tbuckley/cabot-search huggingface dataset:
Master Regulators of Oncogenic KRAS Response in Pancreatic Cancer: An Integrative Network Biology Analysis
Authors: Shivan Sivakumar, Ines de Santiago, Leon Chlon, Florian Markowetz
Journal: PLoS Medicine (2017)

Background KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying the transcriptional response to oncogenic KRAS are still not fully understood. We aimed to uncover transcription factors that regulate the transcriptional response of oncogenic KRAS in pancreatic cancer and to understand their clinical relevance. Methods and Findings We applied a well-established network biology approach (master regulator analysis) to combine a transcriptional signature for oncogenic KRAS derived from a murine isogenic cell line with a coexpression network derived by integrating 560 human pancreatic cancer cases across seven studies. The datasets included the ICGC cohort (n = 242), the TCGA cohort (n = 178), and five smaller studies (n = 17, 25, 26, 36, and 36). 55 transcription factors were coexpressed with a significant number of genes in the transcriptional signature (gene set enrichment analysis [GSEA] p < 0.01). Community detection in the coexpression network identified 27 of the 55 transcription factors contributing to three major biological processes: Notch pathway, down-regulated Hedgehog/Wnt pathway, and cell cycle. The activities of these processes define three distinct subtypes of PDAC, which demonstrate differences in survival and mutational load as well as stromal and immune cell composition. The Hedgehog subgroup showed worst survival (hazard ratio 1.73, 95% CI 1.1 to 2.72, coxPH test p = 0.018) and the Notch subgroup the best (hazard ratio 0.62, 95% CI 0.42 to 0.93, coxPH test p = 0.019). The cell cycle subtype showed highest mutational burden (ANOVA p < 0.01) and the smallest amount of stromal admixture (ANOVA p < 2.2e–16). This study is limited by the information provided in published datasets, not all of which provide mutational profiles, survival data, or the specifics of treatment history. Conclusions Our results characterize the regulatory mechanisms underlying the transcriptional response to oncogenic KRAS and provide a framework to develop strategies for specific subtypes of this disease using current therapeutics and by identifying targets for new groups.
Is clinical stage T2c prostate cancer intermediate- or high-risk disease? Results from the SEARCH database.
Authors: Abhay A Singh, Leah Gerber, Stephen J. Freedland, William J Aronson, Martha K. Terris, Joseph C. Presti, Christopher L Amling, Lionel Lloyds Banez
Journal: Journal of Clinical Oncology (2012)

123 Background: Clinical stage T2c is a nebulous factor in the algorithm for prostate cancer risk stratification. According to D’Amico risk stratification cT2c is high-risk category where NCCN guidelines place this stage in intermediate-risk. As diagnostic work up with the use of MRI continues to escalate clinical staging may become more important. As cT2c represents a possible decision fork in treatment decisions we sought to investigate which risk group the clinical behavior of cT2c tumors more closely resembles. Methods: We retrospectively analyzed data from 1089 men who underwent radical prostatectomy (RP) from 1988 to 2009 who did not have low-risk CaP from the SEARCH database. We compared time to BCR between men with cT2c disease, those with intermediate-risk (PSA 10-20 ng/ml or Gleason sum (GS) =7), and those with high-risk (PSA&gt;20 ng/ml, GS 8-10, cT3) using Cox regression models adjusting for age, race, year of RP, center, and percent cores positive. We also compared predictive accuracy of two Cox models wherein cT2c was considered either intermediate- or high-risk by calculating concordance index c. Results: A total of 68 men (3.4%) had cT2c tumors. After a median follow-up of 47.5 months, there was no difference in BCR risk between men with intermediate-risk CaP and those with cT2c tumors (HR=0.90; p=0.60). In contrast, there was a trend for men with high-risk CaP to have nearly 50% increased BCR risk compared to men with cT2c tumors (HR=1.50; 95% CI=0.97-2.30; p=0.07) which did not reach statistical significance. Concordance index c was higher in the Cox model wherein cT2c tumors were considered intermediate-risk (c=0.6147) as opposed to high-risk (c=0.6106). Conclusions: BCR risk for patients with clinical stage T2c was more comparable to men who had intermediate-risk CaP than men with high-risk. In addition, a model which incorporates cT2c disease as intermediate-risk has better predictive accuracy. These findings suggest men with cT2c disease should be offered treatment options for men with intermediate-risk CaP. As clinical staging more routinely incorporates MRI there is the potential to better identify bilateral organ-confined CaP and further establish risk classification.
Oligomerization of Evi-1 Contributes to Recruitment of Transcriptional Corepressor CtBP and Repression of TGF-β Signaling.
Authors: Eriko Nitta, Koji Izutsu, Yuko Yamaguchi, Yoichi Imai, Seishi Ogawa, Shigeru Chiba, Mineo Kurokawa, Hisamaru Hirai
Journal: Blood (2004)
Pharmacokinetics of a novel PGA-ARQ 501 conjugate in mouse xenografts
Authors: Ronald Savage, Terence Hall, Manish Tandon, Jean Marc Lapierre, Sapna Makhija, Yanbin Liu, Youzhi Li, Mark Ashwell, Thomas Chan
Journal: Cancer Research (2007)

1548  The pharmacokinetics of ARQ 501 and a conjugate, PGA-ARQ501, were compared in athymic mice carrying human tumor xenografts. Both ARQ 501 and the ARQ 501 PGA conjugate were dosed IP at 60 mg/kg and 14 mg/kg, respectively. The PGA-ARQ 501 conjugate showed improved pharmacokinetic properties over ARQ 501 (β lapachone, an anti-cancer drug currently in Phase II clinical trials). These included: improved solubility and ease of formulation for IV administration without cyclodextrin. Administration of ARQ 501-conjugate at a lower equivalent dose (14 mg/kg vs 60 mg/kg) resulted in increased levels of total ARQ 501 in both plasma and tumor tissue. When compared to ARQ 501 (dose normalized), administration of the ARQ 501-conjugate resulted in comparable tumor Cmax in free ARQ 501 and a 6.5 fold increase in tumor AUC(0-∞). These and other data suggest that PGA-ARQ 501 has desirable pharmacokinetic properties and warrants consideration as a second generation candidate to the current drug development program for ARQ501.
HIGH TRIGLYCERIDES, LOW HDL CHOLESTEROL AND A LOW LDL CHOLESTEROL PER APOLIPOPROTEIN B RATIO PREDICT INCIDENT DIABETES IN PATIENTS WITH ESTABLISHED CORONARY ARTERY DISEASE
Authors: Christoph H. Saely, Philipp Rein, Alexander Vonbank, Daniela Zanolin, Andreas Leiherer, Axel Muendlein, Heinz Drexel
Journal: Journal of the American College of Cardiology (2016)
CRM1 Inhibition Abrogates Osteoclast Formation and Bone Resorption Via Inhibition of RANKL-Induced NFκB While Sparing Osteoblastogenesis: Further Therapeutic Implication in Multiple Myeloma
Authors: Chirag Acharya, Mike Y Zhong, Yolanda Calle, Stephen Schey, Michelle Chen, Daniel Tannenbaum, Michaela R Reagan, Irene M. Ghobrial, Yosef Landesman, Sharon Shacham, Michael Kauffman, Kenneth C. Anderson, Yu-Tzu Tai
Journal: Blood (2012)
The role of serratiopeptidase in the resolution of inflammation
Authors: Manju Tiwari
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Inflammation remains a key event during most of the diseases and physiological imbalance. Acute inflammation is an essential physiological event by immune system for a protective measure to remove cause of inflammation and failure of resolution lead to chronic inflammation. Over a period of time, a number of drugs mostly chemical have been deployed to combat acute and chronic inflammation. Recently, enzyme based anti-inflammatory drugs became popular over conventional chemical based drugs. Serratiopeptidase, a proteolytic enzyme from trypsin family, possesses tremendous scope in combating inflammation. Serine protease possesses a higher affinity for cyclooxygenase (COX-I and COX-II), a key enzyme associated with production of different inflammatory mediators including interleukins (IL), prostaglandins (PGs) and thromboxane (TXs) etc. Currently, arthritis, sinusitis, bronchitis, fibrocystic breast disease, and carpal tunnel syndrome, etc. are the leading inflammatory disorders that affected the entire the globe. In order to conquer inflammation, both acute and chronic world, physician mostly relies on conventional drugs. The most common drugs to combat acute inflammation are Nonsteroidal anti-inflammatory drugs (NSAIDs) alone and or in combination with other drugs. However, during chronic inflammation, NSAIDs are often used with steroidal drugs such as autoimmune disorders. These drugs possess several limitations such as side effects, ADR, etc. In order to overcome these limitations and complications, enzyme based drugs (anti-inflammatory) emerged, and aim for a new high since the last decade. Serine protease, the largest proteolytic family has been reported for several therapeutic applications, including anti-inflammatory. Serratiopeptidase is a leading enzyme which has a very long history in medical as an effective anti-inflammatory drug. Current study emphasizes present scenario and future prospect of serratiopeptidase as an anti-inflammatory drug. The study also illustrates a comparative analysis of conventional drugs and enzyme based therapeutic to combat inflammation.
Luminal B breast cancer and prognostic value of HER2 overexpression: Retrospective analysis of a single-institution series.
Authors: C. A. Castaneda, E. Andres, N. Valdivieso, M. Dorta, L. Manso, I. Ghanem, H. Cortes-Funes, E. M. Ciruelos Gil
Journal: Journal of Clinical Oncology (2011)

e11120 Background: Luminal B is a heterogeneous estrogen-receptor positive breast cancer subtype, with a higher proliferation rate and a poorer prognosis than luminal A. Overexpression of HER2 oncogene identifies tumors with a different clinical behavior. This study evaluates the prognostic role of HER2 expression in luminal B tumors. Methods: We retrospectively analyzed the clinicopathologic characteristics of 2005 early breast cancer pts (I-IIIB clinical stages) diagnosed between 1997 and 2007 at our institution. 47% of pts fulfill luminal B-subtype criteria: ki67≥14%, PR<10% stained cells or HER2(+) in addition to ER≥10% stained cells. HER2 was defined as positive if Herceptest 3+or gene amplification confirmed by FISH. Results: Among 772 luminal B patients who received curative surgery for invasive breast cancer from January 1997 to June 2007, 670 patients were included in this analysis, and 212 (27,4%) cases were HER2(+). Median age was 54.4 years (range: 27-87 years). Histologic subtype was as follows: ductal 562 pts (83.9 %); lobular 82 pts (12.2%) Histologic grade: I: 15.1 %, II: 44.8 % , and III: 39 %. Tumor characteristics according to HER2 status were similar, as described in table. With a median follow-up of 82 months, overall relapse rate was 23%. Median DFS or OS were not reached. At the current analysis, no differences were observed in DFS (p 0.64) or OS (p 0.53) in Kaplan-Meier estimates between HER2 positive and negative groups. Conclusions: Luminal B subtype include populations with different behaviour and prognosis. In our series patients with HER2 (+) tumors have a similar prognosis as HER2(-) subgroup for luminal B classified patients. Tumor or patient characteristic HER2-negative subgroup (% pts) HER2-positive subgroup (% pts) Median age 54.7 y 53.4 y Median Ki67 value 20 20 Tumor size T1 T2 T3 T4 46.2 40.3 8.6 4.2 44.9 44.9 4.8 7.2 Node status N0 N1 N2 N3 52.0 28.8 11.8 7.2 57.5 21.7 14.6 6.13 Histologic type Ductal Lobular 80 15 92 5.6 Adjuvant chemotherapy None No taxanes nor anthracyclines Anthracyclines without taxanes Anthracyclines and taxanes 19.7 15.1 24.3 23.9 16.5 20.7 29.7 13.6 Adjuvant trastuzumab None 15
Familiarity breeds better outcomes
Authors: Elizabeth Loder
Journal: BMJ (2017)

Let’s be clear: familiarity breeds better outcomes. People who have a usual, continuous source of primary medical care generally do better than those who don’t. We know this, and yet everywhere primary care and general practice are in crisis.

The United Kingdom is no exception. Its medical schools are “training future doctors for yesterday,” say our editorialists John Oldham and Sam Everington (doi:10.1136/bmj.j294). Only 5.9% of UK medical school professors are GPs. As in the United States, there is prejudice and “institutional discrimination” by medical leaders …
Promoting the Shared-Care Model for Adolescent and Young Adults With Cancer: Optimizing Referrals and Care Coordination With Primary Care Providers
Authors: Karen E. Kinahan, Sheetal Kircher, Jessica Altman, Alfred Rademaker, John M. Salsman, Aarati Didwania, Bridget O'Brien, Alpa C. Patel, Stacy D. Sanford
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: The “shared-care model” for patients with cancer involves care coordination between primary care providers (PCPs) and oncologists, with the goal of optimizing survivorship care. However, a high proportion of adolescent and young adult (AYA) cancer survivors do not have a PCP. Study objectives were to increase the percentage of AYAs with a PCP documented in the electronic medical record (EMR) via the use of a best practice advisory (BPA) or “stopgap” intervention; to increase communication between providers by the number of routed clinic notes; and to assess oncology providers' attitudes/beliefs about the model and intervention. Methods: Data were collected for the 6 months before implementation of the BPA to determine the percentage of AYAs with a PCP and the number of notes routed to providers (time point 1 [T1]). The same data were collected at time point 2 (T2) after the BPA had been implemented for 6 months. Oncology providers participated in an education video module and an online survey at T1 and a survey at T2. Results: At T1, 47.1% of 756 AYAs had a documented PCP in the EMR. At T2, the percentage increased to 55.1% (P<.002). The number of routed notes did not change significantly from T1 to T2. Providers that completed the intervention survey agreed/strongly agreed that the shared-care model is a desirable model of care (T1 = 86%; T2 = 93%) and that a BPA is useful for facilitating PCP referrals (T1 = 76%; T2 = 39%). Conclusions: This BPA is feasible for increasing the percentage of AYAs with a PCP documented in the EMR and could potentially lead to increased PCP referral and communication among providers for the benefit of long-term survivorship care. Providers generally agree with the shared-care model; however, the BPA implementation requires modification.
Updated Analysis of Hematopoietic Stem Cell Transplantations after Reduced Intensity Conditioning Regimen (RIC HSCT) for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.
Authors: Mauricette Michallet, Quoc-Hung Le, Thomas Prebet, Mohamad Mohty, Jean Michel Boiron, Hélène Esperou, Noel Milpied, Nathalie Dhédin, Didier Blaise
Journal: Blood (2005)
Safety and survival analysis of ipilimumab therapy in patients with stable asymptomatic brain metastases.
Authors: K. N. Heller, A. C. Pavlick, F. S. Hodi, J. A. Thompson, K. A. Margolin, D. P. Lawrence, D. F. McDermott, W. E. Samlowski, T. Michener, M. Karasarides
Journal: Journal of Clinical Oncology (2011)

8581 Background: Ipilimumab, a human monoclonal antibody, blocks CTLA-4 to potentiate T-cell antitumor responses. Ipilimumab has survival benefit in patients (pts) with previously treated advanced melanoma and has activity against brain metastases (mets); however, immune-related adverse events were also observed (Hodi et al, NEJM 2010). As pts with brain mets were included in the expanded access program study of ipilimumab, we evaluated the frequency of CNS events in pts with stable brain mets and pts without brain mets. Methods: CA184-045 is an ongoing multicenter, open-label study of ipilimumab 3 or 10 mg/kg. Pts with brain mets were required to be stable and asymptomatic. All pts in this analysis came from the 10 mg/kg cohort and were prospectively monitored for safety. Overall survival (OS) was retrospectively collected via database to confirm if pts were alive at 1 year; pts lost to follow up were assumed dead. Results: Among 869 pts, 165 with brain mets at baseline were analyzed. Pts with brain mets experienced drug-related serious adverse events (SAEs) of any grade at a similar rate to pts without brain mets (26.1% and 24.1%, respectively); grade 3/4 drug-related SAEs were also similar (23.0% and 18.7%, respectively). The most frequently reported CNS adverse events were cerebral hemorrhage and convulsion and judged attributable to tumor. They occurred at low frequency; but were higher in pts with brain mets compared to those with no brain mets (Table). OS rate of pts with brain mets at 1 year was 20%. Conclusions: These data support safety and efficacy observations of the ongoing CA184-042 trial reporting 1-year OS rate in pts with stable brain mets of 31%; updated 2-year OS for these studies will be provided. Brain mets (n=165) No brain mets (n=704) Any grade, n (%) Grade 3/4, n (%) Any grade, n (%) Grade 3/4, n (%) Most frequently reported SAEs Diarrhea 17 (10.3) 15 (9.1) 66 (9.3) 53 (7.5) Dehydration 15 (9.1) 12 (7.3) 56 (7.9) 46 (6.5) Most frequently reported CNS adverse events Cerebral hemorrhage 6 (3.6) 3 (1.8) 1 (0.1) 1 (0.1) Convulsion 6 (3.6) 4 (2.4) 5 (0.7) 1 (0.1)
A Study of Lenalidomide Based Chemotherapy in Multiple Myeloma in Indian Population: Special Appraisal of Thromboembolic Risk.
Authors: Velu Nair, Satyaranjan Das, Sanjeevan Sharma, V. K. Jha, S. Bhattacharya, Jasmeet Kaur, Prosenjit Ganguli, Tathagat Chatterjee, Naresh Kumar, SR Mehta
Journal: Blood (2009)
Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Long-Term Efficacy from the Phase 1b Keynote-013 Study
Authors: Philippe Armand, Margaret A. Shipp, Vincent Ribrag, Jean-Marie Michot, Pier Luigi Zinzani, John Kuruvilla, Ying Zhu, Alejandro Daniel Ricart, Arun Balakumaran, Craig H. Moskowitz
Journal: Blood (2016)
Molecular Characterization in Hairy Cell Leukemia (HCL): Rearrangement Analysis of Heavy Chain in Immunoglobulin Genes (IgH).
Authors: Patricia Martín-Jiménez, Miguel Alcoceba, Maria E. Sarasquete, Ana Balanzategui, David Gonzalez de Castro, Maria C. Chillón, J. A. Queizán, M. Barbón, F. Ortega, M. J. Peñarrubia, D. Borrego, M. Cabezudo, Lorena Blázquez, Adriana Armellini, Carina Fernández, Ramón García-Sanz, Marcos González, J.F. San Miguel
Journal: Blood (2004)
Bone Marrow Fibrosis in Chronic Idiopathic Myelofibrosis Is Associated with Megakaryocyte Expression of Osteoprotegerin.
Authors: Piotr Centkowski, Joanna Sawczuk-Chabin, Monika Prochorec-Sobieszek, Joanna Dobrzanska, Ilona Seferynska, Iwona Solarska, Miroslaw Majewski, Krzysztof Warzocha
Journal: Blood (2005)
Gene Expression Profiling of Bulk CD138+ Plasma Cells in Preneoplastic Gammopathy/Asymptomatic Myeloma Identifies Distinct Subsets of Patients.
Authors: Madhav V. Dhodapkar, Fenghuang Zhan, Erik Rasmussen, Bart Burington, Brian Durie, John Crowley, Bart Barlogie, John Shaughnessy
Journal: Blood (2005)
Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial
Authors: Angelo Ravelli, Sergio Davì, Giulia Bracciolini, Angela Pistorio, Alessandro Consolaro, Evert Hendrik Pieter van Dijkhuizen, Bianca Lattanzi, Giovanni Filocamo, Sara Verazza, Valeria Gerloni, Maurizio Gattinara, Irene Pontikaki, Antonella Insalaco, Fabrizio De Benedetti, Adele Civino, Giuseppe Presta, Luciana Breda, Valentina Marzetti, Serena Pastore, Silvia Magni-Manzoni, Maria Cristina Maggio, Franco Garofalo, Donato Rigante, Marco Gattorno, Clara Malattia, Paolo Picco, Stefania Viola, Stefano Lanni, Nicolino Ruperto, Alberto Martini
Journal: The Lancet (2017)
Association of nuclear accumulation of p53 with ERG fusion and poor prognosis in prostate cancer.
Authors: Sarah Minner, Antje Krohn, Hueseyin Sirma, Ronald Simon, Markus Graefen, Guido Sauter, Thorsten Schlomm
Journal: Journal of Clinical Oncology (2012)

124 Background: We have previously shown that nuclear accumulation of p53 is rare in prostate cancer but strongly linked to early biochemical recurrence (Schlomm et al., Modern Pathology, 2008). The current study was designed to study the association between ERG fusion and p53 in a large series of prostate cancers. Methods: A prostate cancer tissue microarray (TMA) was constructed from 4,699 radical prostatectomie specimens with histological, pathological, and clinical follow-up data. Immunohistochemistry was applied to detect nuclear p53 accumulation as a marker for defective p53 and to detect ERG expression as a surrogate for ERG gene fusion. Results: Nuclear accumulation of p53 was detected in 62/3,667 (1.7%) analyzable tissue spots. Positive staining was significantly linked to advanced tumor stage (p&lt;0.0001), high Gleason score (p&lt;0.0001), presence of lymph node metastases (p=0.0005), and early PSA recurrence (p&lt;0.0001) in all cancers. ERG expression was found in 1,990/4,266 (46.6%) analyzable cancers, but was unrelated to tumor phenotype or patient prognosis. Results of both p53 and ERG were available from 3,392 tumors. Presence of nuclear p53 staining was linked to ERG fusion positive cancers: 40 (2.7%) of 1,491 ERG-positive cancers, but only 20 (1.1%) of 1,901 ERG-negative tumors showed nuclear p53 staining (p=0.0004). A Kaplan-Meier survival analysis of p53 in the subsets of 1,699 ERG positive and 1,280 ERG negative cancers revealed that nuclear p53 accumulation was strongly linked to early PSA recurrence in both subsets (p&lt;0.0001 each). Conclusions: These data demonstrate that the poor prognosis of prostate cancer patients with nuclear p53 accumulation is independently from the ERG fusion status, but suggest a distinct biological role of p53 inactivation in ERG fusion positive cancers. The very high number of prostate cancer samples included in the TMA used in this study allows for analysis of rare events such as p53 alterations with high statistical power.
CMV Reactivations and Their Impact On Outcomes in Patients After Hematopoietic Cell Transplantation
Authors: Naheed Alam, Anna Lambie, Yvette Neme Yunes, Feras Alfraih, Eshetu G Atenafu, Dennis Dong Hwan Kim, Vikas Gupta, John Kuruvilla, Jeff H Lipton, Hans A. Messner
Journal: Blood (2012)
Hyperthyroidism decreases plasma HDL cholesterol by inhibition of hepatic ABCA1 expression
Authors: Ivan Tancevski, Andreas Wehinger, Egon Demetz, Julia Huber, Kathrin Hochegger, Philipp Eller, Wilfried Schgoer, Catherine Fievet, Frans Stellaard, Folkert Kuipers, Bernhard Foeger, Josef R. Patsch, Andreas Ritsch
Journal: Circulation (2006)
Is CDKN2A +/− CDKN2B and MTAP Inactivation of Prognostic Significance in B-Precursor Childhood Acute Lymphoblastic Leukemia? Results of EORTC Studies 58881 and 58951.
Authors: Delphine Mirebeau, Cécile Acquaviva, Stefan Suciu, Raphaëlle Bertin, Alain Robert, Patrick Boutard, Françoise Méchinaud, Emmanuel Plouvier, Jacques Otten, Etienne Vilmer, Hélène Cavé
Journal: Blood (2004)