tbuckley/cabot-search huggingface dataset:
Preclinical Development of a MicroRNA-Based Therapy for Elderly Patients With Myocardial Infarction
Authors: Shashi Kumar Gupta, Ariana Foinquinos, Sabrina Thum, Janet Remke, Karina Zimmer, Christophe Bauters, Pascal de Groote, Reinier A. Boon, Leon J. de Windt, Sebastian Preissl, Lutz Hein, Sandor Batkai, Florence Pinet, Thomas Thum
Journal: Journal of the American College of Cardiology (2016)

Aging populations show higher incidences of myocardial infarction (MI) and heart failure (HF). Cardiac remodeling post-MI leads to progressive impaired cardiac function caused by a disarray of several processes including derailed autophagy. Microribonucleic acids (miRNAs) are known to be key players in cardiovascular disease but their involvement in cardiac autophagy and aging is not well understood.This study sought to identify new miRNA candidates that regulate cardiac autophagy and aging.We exploited a high-throughput, fluorescence-activated cell sorting-based green fluorescent protein-LC3 detection method to measure the autophagic flux in cardiomyocytes after transfection of a precursor miRNA library consisting of 380 miRNAs. This was followed by a series of molecular and in vivo studies.Together with additional expression screenings, we identified miR-22 as an abundant and strong inhibitor of the cardiac autophagy process. Cardiac miR-22 expression levels increased during aging of mice as well as in aging neonatal cardiomyocytes in vitro by a P53-dependent mechanism. Inhibition of miR-22 in aging cardiomyocytes in vitro activated autophagy and inhibited cellular hypertrophy. Pharmacological inhibition of miR-22 post-MI in older mice activated cardiac autophagy, prevented post-infarction remodeling, and improved cardiac function compared with control subjects. Interestingly, similar effects were less pronounced in younger mice with significantly lower cardiac miR-22 expression levels. In addition, circulating levels of miR-22 in 154 patients with systolic HF were highly associated with early mortality.We concluded that miR-22 is an important regulator of cardiac autophagy and a potential therapeutic target, especially in the older myocardium. Finally, circulating miR-22 provides prognostic information for HF patients, highlighting miR-22 as a promising therapeutic and biomarker candidate for cardiovascular disorders.
Rearrangement between MYH11 gene at 16p13 and a gene within cosmid D12S158 at 12p13.3 in a case of AML-M1 with bone marrow eosinophilia
Authors: R La Starza, B Crescenzi, C Matteucci, Iwona Wlodarska, MF Martelli, Peter Marynen, Christina Mecucci
Journal: Blood (1997)
Abstract B30: Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer
Authors: Sarah Deasy, Kent Hunter
Journal: Cancer Research (2016)

Abstract Breast cancer is a leading cause of cancer-related female deaths in the United States, the majority of which are due to distant metastases. Elucidating novel genes that drive metastasis is critical to improving patient outcome. Our laboratory has extensively shown that germline variants impact an individual's susceptibility for metastasis, and we have used this to identify novel metastasis modifier genes. Here we applied a mouse model of spontaneous metastasis to a mouse breeding scheme to screen for strain-specific haplotypes associated with metastatic phenotype. Additional filtering of the haplotype-containing genes was performed for those that were highly expressed in tumors. This screen identified Rnaseh2c, a scaffolding subunit of the Ribonuclease H2 complex which degrades RNA from DNA:RNA heteroduplexes such as those generated during replication and transcription, thus helping maintain genomic stability. Though mutations in RNASEH2C are known to cause the neurological autoinflammatory disorder Aicardi-Goutières Syndrome (AGS), it has not previously been linked to cancer. Given the known pathology of AGS, we hypothesize that differential expression of Rnaseh2c in tumor cells alters tumor progression and metastasis potentially via interaction with the immune system. We directly assessed the effect of tumor cell Rnaseh2c expression on metastasis using in vivo metastasis assays. We implanted into the mammary fat pad tumor cells expressing shRNAs that reduced Rnaseh2c expression and observed significantly fewer pulmonary metastases and reduced tumor burden. To complement this approach, we performed the same metastasis assay with cells overexpressing exogenous Rnaseh2c. In agreement with our initial result, overexpression generated significantly more metastases without affecting primary tumor size, confirming Rnaseh2c as a metastasis modifier. The results thus far validate our approach of employing germline variation in mice to identify novel metastasis modifier genes. Current and future work will focus on elucidating the mechanism by which Rnaseh2c expression impacts metastasis. Specifically, we will determine where Rnaseh2c functions in the metastatic cascade, whether modulated expression disrupts Rnase H2 complex formation, and whether the immune system is involved in mediating this gene's effect on metastasis. Elucidating the mechanism by which this gene acts can contribute to both the development of novel metastasis biomarkers as well as potential therapeutic targets. Citation Format: Sarah Deasy, Kent Hunter. Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B30.
Low-Dose Cyclosporin A Does Not Abrogate the Suppressive Function of In Vitro Expanded Human CD4+CD25+ Regulatory T Cells.
Authors: Biserka Piseshka, Ruediger Eder, Tina J. Boeld, Reinhard Andreesen, Ernst Holler, Petra Hoffmann, Matthias Edinger
Journal: Blood (2006)
GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition
Authors: Hanan E. Shamseldin, Ikuo Masuho, Ahmed Alenizi, Suad Alyamani, Dipak N. Patil, Niema Ibrahim, Kirill A. Martemyanov, Fowzan S. Alkuraya
Journal: Genome biology (2016)

Neuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mendelian neuropsychiatric disorders are rare but their study has the potential to unravel novel mechanisms that are relevant to their complex counterparts. In an extended consanguineous family, we identified a novel neuropsychiatric phenotype characterized by severe speech impairment, variable expressivity of attention deficit hyperactivity disorder (ADHD), and motor delay. We identified the disease locus through linkage analysis on 15q21.2, and exome sequencing revealed a novel missense variant in GNB5. GNB5 encodes an atypical β subunit of the heterotrimeric GTP-binding proteins (Gβ5). Gβ5 is enriched in the central nervous system where it forms constitutive complexes with members of the regulator of G protein signaling family of proteins to modulate neurotransmitter signaling that affects a number of neurobehavioral outcomes. Here, we show that the S81L mutant form of Gβ5 has significantly impaired activity in terminating responses that are elicited by dopamine. We demonstrate that these deficits originate from the impaired expression of the mutant Gβ5 protein, resulting in the decreased ability to stabilize regulator of G protein signaling complexes. Our data suggest that this novel neuropsychiatric phenotype is the human equivalent of Gnb5 deficiency in mice, which manifest motor deficits and hyperactivity, and highlight a critical role of Gβ5 in normal behavior as well as language and motor development in humans.
The criteria of aggressiveness and other prognostic factors for predicting relapses of primary tumors and imatinib (IM) treatment outcomes in advanced KIT immunopositive gastrointestinal stromal tumors (GIST): A report of the Polish Clinical GIST Registry (PCGR)
Authors: P. Rutkowski, Z. I. Nowecki, W. Michej, M. Debiec-Rychter, J. Limon, J. A. Siedlecki, M. Kakol, S. Gluszek, C. Osuch, W. Ruka
Journal: Journal of Clinical Oncology (2006)

9544 Background: The development of adjuvant treatment trials with imatinib in GIST has raised the debate about the accuracy of NIH risk criteria consensus and about the significance of other prognostic factors. Methods: We analyzed the criteria of aggressiveness and other clinico-pathological and genetic factors influencing disease-free survival (DFS) in patients with primary CD117-positive tumors (group I: 274 patients; median follow-up 29 months; calculated from primary tumor resection) and progression-free survival (PFS) in metastatic/unresectable GIST patients treated with IM (group II: 179 patients; median follow-up 19 months; calculated from the start of imatinib therapy) enrolled into PCGR. Results: In group I statistically significant (p&lt;0.05) factors negatively influencing DFS both in univariate (log-rank test) and multivariate (Cox’s model) analysis were: primary tumor size &gt; 5 cm, mitotic index &gt; 5/50HPF, male gender, primary tumor R1 resection or tumor rupture, non-gastric primary tumor localization and intermediate/high risk group (3-year DFS for high, intermediate and low/very low risk group was: 28%, 75% and 99%, respectively). In group II we identified 5 factors negatively affecting PFS statistically significant both in univariate and multivariate analyses (p&lt;0.05): tumor genotype indicating other than exon 11 KIT mutation, mitotic index &gt; 10/50HPF, age below 45 years at diagnosis, high baseline pre-IM granulocyte count and poor WHO performance status ≥ 2. Conclusions: We validated the value of criteria of risk groups for the assessment of the natural course of primary GIST, but we also identified additional independent prognostic factors. For the prediction of PFS during IM therapy for advanced GIST we detected 5 different, independent biological and pathological factors. No significant financial relationships to disclose.
Epidermal growth factor receptor (<i>EGFR</i>) mutations detected by denaturing high performance liquid chromatography (dHPLC) in non-small cell lung cancer (NSCLC): Correlation with disease stage and response to tyrosine kinase inhibitors (TKI) therapy
Authors: J. S. Agulnik, V. Cohen, S. Sun, C. Ang, G. Kasymjanova, G. Chong, G. Brandao, C. Pepe, D. Small, W. H. Miller
Journal: Journal of Clinical Oncology (2008)

22118 Background: Somatic mutations of the EGFR gene predict sensitivity to EGFR-TKI in NSCLC patients. dHPLC is a sensitive method for detecting EGFR mutations in NSCLC tumours. The goal of this study was to investigate the relationship between EGFR status (mutation and type) and disease stage and response to TKI therapy. Methods: All patients (pts) diagnosed with NSCLC in 2005 were identified and genotyped for EGFR exons 19 and 21 mutations using dHPLC. Results were correlated with the stage of disease. In addition, all genotyped tumours were correlated with patient demographics, smoking status, tumor histology, disease stage, response to TKI, and overall survival. Results: 144 pts were diagnosed with NSCLC at our institution in 2005. 62 pts were genotyped, 82 are still pending. Our preliminary data show 34% (10/29) of pts with advanced disease (stage 3B/4) were mutation positive compared with 6% (2/33) of early stage disease (p=0.007). Since 2004 we have genotyped a total of 228 NSCLC pts. Using dHPLC, we identified mutations in 26% of tumour samples (59 of 228). Mutations were more common in women, non-smokers, adenocarcinomas, and late stage disease. 50 out of 157 patients with advanced NSCLC received TKI therapy. Of these, 17 had mutations on exon 19 and 4 on exon 21. Patients with EGFR mutations were more likely to benefit (partial response or stable disease) from TKI therapy (76% vs 31%; p=0.002). There was a trend towards better survival in patients with exon 19 mutations regardless of therapy. Conclusion: dHPLC is a sensitive and reliable test for EGFR mutation identification. EGFR mutations seem to be more common in advanced disease, although full genotyping is still ongoing and final results will be presented. Pts with EGFR mutations were more likely to benefit from TKI therapy. The presence of an exon 19 deletion appears to be a good prognostic factor regardless of therapy. These observations warrant further confirmation in large prospective studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Canada
Biospecimen Sharing Among Hispanic Women in a Safety-Net Clinic: Implications for the Precision Medicine Initiative
Authors: Jesse N. Nodora, Ian K. Komenaka, Marcia E. Bouton, Lucila Ohno-Machado, Richard Schwab, Hyeon-eui Kim, Claudiu Farcas, Giovanna Perez, Maria Elena Martinez
Journal: JNCI Journal of the National Cancer Institute (2016)

Biospecimen donation is key to the Precision Medicine Initiative, which pioneers a model for accelerating biomedical research through individualized care. Personalized medicine should be made available to medically underserved populations, including the large and growing US Hispanic population. We present results of a study of 140 Hispanic women who underwent a breast biopsy at a safety-net hospital and were randomly assigned to receive information and request for consent for biospecimen and data sharing by the patient's physician or a research assistant. Consent rates were high (97.1% and 92.9% in the physician and research assistant arms, respectively) and not different between groups (relative risk [RR] = 1.05, 95% confidence interval [CI] = 0.96 to 1.10). Consistent with a small but growing literature, we show that perceptions of Hispanics' unwillingness to participate in biospecimen sharing for research are not supported by data. Safety-net clinics and hospitals offer untapped possibilities for enhancing participation of underserved populations in the exciting Precision Medicine Initiative.
Is the Proposed World Health Organization (WHO) Classification for Chronic Myeloid Leukemia (CML) of Clinical Value in the Imatinib Era?.
Authors: Jorge Cortes, Susan O’Brien, Guillermo Garcia-Manero, Stefan Faderl, Jenny Shan, Francis Giles, Srdan Verstovsek, Mary Beth Rios, Moshe Talpaz, Hagop Kantarjian
Journal: Blood (2004)
Insights into the Management of Adverse Events in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Experience from the Phase 3 HELIOS Study of Ibrutinib Combined with Bendamustine/Rituximab
Authors: Asher Chanan-Khan, Paula Cramer, Fatih Demirkan, Graeme Fraser, Rodrigo Santucci Silva, Halyna Pylypenko, Sebastian Grosicki, Ann Janssens, Aleksander Pristupa, Andre Goy, Jiri Mayer, Marie Sarah Dilhuydy, Javier Loscertales, Nancy L. Bartlett, Abraham Avigdor, Simon Rule, Steven Sun, Charles Phelps, Michelle Mahler, Mariya Salman, Angela Howes, Michael Hallek
Journal: Blood (2015)
Allogeneic stem cell transplantation with matched related and unrelated donors for patients with refractory anemia: T-cell depletion and reduced intensity regimens are associated with increased relapse risk
Authors: TM De Witte, R Brand, A van Biezen, P Guardiola, R Barge, T Ruutu, Michel Delforge, R Arnold, G Mufti, A Vitek, J Finke, D Niederwieser
Journal: Blood (2003)
A Randomized, Multicenter Study (PALG CLL4/ ML 21283) Of Maintenance Treatment With Rituximab Versus Observation After Induction Treatment With Rituximab, Cladribine, and Cyclophosphamide (RCC) Regimen In Patients With Progressive Chronic Lymphocytic Leukemia: Interim Analysis
Authors: Tadeusz Robak, Jerzy Z. Blonski, Krzysztof Jamroziak, Aleksander Skotnicki, Magdalena Piotrowska, Anatoly Uss, Janusz Kloczko, Jaroslaw Piszcz, Kazimierz Kuliczkowski, Tomasz Wrobel, Bozena Katarzyna Budziszewska, Marta Fidecka, Piotr Smolewski
Journal: Blood (2013)
Bortezomib–Melphalan–Prednisone (VMP) in Newly Diagnosed Multiple Myeloma Patients with Impaired Renal Function: Cohort Analysis of the Phase III VISTA Study.
Authors: Meletios A Dimopoulos, Paul Richardson, Rudolf Schlag, Nuriet K Khuageva, Ofer Shpilberg, Efstathios Kastritis, Martin H Kropff, Maria Teresa Petrucci, Michel Delforge, Julia A Alexeeva, Rik Schots, Tamas Masszi, Maria-Victoria Mateos, William Deraedt, Kevin Liu, Andrew Cakana, Helgi van de Velde, Jesus F San Miguel
Journal: Blood (2008)
Association of reduced intensity conditioning (RIC) allograft (alloHCT) as first transplant approach in relapsed/refractory grade 3(G-3) follicular lymphoma (FL) with improved outcomes in long-term survivors.
Authors: Evgeny Klyuchnikov, Ulrike Bacher, Nicolaus Kröger, Parameswaran Hari, Kwang Woo Ahn, David G. Maloney, Sonali M. Smith, Anna M. Sureda, Jeanette Carreras, Mehdi Hamadani
Journal: Journal of Clinical Oncology (2015)

7009 Background: No studies to date have evaluated the role of RIC alloHCT compared to autologous (auto) HCT in pts with G-3 FL, in the rituximab-era. Methods: Adult pts with relapsed/refractory G-3 FL undergoing first RIC alloHCT or first autoHCT and reported to CIBMTR during 2000-12 were eligible. Pts with large cell transformation and those not receiving rituximab before HCT were excluded. Results: Characteristics of 197 pts included in this analysis are shown in the table below. AlloHCT pts were younger, more heavily pretreated, and had longer interval between diagnosis and HCT. The 5-yr adjusted probabilities of non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) of autoHCT vs. alloHCT groups were 4% vs. 27% (p < 0.0001); 61% vs. 20% (p < 0.0001); 36% vs. 51% (p = 0.06) and 59% vs. 54% (p = 0.7) respectively. 5-year incidence of second malignancies was similar (alloHCT = 8%; autoHCT = 9%). On multivariate analysis autoHCT was associated with reduced NRM (RR = 0.20; p = 0.001). Within the first 11 months post HCT, auto- and alloHCT were similar in terms of relapse and PFS. Beyond 11 months post HCT, autoHCT was associated with higher relapse (RR = 21.8; p = 0.003) and worse PFS (RR = 3.2; p = 0.005). In the first 24 months post HCT, autoHCT was associated with improved OS (RR = 0.42; p = 0.005), but beyond 24 months it was associated with lower OS (RR = 3.6; p = 0.04). Conclusions: RIC alloHCT as first transplant approach can provide better long-term survival outcomes for G-3 FL. Table AlloHCT (%) AutoHCT (%) P-value 61 136 Median age, years 53 (36-64) 57 (27-76) 0.01 KPS ≥ 90 42 (69) 86 (63) 0.21 Stage III-IV at diagnosis 52 (85) 105 (77) 0.11 Prior rituximab-resistance 30 (49) 84 (62) 0.12 Median lines of therapy 3 (1-5) 3 (1-5) 0.01 Duration of first response 0.31 < 1 year 22 (36) 44 (32) ≥ 1 year 34 (56) 87 (64) Time from diagnosis to HCT, months 32 (5-159) 24 (6-224) 0.02 Type of donor Matched sibling 36 (59) 8/8 MUD 23 (38) 7/8 MUD 2 ( 3) PB graft 58 (95) 135 (99) 0.05 TBI in conditioning 9 (15) 8 ( 6) 0.04 Chemosensitive at HCT 49 (80) 123 (90) 0.07 Median follow up 57 (5-132) 59 (3-145)
Germinal Center B Cell and Non-Germinal Center B Cell-Like DLBCL Have Similar Clinical Features at the Time of Progression and Comparable Outcome Following Autologous HSC Transplantation.
Authors: Luciano J. Costa, Andrew L. Feldman, Ivana N. Micallef, David J. Inward, Patrick B. Johnston, Luis F. Porrata, Mark R. Litzow, Stephen M. Ansell
Journal: Blood (2007)
A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01).
Authors: Atilla Soran, Vahit Ozmen, Serdar Ozbas, Hasan Karanlik, Mahmut Muslumanoglu, Abdullah Igci, Zafer Canturk, Zafer Utkan, Cihangir Ozaslan, Turkkan Evrensel, Cihan Uras, Erol Aksaz, Aykut Soyder, Umit Mustafa Ugurlu, Cavit Col, Neslihan Cabioglu, Betul Bozkurt, Efe Sezgin, Ronald Johnson, Barry C. Lembersky
Journal: Journal of Clinical Oncology (2016)

1005 Background: The MF07-01 trial is a multicenter phase III randomized trial of treatment naive stage IV BC patients comparing loco-regional surgery (LRS) followed by appropriate systemic therapy (ST) vs ST alone. Aims: To compare 3-year survival and loco-regional progression (LRP). Methods: At initial diagnosis patients were randomized 1:1 to LRS group or ST group. After consideration of retrospective studies, we hypothesized at 36 months a survival difference between the two groups to be 18%. Assuming a 10% drop out rate and with a one sided log-rank test with a 95% CI and a 90% power 271 patients needed to be randomized. Results: 274 patients were accrued; 138 in the LRS group and 136 in the ST group. The groups were comparable regarding age, BMI, HER2 neu, tumor type and size, histologic grade, and bone and visceral metastasis (all p > 0.05). There were 76 (55%) deaths in the LRS group and 101 (74%) in the ST group during the median 40 (20-51) months follow-up. At 36 months the survival rate was similar the LRS group and the ST group (60% and 51%, respectively; p = 0.5). Overall survival (OS) was 34% higher in the LRS group compared to the ST group (HR: 0.66, 95%CI 0.49-0.88: p = 0.005). In unplanned subgroup analyses, OS was statistically higher in LRS group than ST group; ER/PR (+) (HR: 0.64, 0.46-0.91, p = 0.01), HER2 neu (-) (HR: 0.64, 95%CI 0.45-0.91; p = 0.01), patients < 55 years (HR: 95%CI 0.57, 0.38-0.86; p = 0.006), and solitary bone only metastasis (HR: 0.47, 95%CI 0.23-0.98; p = 0.04). The median survival was 14 months higher in the LRS group comparing with the ST group in bone only metastasis (56 vs 42 months, respectively; HR 0.67, 95%CI 0.43-1.07; p = 0.09). LRP was 1% (n = 2) in the LRS group and it was 11% (n = 15) in the ST group (p = 0.001). Conclusion: In this trial we did not observe improvement in 36 month survival with surgery. However, longer follow up revealed statistically significant improvement in median survival with surgery (46 vs.37 months) at median 40 months follow up. Additionally, patients with a more indolent form of metastatic BC such as ER (+), HER2 neu (-), solitary bone metastasis, and patients < 55 years old have a significant survival benefit with initial surgery. Clinical trial information: NCT00557986.
Integrative Genomic Analysis Reveals Aberrant Epigenetic Marks in MDS That Can Be Seen in Peripheral Blood Leucocytes
Authors: Li Zhou, Joanna B. Opalinska, Davendra P. Sohal, Yongkai Mo, Suman Kambhampati, Simrit Parmar, Christina Alencar, Christoph Heuck, Ivette Vigoda, Chun Ng, Perry Pahanish, Swati Goel, Carolina Schinke, Lawrence Cytryn, Ellen Friedman, Maria E Figueroa, Amittha Wickrema, John Greally, Amit Verma
Journal: Blood (2008)