03), MYH6 ( r = -0.69, P = 0.04), MYH7 ( r = -0.82, P = 0.008), MYL4 ( r = -0.71, P = 0.03), NPPA ( r = -0.9, P = 0.001) and NPPB ( r = -0.79, P = 0.01). In end-stage HF, the levels of the chemokine receptor CXCR4 were higher ( P = 0.04) in LV samples of female ( n = 5) vs. male ( n = 4) patients. Collectively, in PO and HF, the expression of inflammatory and remodeling genes is regulated in a sex-specific manner, which may contribute to the mechanisms underlying sex differences in disease progression and outcome.
Integrating family caregiver identification into a gynecologic oncology practice: An ASCO quality training program project.
Authors: Grace Campbell, Michelle M. Boisen, Lauren Hand, Nora Lersch, Barbara Suchonic, Heidi AS Donovan
Journal: Journal of Clinical Oncology (2019)

177 Background: Family caregivers (CGs) in gynecologic (gyn) cancer are essential members of the care team, but no formal systems exist to provide CGs with information and support. A needs assessment of family caregivers (CGs) in our clinic found 50% of CGs report &gt; 9 distressing unmet needs, but chart reviews found only 19% of patients had a documented CG--the first step in mitigating unmet needs. Our ASCO QTP-supported project aim was to identify (ID) and document primary CGs for 85% of patients within 2 clinic visits of a gyn cancer diagnosis. Methods: An Interprofessional team reviewed baseline data, defined the problem and project aim, created process maps, and identified root causes of poor CG documentation. After securing stakeholder buy-in we implemented eight successive PDSA cycles to intervene on root causes. Biweekly team meetings were held to study results, troubleshoot, and plan each PDSA cycle. Primary outcome was the percentage of patients with a CG documented. Results: Root causes of poor CG ID were 1) no protocol for IDing CGs, 2) no designated EHR field for CGs, 3) no designated staff to “own” CG ID, and 4) lack of CG awareness of available support in clinic. Interventions to prepare for project launch (PDSA 1) included protocol development, staff training, spirit activities, and selection of staff ‘champions’. In PDSA 2 CGs were ID’d for 25.3% of all patients in the clinic. By PDSA 4, CG ID dropped to a low of 12.5%. Major changes to PDSA 5 sought to reduce staff burden by narrowing focus to newly diagnosed patients, with an increase in CG ID to 56% of new patients. PDSA cycles 6-8 focused on increasing process efficiency while broadening CG ID to other times of high CG stress (e.g. recurrence; inpatient stays); CG ID rate stabilized at 57-60% over the last 6 weeks. In total, 288 primary CGs were documented. Conclusions: Proportion of CGs ID’d increased initially and then again after PDSA 4 as process efficiency improved. Despite falling short of our benchmark, CG ID more than doubled and we are planning further PDSA cycles to continue this momentum. Our results demonstrate systematic CG ID is feasible in a high volume Gyn Onc clinc and sets the stage for CG assessment and intervention.
Myc and the Warburg Effect
Authors: Stefano Casola, Gabriele Varano, Laura Perucho, Marianna Ossorio, Federica Zanardi, Martina Sormani, Valentina Petrocelli, Christin Zasada, Stefan Kempa, Klaus Rajewsky, Maurilio Ponzoni, Fabio Facchetti
Journal: Blood (2018)
Pilot Trial AMC-063: Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma
Authors: Erin G. Reid, Adrienne Suazo, Shelly Y. Lensing, Dirk P. Dittmer, Richard F. Ambinder, Frank Maldarelli, Robert J. Gorelick, David Aboulafia, Ronald Mitsuyasu, Mark A. Dickson, William Wachsman
Journal: Clinical Cancer Research (2019)

AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV. The primary objective was determining the MTD of bortezomib in AIDS-Kaposi sarcoma. Secondary objectives included estimating the impact of bortezomib on Kaposi sarcoma response, KSHV plasma DNA copy number (PDCN), and HIV viral loads (VL).
Towards a Reference Human Platelet Transcriptome: Evaluation Of Inter-Individual Correlations and Its Relationship With a Platelet Proteome
Authors: Eric R. Londin, Eleftheria Hatzimichael, Phillipe Loher, Leonard C. Edelstein, Chad Shaw, Kathleen Delgrosso, Paolo M. Fortina, Paul F Bray, Steven E. McKenzie, Isidore Rigoutsos
Journal: Blood (2013)
Antigen-driven selection of antibodies against SSA, SSB and the centromere ‘complex’, including a novel antigen, MIS12 complex, in human salivary glands
Authors: Masaru Takeshita, Katsuya Suzuki, Yukari Kaneda, Humitsugu Yamane, Kazuhiro Ikeura, Hidekazu Sato, Shin Kato, Kazuyuki Tsunoda, Hisashi Arase, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Recent evidences have revealed that anti-SSA/SSB antibodies, the major autoantibodies in Sjögren's syndrome (SS), are produced in salivary glands. This study aims to clarify overall of autoantibody production at lesion site, including anti-centromere antibody (ACA)-positive SS. Methods Antibodies of antibody-secreting cells in human salivary glands were produced as recombinant antibodies. The reactivity of these antibodies and their revertants were investigated by ELISA and newly developed antigen-binding beads assay, which can detect conformational epitopes. The target of uncharacterised antibodies was identified by immunoprecipitation and mass spectrometry. Autoantibody-secreting cells in salivary gland tissue were identified by immunohistochemistry using green fluorescent protein-autoantigen fusion proteins. Results A total of 256 lesion antibodies were generated, and 69 autoantibodies including 24 ACAs were identified among them. Beads assay could detect more autoantibodies than ELISA, suggesting autoantibodies target to antigens with native conformation. After somatic hypermutations were reverted, autoantibodies drastically decreased antigen reactivity. We showed that MIS12 complex, a novel target of ACA, and CENP-C are major targets of ACA produced in salivary glands by examining cloned antibodies and immunohistochemistry, whereas few anti-CENP-B antibodies were detected. The target profiling of serum ACA from 269 patients with SS, systemic sclerosis (SSc), primary biliary cirrhosis (PBC) and healthy controls revealed that ACA-positive patients have antibodies against various sites of centromere complex regardless of disease. Conclusion We showed direct evidences of antigen-driven maturation of anti-SSA/SSB antibody and ACA in SS lesion. ACA recognises centromere ‘complex’ rather than individual protein, and this feature is common among patients with SS, SSc and PBC.
Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model
Authors: Tien-Phat V. Huynh, Chao Wang, Ainsley C. Tran, G. Travis Tabor, Thomas E. Mahan, Caroline M. Francis, Mary Beth Finn, Rebecca Spellman, Melissa Manis, Rudolph E. Tanzi, Jason D. Ulrich, David M. Holtzman
Journal: Molecular Neurodegeneration (2019)

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown.We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition.As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected.Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.
Pseudoprogression (PsP) in Patients with Peripheral T-Cell Lymphoma (PTCL) Treated with the Novel Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2
Authors: Andrei R. Shustov, Amitkumar Mehta, Lubomir Sokol, Luis A. Carvajal, Vincent Guerlavais, Manoj Samant, Narayana Narasimhan, David Sutton, D. Allen Annis, Dawn Pinchasik, Manuel Aivado, Ronald Korn
Journal: Blood (2018)