tbuckley/cabot-search huggingface dataset:
Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone: A rationale for increasing drug exposure in castration-resistant prostate cancer.
Authors: Nima Sharifi, Rui Li, Kristen Evaul, Kamalesh Sharma, Richard J Auchus
Journal: Journal of Clinical Oncology (2012)

4645 Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ 5 -structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [ 3 H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC 50 of &lt; 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.
Immunoglobulin G fragment C receptor polymorphisms and response to trastuzumab-based treatment in patients with HER-2/neu-positive metastatic breast cancer
Authors: A. Musolino, N. Naldi, B. Bortesi, M. Capelletti, D. Pezzuolo, G. Missale, D. Laccabue, R. Camisa, V. Franciosi, A. Ardizzoni
Journal: Journal of Clinical Oncology (2006)

13090 Background: A potential mechanism of action of the humanized anti-HER-2/neu monoclonal antibody Trastuzumab involves antibody-dependent cellular cytotoxicity (ADCC) with the activation of immune effector cells via their immunoglobulin G fragment C receptors (FcγRs). Trastuzumab has been shown to engage both activation (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors on myeloid cells and several FcγR polymorphisms have been identified that may affect the antibody-dependent cytotoxicity of natural killer cells and macrophages. Methods: Forty consecutive HER-2/neu-positive (FISH+) metastatic breast cancer patients receiving a trastuzumab-based treatment (combined with paclitaxel for the majority) were examined for the FcγRIIIa 158 valine (V)/phenylalanine (F), FcγRIIa 131 histidine (H)/arginine (R), and FcγRIIb 232 isoleucine (I)/threonine (T) polymorphisms. A PCR-RFLP based assay using genomic DNA was performed for FcγRIIIa and FcγRIIa genotyping, while PCR-SSCP methods using complementary DNA were utilized for FcγRIIb. Patients’ peripheral blood mononuclear cells were drawn before treatment initiation and their trastuzumab-mediated killing function was measured by 51 Cr release using a HER-2/neu-expressing human breast cancer cell line as a target. The results were then correlated with clinical outcome of these patients. Results: Median age was 60 years (range 26–83 years). Thirty-six (90%) patients received a trastuzumab-based treatment as first-line therapy. The overall clinical benefit rate (CR+PR+SD) was 65% (95% Confidence Interval: 62–71%), including 8 (20%) complete and 11 (27.5%) partial responses. Median survival was 22.3 mo with a median PFS of 7 mo. Trastuzumab-based treatment was well tolerated and no changes in cardiac function were observed. Conclusions: This study evaluates for the first time the potential role of FcγR polymorphisms in predicting response to trastuzumab-based treatment. Results according to this study purpose will be presented at the meeting. No significant financial relationships to disclose.
Abstract 13064: Cell Functionality of Administered Autologous Bone Marrow-Derived Mononuclear Cells Predicts 5-Year Clinical Outcome in Patients with Acute Myocardial Infarction - Results of The REPAIR-AMI Trial
Authors: Birgit Assmus, Volker Schächinger, Sandra Erbs, Albrecht Elsässer, Werner Haberbosch, Rainer Hambrecht, Daniel Sedding, Jiangtao Yu, Roberto Corti, Detlef G Mathey, Christian Hamm, Tim Súselbeck, Christine Barth, David M Leistner, Torsten Tonn, Stefanie Dimmeler, Andreas M Zeiher
Journal: Circulation (2012)

Background: In the REPAIR-AMI trial, intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) was associated with a significantly greater recovery of contractile fu...
Clonal Evolution of Therapy-Related Myeloid Neoplasm Analyzed Sequentially By Targeted Deep Sequencing Using Bone Marrow Cells
Authors: Katagiri Seiichiro, Kenko Azuma, Yuu Saitoh, Seiichiro Yoshizawa, Daigo Akahane, Hiroaki Fujimoto, Yoshikazu Ito, Tomohiro Umezu, Junko.H Ohyashiki, Kazuma Ohyashiki
Journal: Blood (2018)
Pathogenic Relevance of Germ Line TET2 Alterations
Authors: Cassandra M. Hirsch, Aziz Nazha, Kassy E Kneen, Manja Meggendorfer, Bartlomiej P Przychodzen, Niroshan Nadarajah, Hetty E. Carraway, Mikkael A. Sekeres, Torsten Haferlach, Thomas LaFramboise, Tomas Radivoyevitch, Jaroslaw P. Maciejewski
Journal: Blood (2016)
Synthetic Lethal Interactions for Kinase Deficiencies to DNA Damage Chemotherapeutics
Authors: Lydia Robinson-Garcia, Joana Ferreira da Silva, Joanna I. Loizou
Journal: Cancer Research (2019)

Kinases are signaling enzymes that regulate diverse cellular processes. As such, they are frequently mutated in cancer and therefore represent important targets for drug discovery. However, until recently, systematic approaches to identify vulnerabilities and resistances of kinases to DNA-damaging chemotherapeutics have not been possible, partially due to the lack of appropriate technologies. With the advent of CRISPR-Cas9, a comprehensive study has investigated the cellular survival of more than 300 kinase-deficient isogenic cell lines to a diverse panel of DNA-damaging agents, enriched for chemotherapeutics. Here, we discuss how this approach has allowed for the rational development of combination therapies that are aimed at using synthetic lethal interactions between kinase deficiencies and DNA-damaging agents that are used as chemotherapeutics.
Targeting protease nexin-1, a natural anticoagulant serpin, to control bleeding and improve hemostasis in hemophilia
Authors: Karen Aymonnier, Charlotte Kawecki, Laurence Venisse, Yacine Boulaftali, Olivier D. Christophe, Peter J. Lenting, Véronique Arocas, Emmanuelle de Raucourt, Cécile V. Denis, Marie-Christine Bouton
Journal: Blood (2019)
Acute myeloid leukemia: Comparison of epidemiology and treatment outcomes between insured and uninsured patients.
Authors: Samer Ali Srour, Michael Machiorlatti, Usman Bhutta, Namali Pierson, Mohamad Ali Cherry, Shubham Pant, David Thompson, Carla Kurkjian
Journal: Journal of Clinical Oncology (2012)

e17012 Background: The overall prognosis for most acute myeloid leukemia (AML) patients remains poor. The majority of adult patients (pts) with AML will ultimately need allogeneic stem cell transplant (allo-SCT). Limited data is available comparing epidemiology and treatment outcomes between uninsured and insured pts with AML. We describe a retrospective analysis of adult pts with AML treated at our institution. Methods: From January 2000 to June 2011 we identified 239 pts with AML, of which 185 met inclusion criteria. Patients were classified as having private insurance, public insurance (Medicaid and Medicare), or no insurance. Primary outcomes were overall survival at follow up (OS), complete remission (CR), and percent of pts receiving allo-SCT. Kaplan-Meier analysis was used to estimate survival rates. Results: Of the 185 pts studied, 146 (81%) were white, 16 (9%) African-American and 11 (6%) were Native American. The median age at diagnosis was 49 years. 75 pts had private insurance at the time of diagnosis, 70 had public insurance, and 33 were uninsured. Of those receiving allo-SCT (n=60; 38 male) 48% had private insurance, 30% public, and 22% were uninsured. Whether a patient underwent allo-SCT did not differ according to insurance source (p=0.2189) nor to status at follow-up (p= 0.6480). The proportion of patients achieving CR was higher among those undergoing allo-SCT (p=0.0002). Median OS was 920 days for those who underwent allo-SCT and 192 days for those who did not (p&lt; 0.0001). Median OS did not differ by insurance type (p = 0.1454). The proportion of patients achieving CR did not differ by insurance type (p=0.2665) (66.7% of those with private, 62.7% of those with public, and 78.8% of those with no insurance). Conclusions: For the population referred to our institution, a tertiary referral center for the state, there were no differences in treatment outcomes or in the percent of pts receiving allo-SCT when pts were stratified according to insurance source. Further analysis of this dataset will identify the impact of pretreatment variables stratified by type of insurance.
Quad Rooms at the VA
Authors: Emily Dollar
Journal: JAMA (2019)

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A phase II trial of novel anthracycline amrubicin in advanced soft tissue sarcoma.
Authors: Launce Gouw, R Lor Randall, Kevin Jones, Sant P. Chawla, Sunil Sharma
Journal: Journal of Clinical Oncology (2013)

10587 Background: Amrubicin is a 9-aminoanthracycline with significantly less cardiotoxicity than doxorubicin, a current standard against soft tissue sarcoma, and may represent an appealing alternative first line therapy. We report findings in a phase II study investigating tolerability and efficacy of amrubicin in patients with advanced STS. Methods: We enrolled adult patients in a single-arm open label study with locally advanced or metastatic soft tissue sarcoma, no prior systemic treatment, measurable disease, an ECOG PS &lt;2, and adequate organ function. We administered amrubicin (40 mg/m 2 IV over 10’) on D#1-3 of a 21D cycle with GCSF support. Six cycles were planned with continuation at clinician discretion. We used RECIST 1.1 to radiologically assess response to therapy. Toxicities were assessed using CTCAE 4.0. The primary objective was overall response rate (CR+PR), and clinical benefit (CR+PR+SD). We employed a 2- stage design, with 15 patients treated in the first stage. Error rates were α=5% for accepting a poor regimen and β=10% for rejecting a promising regimen, with planned enrollment of 30 patients through the second stage if activity was observed. Results: 15 of 15 planned patients enrolled in the first stage of this phase II clinical trial; 10 males and 5 females, with median age 59 (range 30-73). Of the 13 evaluable patients, at 6 cycles 3 patients achieved a PR, with best response of 78% reduction of target lesions; 4 patients demonstrated minor response/stable disease (SD), ranging from 11-28% reduction of target lesions, and 4 patients had minor progression/SD (less than 20% progression). Two patients progressed &gt;20%. Clinical benefit is currently 85.7% (12/14). Amrubicin has been well tolerated, with primarily grade I and II AEs. A single dose adjustment has occurred but no treatment delays. No cardiac complications, ECG or significant echocardiogram changes have been noted. Conclusions: Amrubicin is a novel anthracycline with encouraging activity against STS and an extremely well tolerated side effect profile. Further study of amrubicin in STS is warranted. With minor treatment-related morbidity, amrubicin would also be a good candidate for combination therapy with other standard or experimental therapeutics. Clinical trial information: NCT01259375.
Correlation of biologic recurrence after radical prostatectomy and a positive surgical margin with the predominant Gleason pattern on the specimen.
Authors: Yann Neuzillet, Audrey Pichon, Thierry Lebret, Jean-Pierre Raynaud, Henry Botto
Journal: Journal of Clinical Oncology (2012)

e15145 Background: The risk of biological recurrence following radical prostatectomy depends, among other factors, on surgical margins status. This study compared the prognosis of prostate cancer patients with positive surgical margins according to the predominant Gleason pattern (PrdGP). Methods: Prospective study of 247 consecutive prostate cancer patients, who underwent radical prostatectomy (RP) from 3/2007 to 12/2009, and were followed up in our institution. Pathological stage and Gleason score were determined in RP specimens by a pathological reference. Biological recurrence was defined as two consecutive values of PSA &gt; 0.2 ng/mL. The median overall follow-up was 33 months (2 to 54 months). Biological recurrence-free survival was estimated and compared using Kaplan-Meier plots and Log rank test. A multivariate logistic regression model was done with PrdGP4, and two other predictive variables (pT≥3a, preoperative PSA level) entered as statistically significant independent predictors of biological recurrence. Results: Forty-eight patients (19.4%) had a positive surgical margins, 26 patients have PrdGP3 (54%) and 22 have PrdGP4 (46%). Whereas 7 biological recurrences were observed in PrdGP4 patients, none occurred in PrdGP3 patients. Biological recurrence-free survivals were significantly different (Log rank p=0.001). In multivariate analysis, PrdGP4 was a predictor of biological recurrence (p&lt;0.0001, OR= 9.023, 95% CI [3.161–25.757]). Conclusions: This study demonstrates that biological recurrence after positive surgical margin are correlated with the predominant Gleason pattern assessed on radical prostatectomy specimen which s more easily evaluable than accurate margins features. Adjuvant treatment, specifically external beam radiotherapy, should be indicated in accordance to this result. [Table: see text]
Coronary thrombolysis and myocardial salvage by tissue plasminogen activator given up to 4 hours after onset of myocardial infarction
Authors: P. L. Thompson, P. Aylward, J. Federman, P. Harris, R. Hodge, N. Latt, A. Pitt, A. Thomson, A. Tonkin, A. Byrne, D. English, R. Parsons, K. Jamrozik, S. M. Nidorf, P. Barter, H. S. Heasman Hammond, R. Blackett, T. Robertson, J. Mc Neill
Journal: The Lancet (1988)
Outcomes of advanced angiosarcoma and hemangioendothelioma on propranolol based regimens from sarcoma medical oncology clinic in North India.
Authors: Naresh G, Sameer Rastogi, Adarsh Barwad, Ekta Dhamija, Winan J. van Houdt, Neeltje Steeghs, Rambha Panday, Aditi Aggarwal, Rakesh Garg
Journal: Journal of Clinical Oncology (2019)

e22539 Background: Angiosarcoma is an extremely rare subtype of soft tissue sarcoma with a dismal prognosis. The response rate with current standard treatment is low and new approaches are needed. Propranolol is a well-known, generic ß-blocker that has recently been approved for the treatment of a benign vascular tumor, hemangioma, with high response rates. Several preclinical studies and case reports suggest that propranolol could also be repurposed to treat malignant vascular tumors like angiosarcoma. Methods: All patients with advanced or unresectable angiosarcoma and hemangioendothelioma that were treated in the Sarcoma medical oncology clinic in North India from January 2016 to August 2018 were included. Patients were treated with 40 mg BID propranolol with or without chemotherapy or targeted agents. Results: Eight patients with angiosarcoma or hemangioendothelioma were treated with propranolol in combination with pazopanib, methotrexate and vinblastine or methotrexate monotherapy. The median follow up period was 15 months, response rates were 14%. Median PFS was not reached, but the 10 months PFS was 60%. Median OS was not reached, but the 10 months OS was 80%. Conclusions: Treatment of angiosarcoma or hemangioendothelioma patients with propranolol in combination with chemotherapy or targeted therapy shows promising results in terms of survival albeit with relatively low response rates .To determine the exact place of propranolol in the treatment of angiosarcoma, more patients need to be treated, the efficacy of propranolol as monotherapy needs to be evaluated and the role of β-adrenergic receptor as a predictive biomarker needs to be clarified further. Additionally, different combination partners should be tested to determine the optimal backbone for the combination therapy with propranolol.
PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice
Authors: Ismail Syed, Maria F. Rubin de Celis, James F. Mohan, Pedro M. Moraes-Vieira, Archana Vijayakumar, Andrew T. Nelson, Dionicio Siegel, Alan Saghatelian, Diane Mathis, Barbara B. Kahn
Journal: Journal of Clinical Investigation (2019)

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are endogenous antidiabetic and antiinflammatory lipids. Here, we show that PAHSAs protect against type 1 diabetes (T1D) and promote β cell survival and function. Daily oral PAHSA administration to nonobese diabetic (NOD) mice delayed the onset of T1D and markedly reduced the incidence of T1D, whether PAHSAs were started before or after insulitis was established. PAHSAs reduced T and B cell infiltration and CD4+ and CD8+ T cell activation, while increasing Treg activation in pancreata of NOD mice. PAHSAs promoted β cell proliferation in both NOD mice and MIN6 cells and increased the number of β cells in NOD mice. PAHSAs attenuated cytokine-induced apoptotic and necrotic β cell death and increased β cell viability. The mechanism appears to involve a reduction of ER stress and MAPK signaling, since PAHSAs lowered ER stress in NOD mice, suppressed thapsigargin-induced PARP cleavage in human islets, and attenuated ERK1/2 and JNK1/2 activation in MIN6 cells. This appeared to be mediated in part by glucagon-like peptide 1 receptor (GLP-1R) and not the G protein–coupled receptor GPR40. PAHSAs also prevented impairment of glucose-stimulated insulin secretion and improved glucose tolerance in NOD mice. Thus, PAHSAs delayed the onset of T1D and reduced its incidence by attenuating immune responses and exerting direct protective effects on β cell survival and function.
Addressing and proposing solutions for unmet clinical needs in the management of myeloproliferative neoplasm-associated thrombosis: A consensus-based position paper
Authors: Tiziano Barbui, Valerio De Stefano, Anna Falanga, Guido Finazzi, Ida Martinelli, Francesco Rodeghiero, Alessandro M. Vannucchi, Giovanni Barosi
Journal: Blood Cancer Journal (2019)

Abstract This article presents the results of a group discussion among an ad hoc constituted Panel of experts aimed at highlighting unmet clinical needs (UCNs) in the management of thrombotic risk and thrombotic events associated with Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs). With the Delphi technique, the challenges in Ph-neg MPN-associated thrombosis were selected. The most clinically relevant UCNs resulted in: (1) providing evidence of the benefits and risks of direct oral anticoagulants, (2) providing evidence of the benefits and risks of cytoreduction in patients with splanchnic vein thrombosis without hypercythemia, (3) improving knowledge of the role of the mutated endothelium in the pathogenesis of thrombosis, (4) improving aspirin dosing regimens in essential thrombocythemia, (5) improving antithrombotic management of Ph-neg MPN-associated pregnancy, (6) providing evidence for the optimal duration of anticoagulation for prophylaxis of recurrent VTE, (7) improving knowledge of the association between somatic gene mutations and risk factors for thrombosis, and (8) improving the grading system of thrombosis risk in polycythemia vera. For each of these issues, proposals for advancement in research and clinical practice were addressed. Hopefully, this comprehensive overview will serve to inform the design and implementation of new studies in the field.
Avatrombopag, a Novel Thrombopoietin Receptor Agonist, Increases Platelet Counts without Increasing Platelet Activation in Patients with Thrombocytopenia Due to Chronic Liver Disease
Authors: Andrew L Frelinger, Elena Smolensky Koganov, Emma E Forde, Sabrina L Carmichael, Alan D Michelson
Journal: Blood (2017)