tbuckley/cabot-search huggingface dataset:
Final Results From a Phase II Trial with the First in Class Recombinant Polyclonal Antibody Product Rozrolimupab in Primary Immune Thrombocytopenia
Authors: Tadeusz Robak, Jacek Trelinski, Mario von Depka Prondzinski, Aristoteles Giagounidis, Chantal Doyen, Ann Janssens, Mayte Álvarez Román, Javier Loscertales Pueyo, Isidro Jarque Ramos, Javier Loscertales, Gloria Pérez Rus, Andrzej Hellmann, Wieslaw Wiktor-Jedrzejczak, Kazimierz Kuliczkowski, Lana Golubovic, Dusica Celeketic, Andrei Cucuianu, Emanuil Gheorghita, Lazaroiu Mihaela, Dina Attias, Ofer Shpilberg, Elena Karyagina, Kateryna Vilchevska, Kalinina Svetlana, Nichola Cooper, Kate Talks, Mukyaprana Prabhu, Sripada V.S.S Prasad, T. P. Raghava Bharadwaj, Mimi Folden Flensburg, Jorgen Petersen, Jerzy Windyga
Journal: Blood (2011)
Abstract 235: A Micropeptide Regulator of Voltage-gated Potassium Channels Controls Cardiac Rhythm
Authors: Kelly M Anderson, Xiaorong Parks, Pornthida Poosala, Sean Lindley, Coeli Lopes, Douglas M Anderson
Journal: Circulation Research (2019)

Voltage-gated potassium (K + ) channels (VGKCs) are essential regulators of the cardiac action potential and are required to maintain normal heart rhythm and contractility. Voltage-dependent activation, conductance and membrane trafficking of K + channels are tightly controlled by a family of single transmembrane regulatory cofactors (KCNE1-5), which co-assemble with pore forming K + channels in cell membranes. Human mutations in voltage-gated K + channels and their regulatory subunits are associated with Long QT syndrome (LQTS), a condition in which the repolarization of the heart is delayed and can lead to arrhythmias, syncope and sudden death. Here we identify a cardiac-enriched transmembrane micropeptide encoded by a small open reading frame, which we named KCNEmini, due to its sequence and structural homology with members of the KCNE family of VGKC regulators. We show that KCNEmini directly binds to and co-localizes with VGKCs in the plasma membrane and functions as a novel regulator of K + channel kinetics. Disruption of KCNEmini in mice resulted in QT interval prolongation and cardiac dysfunction. These studies shed light on a previously unrecognized regulator of K + handling in the heart, which may be an important future therapeutic target for the early diagnosis and treatment of human lethal cardiac arrhythmias.
Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Relapsed or Refractory Follicular Lymphoma.
Authors: Michael B. Maris, Brenda M. Sandmaier, Barry Storer, Edward Agura, James Wade, Richard T. Maziarz, Stephen Forman, Judy Shizuru, Thomas Chauncey, Christoph Kahl, Amelia A. Langston, Dietger Niederwieser, Rainer Storb, David G. Maloney
Journal: Blood (2005)
Sequential Treatment with Rigosertib Followed By Azacitidine Maximizes the Effects on the Interferon Signaling Pathway in Hematopoietic Cells in Myelodysplastic Syndrome (MDS)
Authors: Richa Rai, Stella Melana, Shyamala C. Navada, Rosalie Odchimar-Reissig, Erin P. Demakos, E. Premkumar Reddy, Lewis R. Silverman
Journal: Blood (2018)
Efficacy and Tolerability of Daratumumab in Heavily Pretreated AL Amyloidosis: A Systematic Review
Authors: Muhammad Aadil Rahman, Ali Younas Khan, Awais Ijaz, Muhammad Junaid Tariq, Muhammad Usman, Muhammad Jahanzeb Khalil, Muhammad Asad Fraz, Faiza Jamil, Abdul Rafae, Mustafa Nadeem Malik, Insija Ilyas Selene, Jemin Aby Jose, Ahmad Safdar, Ali McBride, Faiz Anwer
Journal: Blood (2018)
A pilot study of a comprehensive financial navigation program in cancer patients and caregivers.
Authors: Jordan Steelquist, Kate Watabayashi, Karen Overstreet, Tony Leahy, Alan James Balch, Erin Bradshaw, Kathleen D. Gallagher, Rebecca Lobb, Laura Lavell, Hannah M. Linden, Scott David Ramsey, Veena Shankaran
Journal: Journal of Clinical Oncology (2019)

174 Background: Few studies have reported on interventions to alleviate financial toxicity (FT) in cancer patients (pts) and informal caregivers (cgs). We developed a financial navigation program in collaboration with Consumer Education and Training Services (CENTS), Patient Advocate Foundation (PAF), and Family Reach Foundation (FRF), to offer financial coaching, insurance navigation, and assistance with unpaid non-medical bills. We conducted a pilot study to assess feasibility of enrolling cgs with pts and to describe the assistance provided. Methods: Pts with any stage solid tumor actively receiving treatment (tx) at the Seattle Cancer Care Alliance were asked to identify a cg who could participate. Pts or pt/cg dyads received an online financial education course and monthly contact for 6 months (mo) with CENTS and PAF. Subjects were referred to FRF for assistance in paying non-medical bills. We describe pt and cg characteristics, and assistance provided by the program. Results: Of 54 pts approached, 30 (median age 59.5, 61% white, 97% stage III/IV disease) were consented. Most pts (53%) had income ≤ $25,000, and all were insured (48% commercial, 28% Medicare, 21% Medicaid). 18 cgs (67% spouse/partner) were consented. At consent, 55% of pts reported debt in the prior 3 mo. Mean score using the COST PRO FT measure (range 0-44, lower score = higher FT) was 17.4 at baseline. After pts’ physical health, out-of-pocket costs were the most stressful aspects of tx for cgs. Cgs with high financial burden from caregiving more often reported taking on new debt, dipping into retirement accounts, or changing their jobs or hours. CENTS coaches assisted with budgeting, updating wills, and employment rights counsel. PAF case managers assisted with financial assistance for drugs, cost of living (e.g. transportation), disability applications, and secured $6,950 in debt relief. FRF dispersed $4,133, primarily for housing expenses. Conclusions: Implementing a financial navigation program that engages both pts and cgs is feasible. This lower income, financially stressed population received $11,000 in financial assistance. Future work will focus on evaluating the impact of this program on financial and psychosocial outcomes in pts and cgs.
Reduced-Dosage Of Three Drugs Combination Of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Is Suitable For Elderly Frail Patients With Multiple Myeloma
Authors: Hideo Yagi, Ryosuke Fujiwara, Keigo Sano, Keiko Yamazaki, Hitoshi Hanamoto, Kazuo Tsubaki
Journal: Blood (2013)
Abstract 137: The Role of TNNI3K in Adult Mammalian Heart Regeneration
Authors: Peiheng Gan
Journal: Circulation Research (2019)

Adult mammalian heart regenerative capacity is thought to be extremely limited. All fetal and newborn mouse cardiomyocytes are mononuclear and diploid, and most become polyploid during the first postnatal week. Our lab showed that mononucleated diploid cardiomyocytes (MNDCMs) retain regenerative capacity, and that the percentage of this subpopulation in the adult mouse heart is variable across strains and correlated with the regeneration capacity of mouse heart. We reported cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific gene, to be a key regulator of MNDCM frequency. Nonetheless, a detailed mechanism of how Tnni3k regulates MNDCM frequency is still lacking. TNNI3K is a MAPKKK by sequence, but no change in MAPK signaling pathways (p38, ERK1/2, JNK) occurs in Tnni3k knock-out mice. To distinguish whether Tnni3k plays a kinase role, we created a mouse line harboring the kinase-dead mutant of Tnni3k (Tnni3k-k489r) , which recapitulates the high MNCM frequency of Tnni3k knock-out mice. Engineered Tnni3k truncations in mice yield no stable protein, and these mice also show a high MNCM frequency. Interestingly, we found that naked mole-rat ( Heterocephalus glaber ) has a Tnni3k truncation mutation, doesn't express a stable TNNI3K protein, and has a high level of MNCM frequency and cardiomyocyte polyploidy. These results indicate that Tnni3k may influence cardiomyocyte karyokinesis and cytokinesis across mammalian species. We also found that several human TNNI3K polymorphisms compromise kinase activity, which may influence variation in MNDCM frequency and heart regenerative capacity in the human population.
The impact of depression in cancer patients on healthcare utilization.
Authors: Star Ye, Aidan Gilbert, Chao-Hui Huang, Gabrielle Betty Rocque
Journal: Journal of Clinical Oncology (2019)

243 Background: The Oncology Care Model (OCM) has set several initiatives to improve payment and care delivery in the Medicare patient population, including screening for depression in cancer patients. We evaluated the prevalence of depression in OCM patients and the relationship between depression and healthcare utilization. Methods: This cross-sectional study used patient-reported outcome (PRO) surveys administered in the outpatient setting as part of OCM at the University of Alabama at Birmingham (UAB). Depression scores and Eastern Cooperative Oncology Group performance status were obtained from PRO surveys. Moderate to severe depression was defined as a score ≥10 on the Patient Health Questionnaire 2/9 (PHQ-2/9). Sex, marital status, phase of care, race, disease aggressiveness (stage, progression, cancer type), number of emergency department (ED) visits and inpatient admissions within a 3-month period from survey completion were abstracted from the electronic health record. The relationship between depression and hospital visits was assessed using rate ratios and 95% confidence limits from Poisson regression models adjusting for clinical and demographic characteristics. Results: Of 856 patients surveyed, 68% of patients were female, and 27% of patients were non-Caucasian. Notably, almost 14% of patients had moderate to severe depression (PHQ-2/9≥10). The cancer-specific prevalence of at least moderate depression was 2% in breast, 1% in gastrointestinal, 2% in genitourinary, 5% in gynecologic, and 2% in hematologic cancers. In adjusted models, the inpatient admission and ED visit rate in the 3 months following PRO survey completion did not differ by depression category (RR: 1.22; CI: 0.93-1.61). Conclusions: Over 13% of cancer patients report clinically significant depression during routine screening, which highlights the continued need for outpatient counseling and behavioral services. Although rates of inpatient admissions and ED visits were not impacted by the presence of depression, further analysis is needed to evaluate the impact of treating depression on healthcare utilization over time.
Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease
Authors: Hang Liu, Cory A. Perugino, Musie Ghebremichael, Zachary S. Wallace, Sydney B. Montesi, John H. Stone, Shiv Pillai
Journal: Arthritis & Rheumatology (2019)

Objective Four autoantigens have been described recently in IgG4‐related disease (IgG4‐ RD ): prohibitin, annexin A11, laminin 511‐E8, and galectin‐3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4‐ RD . Methods Autoantibody responses against prohibitin, annexin A11, and laminin 511‐E8 were measured among a clinically diverse cohort of IgG4‐ RD patients (n = 100) using enzyme‐linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution. Results The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511‐E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti–galectin‐3 antibody responses, with 25 patients (29%) having IgG4 anti–galectin‐3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C‐reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement. Conclusion Antibodies against prohibitin, annexin A11, and laminin 511‐E8 were found in only a small portion of patients with IgG4‐ RD . A subset of IgG4‐ RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4‐ RD was associated with more severe disease.
Abstract 372: CRISPR-based Gene Activation for Transcriptional Reprograming of Mammalian Cardiomyocytes
Authors: Eric Schoger, Kelli J Carroll, John McAnally, Wei Tan, Norman Liaw, Lavanya M Iyer, Claudia Noack, Wolfram H Zimmermann, Rhonda Bassel-Duby, Laura C Zelarayan
Journal: Circulation Research (2019)

Cardiac remodelling is accompanied by silencing of genes necessary for cardiac homeostasis including Krüppel-like factor 15 ( Klf15 ), an anti-hypertrophic factor. Due to a lack of tools for gene activation, we aim to adapt a CRISPR-based approach for gene expression control for mammalian cardiomyocytes. We generated a transgenic mouse model (TG) expressing an enzymatically inactive, gRNA-programmable Cas9 protein under Myh6 promoter control fused to transcriptional activators (VPR) to drive gene expression. As a proof of concept, we systemically injected mice at postnatal day P4 with AAV9 carrying a triple gRNA expression cassette containing gRNAs targeted to the Klf15 promoter region. Significant Klf15 activation was observed at P10 up to 10-fold compared to controls in three independent TG lines. This Klf15 activation was sufficient to drive target gene expression of Aldh2 and Adhfe1 (controls = WT + saline, WT + AAV9, TG + saline, n ≥ 3 per group, ANOVA and Bonferroni correction). Importantly, at the neonatal stage, the Klf15 promoter is characterized by low H3K27ac presence indicating that endogenous gene activation can enhance transcription from an epigenetically inactive locus. We demonstrated that CRISPR/Cas9 mediated loss of KLF15 expression results in impaired contractile function in a 3D model of engineering heart muscle, similar to the Klf15 -/- mouse heart phenotype. Encouraged by the evolutionary conserved KLF15 -mediated mechanisms, we aimed to generate a human induced pluripotent stem cells, which constitutively express dCas9VPR (hIPSC-dCas9VPR) for gene activation in hIPSC-derived cardiomyocytes to complement the in vivo findings upon disease. We targeted the transgene integration to the AAVS1 site by CRISPR gene editing, confirmed correct integration by PCR followed by sequencing and hIPSC-dCas9VPR were successfully differentiated into beating cardiomyocytes. To this end, we have tested gRNAs targeted to the KLF15 promoter region in HEK293 cells and observed significant KLF15 activation of up to 5.5-fold (n = 3, ANOVA and Bonferroni correction). In summary, we report transgenic mammalian tools for endogenous gene (re-) activation purposes to identify potential therapeutic targets for preventing heart failure progression.
Abstract 432: Rapamycin Can Ameliorate Antiretroviral Drug Mediated Cardiotoxicity
Authors: Spoorthi Alapati, Manish K Gupta
Journal: Circulation Research (2019)

Introduction: In current therapy, due to application of combined antiretroviral drugs (cART), HIV related mortality significantly reduced, and AIDS became a chronic disease. Although, cART treatment increases life expectancy of AIDS patients, growing AIDS population suffer due to several organ diseases and heart failure is one of the leading causes of comorbidity and mortality. Hypothesis: We tested the hypothesis that application of cART induces cardiotoxicity through inhibition of cellular protein quality control (PQC) and dysregulation of mitochondrial function. Method and results: Cellular protein quality control was analyzed using cardiac tissue samples from HIV+ patients treated with cART and healthy donors. Western blot shows that there is upregulation of autophagy marker protein LC3 II in ART treated heart compared to healthy donor. Additionally, we found that there are abnormalities in the mitochondrial oxidative phosphorylation complexes (OXOPHOS) in the ART treated patient’s heart, compared to healthy donor heart. Using neonatal rat ventricular cardiomyocytes, we tested the role of ART in cellular PQC and mitochondrial function. Our data shows that cardiomyocytes treated with the cART (Ritonavir+ Atazanavir+ abacavir+ Lamivudine) have increased expression of autophagy proteins LC3 II and P62 and higher level of pELF2α. These suggest that, the cardiomyocytes treated with ART have dysregulation of autophagy and increased ER stress. Further, we found that cardiomyocytes treated with cART have high level of mitochondrial superoxide and decreased mitochondrial membrane potential. Mitochondrial function detected in whole cells shows that in ART treated cardiomyocytes there is significantly low OCR compared to control cells. Interestingly, application of pharmacological drug rapamycin can improve the cellular PQC and mitochondrial function in ART treated cells. Conclusion: ART treatment induces cardiotoxicity through inhibition of cellular PQC and dysregulation of mitochondrial function and rapamycin might be important therapeutic drug to reduce the ART mediated cardiotoxicity.
Transcription Activator-Like Effector Nucleases (TALENs)-Mediated Deletion Of MIR17HG In Burkitt Lymphoma Cells Decreases mTOR Pathway Activity and Increases Chemosensitivity
Authors: Faye Pais, Sanghoon Lee, Vladimir Rodic, Matthew J. Barth, Mitchell S. Cairo, Michelle L. Hermiston, Rodney R. Miles
Journal: Blood (2013)
ICU utilization among oncology patients at the end of life.
Authors: Jennifer Hong, Christine Kurian, Jared Minetola, Valerie Pracilio Csik, Adam Binder
Journal: Journal of Clinical Oncology (2019)

118 Background: Patients with advanced cancer have high rates of hospitalizations as a result of their oncologic care. Furthermore, these patients receive aggressive end of life care despite evidence that aggressive end of life care does not improves quality of life or outcomes for patients and is associated with worse bereavement adjustment for caregivers. The American Society of Clinical Oncology has endorsed several indicators of aggressive end of life care, but most striking is intensive care unit (ICU) admission within 30 days before death. Methods: Adult oncology patients who died within 30 days of hospitalization and/or admitted to the ICU from 10/2018-3/2019 at an academic medical center were evaluated. The cohort was identified using ICD-10 codes, EMR systems support, and manual chart review. Patient demographic data, cancer type, stage, line of therapy, code status, advanced care plan, prior admissions as well as other clinical characteristics were collected. Results: In total, 180 patients were included for analysis; 106 of which were admitted to the ICU. Of patients admitted to the ICU, 58 patients died (54.7%). Mean ECOG performance status was 1.24. Average number of admissions 3 and 6 months prior to death was 0.71 and 1.26. Thirty six percent of patients were on first or second-line chemotherapy. 41.37% of patients who died in the ICU had prolonged length of stay (&gt;1 week). Only 34.48% were known to palliative care prior to admission and 12.06% of patients had advanced care plans in place at time of hospitalization. Palliative care was consulted on 32.75% of patients who died in the ICU. Ninety Three percent had their code status changed prior to death. Conclusions: Despite established recommendations to support otherwise, at our institution there continues to be high utilization of ICU care near the end of life. Previous admissions and ECOG status are poor predictors of death in this cohort. The majority of patients had relapsed and refractory disease. There was a low rate of advanced care planning or palliative care involvement prior to the patient’s hospitalization. Further interventions are underway to improve end of life planning in order to improve our quality of care.
Implementing individualized care plans in high-risk oncology patients: A team-based model to increase hospice utilization.
Authors: Sarah Lee, Benjamin Switzer, Mohammad Khan, Pramod Pinnamaneni, Joseph Hooley, Girish Chandra Kunapareddy, Ruth Lagman, Christa Poole, Alberto J. Montero
Journal: Journal of Clinical Oncology (2019)

64 Background: In the era of increasing therapeutic options and complexity of disease, some cancer patients (pts) continue aggressive treatment even within days of death. Previous studies report 30-66% of pts do not receive hospice or palliative services in the last month of life and many are enrolled in hospice &lt; 3 days before death. Quality measures are endorsed by ASCO, National Quality Forum, and Oncology Care Model to increase hospice utilization. It is shown that pts enrolled in hospice have increased survival time with reduced in-hospital resources. These benefits increase the longer pts are in hospice. We hypothesize early identification of high risk pts by a multidisciplinary group and formulation of a care plan will prompt early discussion for hospice eligibility, increasing referrals to hospice and the number of days spent in hospice. Methods: As reported (ASCO 2018, Abst 6547), an Interdisciplinary Care Team (ICT) was created with palliative medicine and oncology physicians, nurses, and social workers. Twice monthly pts with high utilization over a 60-day period were identified. Care plans (CP) were created using a team based approach with parallel input from outpatient teams. CP was communicated back to the primary team. Results: 112 pts were discussed over 24 months; 39 pts died with a solid tumor malignancy and this was our study cohort. 85% pts (33/39) were referred to or had a hospice discussion and 82% pts (27/33) enrolled. 6 pts declined and 6 acutely died. Of the 27 pts that entered hospice 78% (21/27) were enrolled &gt; 3 days and 22 % (6/27) &lt; 3 days. Average number days in hospice was 19.7 (median 11) for all who entered hospice. In the subgroup that were enrolled for &gt; 3 days, average number days was 25 (median 21). 62% pts (17/27) entered hospice within 60 days of ICT meeting and CP. Conclusions: Early identification of high-utilizing cancer patients along with review by ICT may correlate with early recognition of hospice eligibility, enrollment, and therefore greater number days spent in hospice. This increases hospice utilization allowing patients and families to experience the full benefit of hospice-directed care. Further interventions should be explored in optimizing transitions of care.