tbuckley/cabot-search huggingface dataset:
Discovery and development of novel therapies in advanced breast cancer: rapid development of ribociclib
Authors: C. Germa, M. Miller, P. Mukhopadhyay, B. Hewes, G. Caponigro, S.J. Scherer, S. Hirawat
Journal: Annals of Oncology (2017)

The treatment landscape for advanced breast cancer has changed radically over the last 30–40 years with the refinement of surgical and radiographic techniques, approval of a range of chemotherapy regimens in the adjuvant and metastatic settings, and improvements in screening procedures. A deeper understanding of the molecular pathways underpinning tumor growth has led to the identification and development of a number of targeted therapies with particularly high activity in breast cancer. As an example, the prognosis of women with human epidermal growth factor receptor 2-positive (HER2+) breast cancer has improved dramatically since the introduction of HER2-targeted therapies [1].
Review: After coronary DES, ≤ 6 mo and 1 y of dual-antiplatelet therapy do not differ for CV events at 1 y
Authors: Nick Fitterman, Varinder Singh
Journal: Annals of Internal Medicine (2017)

Source Citation Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients. Eur Heart J. 2017;38:1034-43. 28110296
Stress Testing in Asymptomatic Aortic Stenosis
Authors: Björn Redfors, Philippe Pibarot, Linda D. Gillam, Daniel Burkhoff, Jeroen J. Bax, Brian R. Lindman, Robert O. Bonow, Patrick T. O’Gara, Martin B. Leon, Philippe Généreux
Journal: Circulation (2017)

Aortic stenosis is 1 of the most common heart valve diseases among adults. When symptoms develop, prognosis is poor, and current guidelines recommend prompt aortic valve replacement. Depending of the severity of the aortic stenosis and the presence of concomitant heart disease and medical comorbidities, stress testing represents a reasonable strategy to help better risk stratify asymptomatic patients. The present report provides a comprehensive review of the current available data on stress testing in aortic stenosis and subsequently summarizes its potential for guiding the optimal timing of aortic valve replacement.
Molecular evaluation of ribosomal protein L9 gene (RPL9) in lung cancer
Authors: Zodwa Dlamini, Lebogang Mphahlele
Journal: Cancer Research (2006)

3272  Background: The human ribosomal protein gene (RPL9) is approximately 5.5 kb in length and contains 8 exons. It is located in chromosome 4p13. This gene encodes a ribosomal protein that is a component of the 60S subunit and it has been localized in the cytoplasm. The possible function of this gene is in cell growth and development as the highest expression levels of this gene has been observed in cells undergoing growth and development and that the level of expression declines as the tissue reaches developmental maturity. Aim: The objective of this study was to determine the expression pattern of RPL9 in various lung cancers. Materials and Method: Wax embedded tissue sections for the normal lung and lung cancer (small cell lung carcinoma, adernocarcinoma, large cell carcinoma and squamous cell carcinoma) were used to investigate the expression of RPL9. Antisense and sense RNA probes were synthesized by in vitro transcription and labeled with Digoxygenin. Anti-sense RNA probe complimentary to the RPL9 mRNA was used to localize RPL9 mRNA transcript in tissue sections by in situ hybridization. Results: RPL9 was found to be accumulating in the cytoplasm and was found to be up-regulated in lung cancer tissue sections as compared to normal lung tissue sections. The expression pattern for RPL9 in lung cancer was found to be significantly higher in small cell lung carcinoma, followed by Adernocarcima, Large cell carcinoma and least expressed in squamous cell lung carcinoma. Conclusion: The up-regulation of RPL9 in cancer tissues as compared to normal tissues suggest that RPL9 might be playing a crucial role in cell growth, development and cell proliferation. Determination of RPL9 expression in cancer can serve as a potentially useful marker to future studies for drug development aimed against cancer cells.
Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response
Authors: Zhiguo Li, Jie Li, Yifan Kong, Shan Yan, Nihal Ahmad, Xiaoqi Liu
Journal: Cancer Research (2017)

The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment. Cancer Res; 77(12); 3169-80. ©2017 AACR.
Biologic Crystals and Particles Produced in Tissue Culture
Authors: George G. Rose
Journal: Cancer Research (1963)

A method for the cultivation of embryo chick tissues which gave rise to numerous and unusually large crystals and particles is detailed. Forms were helical, tubular, ribbon-like, hexagonal, rhomboidal, and filamentous. Rhomboids and hexagonals often had surface areas several times the size of the broad and flat tissue-cultured cells, and helices were observed up to 300 µ in length. Transformations of helical and related forms were observed. Their chemical identity could not be determined by conventional cytochemical technics. With modifications, however, helical and related forms were shown to give a positive reaction to pyronin staining which was inhibited by prior digestion in ribonuclease.
Diffuse large B cell lymphoma: Characterisation of immunohistochemical and interim PET scan analysis and correlation with outcome.
Authors: P A Fields, G Mikhaeel, E Navarit-Adeline, J Freeman, K Ryder, M Kazmi, N Mir, R Ireland, Eva Wegner, T Nunan, Jon van der Walt, Stephen Schey, A R Timothy
Journal: Blood (2003)
Abstract 310: Role of Cardiac Fibroblast in Cardioprotective Effects of Prior Transient ACE Inhibition
Authors: Taben M Hale, Lauren A Biwer, Karen M D’Souza
Journal: Circulation Research (2013)

Prior treatment with the ACE inhibitor enalapril followed by washout protects against nitric oxide synthase inhibitor (L-NAME) induced fibrosis, cellular proliferation, and cardiac dysfunction. The present study investigated i) whether in vivo L-NAME administration induces a change in cardiac fibroblast phenotype that persists in vitro, ii) whether prior ACE inhibition protects against L-NAME induced changes in cardiac fibroblasts. SHR were divided into 3 groups: Control, L-NAME (C+L: 7d), enalapril+L-NAME (E+L: 14d enalapril + 14d washout + 7d L-NAME). MAP was measured by radiotelemetry (n=5-9), injury assessed by histology (n=6-10), and heart weight to body weight (HW/BW) was determined after 0 or 7 days of L-NAME in C+L and E+L (n=6-10). In separate rats cardiac fibroblasts were isolated after 7 days of L-NAME (C+L, E+L) or placebo (Con) and cultured to passage 1 (n=10-12). Gene expression was measured by quantitative real-time PCR. L-NAME increased MAP in C+L (22±4.1%) and E+L (21±3.6%) rats. Prior enalapril induced a persistent 13% reduction in HW/BW. L-NAME increased heart mass in E+L (7%) but not C+L; however, HW/BW remained 8% lower than C+L at sacrifice. L-NAME induced infarct in 70% of C+L and 40% of E+L hearts. Cardiac fibroblasts demonstrated a significant increase in proliferation rate in C+L, but not E+L, relative to control (C+L: 1.75-fold vs. con; E+L 1.09-fold vs. con). Fibroblasts from C+L hearts tended to have increased Collagen I and III gene expression. Despite hypertension, cardiac injury, and increased HW/BW; fibroblasts isolated from E+L proliferated at the same rate as those from control. In contrast, those isolated from C+L were hyperproliferative with a tendency toward increased capacity for collagen production. It may be that the fibroblast phenotype from E+L hearts would protect against infarct expansion and account, in part, for the previously reported cardioprotection in these rats.
Postoperative Opioid Prescribing and the Pain Scores on Hospital Consumer Assessment of Healthcare Providers and Systems Survey
Authors: Jay S. Lee, Hsou M. Hu, Chad M. Brummett, John D. Syrjamaki, James M. Dupree, Michael J. Englesbe, Jennifer F. Waljee
Journal: JAMA (2017)

In 2012, the Centers for Medicare & Medicaid Services (CMS) implemented the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) to capture key elements of patient satisfaction, including pain management. HCAHPS surveys are administered to patients 48 hours to 6 weeks after discharge, and scores are used to determine hospital payments.1 However, patients complete surveys during a time when many are filling postdischarge opioid prescriptions. This timing has raised concerns that HCAHPS measures could inadvertently incentivize clinicians to overprescribe opioids after discharge to ensure satisfactory ratings and reimbursement.2,3 Citing these concerns, CMS announced it will remove pain management from its determination of hospital payments beginning in 2018, even though little is known regarding the potential correlation between HCAHPS scores and postdischarge opioid prescribing.3 We sought to evaluate the association between HCAHPS pain measures and postoperative opioid prescribing in surgical patients, which accounts for nearly 40% of surgical prescriptions.
Mantle cell lymphoma: 2015 update on diagnosis, risk-stratification, and clinical management
Authors: Julie M. Vose
Journal: American Journal of Hematology (2015)

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years.Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma.The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median OS for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group.For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression-free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti-angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients.
Reply to Jae Heon Kim and Benjamin I. Chung's Letter to the Editor re: Maria Carmen Mir, Ithaar Derweesh, Francesco Porpiglia, Homayoun Zargar, Alexandre Mottrie, Riccardo Autorino. Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta-analysis of Comparative Studies. Eur Urol 2017;71:606–17
Authors: Maria Carmen Mir, Ithaar H. Derweesh, Riccardo Autorino
Journal: European Urology (2017)
Clinical characterization of hypoxia in pancreatic ductal adenocarcinoma (PDAC) by <sup>18</sup>F-FAZA PET and pimonidazole.
Authors: Cristiane Metran Nascente, Neesha C. Dhani, Douglass Vines, Ivan Yeung, Ur Metser, Stefano Serra, Michael Milosevic, Steven Gallinger, David W. Hedley
Journal: Journal of Clinical Oncology (2013)

4049 Background: We previously demonstrated correlation between hypoxia and aggressive tumor biology in orthotopic, patient-derived pancreatic xenografts (Chang et al. Cancer Res 2011). With the development of hypoxia-directed therapies, there is a need to understand the range and relevance of hypoxia in PDAC patients. We therefore launched two complementary clinical trials using 2-nitroimidazole-based hypoxia probes. Methods: PIMO-PANC involves pre-operative administration of pimonidazole to patients (pts) undergoing PDAC resection. Hypoxic percent (HP) of tumors is determined by semi-automated image analysis (on Aperio’s Genie) of multiple histological sections stained for pimonidazole by immunohistochemistry (IHC). FAZA-PANC uses the positron emission tomography (PET) tracer fluoroazomycin arabinoside ( 18 F-FAZA) to evaluate hypoxia by functional imaging. 2 hours post-injection of (5.2 MBq/kg) 18 F-FAZA, static scans are acquired followed by computed tomography for anatomic registration. Skeletal muscle is a non-hypoxic reference tissue to define standardized uptake values (SUV), tumor to muscle uptake ratios (T/M’s) and a threshold for hypoxia. Results: PIMO-PANC has enrolled 29 pts and FAZA-PANC 16. IHC analysis of the first 10 pt tumors demonstrates considerable intra- and inter-tumoral heterogeneity of hypoxia (HP: 1 to 26% across pt tumors); minimal hypoxia (&lt; 5%) was observed in 3 pts. 18 F-FAZA-PET in the first 11 pts demonstrates SUV max from 1.02 to 1.83, median T/M's from 0.84 to 1.31. A threshold of 1.27 SUV max defines HP of 0 to 60% with minimal hypoxia (&lt;10%) in 5 pts. Conclusions: There is significant heterogeneity of hypoxia across the spectrum of clinical PDAC (local to metastatic disease) using the 2-nitroimidazole hypoxia probes pimonidazole and 18 F-FAZA. Given the intra-tumoral heterogeneity of hypoxia by histopathology, functional imaging is the preferred method to assess hypoxia in PDAC patients. Importantly, both methods identified a group of PDAC tumors with low levels of hypoxia. This is relevant to the on-going development of hypoxia-targeting strategies. Accrual to PIMO-PANC is on-going and will address the prognostic relevance of hypoxia in PDAC. Clinical trial information: NCT01542177 and NCT01248637.
Divergent Requirements for EZH1 in Heart Development Versus Regeneration
Authors: Shanshan Ai, Xianhong Yu, Yumei Li, Yong Peng, Chen Li, Yanzhu Yue, Ge Tao, Chuanyun Li, William T. Pu, Aibin He
Journal: Circulation Research (2017)

Rationale: Polycomb repressive complex 2 is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are 2 alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown. Objective: We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration. Methods and Results: Heart development was normal in Ezh1 −/− ( Ezh 1 knockout) and Ezh2 f/f ::cTNT −Cre ( Ezh 2 knockout) embryos. Ablation of both genes in Ezh1 −/− ::Ezh2 f/f ::cTNT −Cre embryos caused lethal heart malformations, including hypertrabeculation, compact myocardial hypoplasia, and ventricular septal defect. Epigenome and transcriptome profiling showed that derepressed genes were upregulated in a manner consistent with total EZH dose. In neonatal heart regeneration, Ezh1 was required, but Ezh2 was dispensable. This finding was further supported by rescue experiments: cardiac myocyte-restricted re-expression of EZH1 but not EZH2 restored neonatal heart regeneration in Ezh 1 knockout. In myocardial infarction performed outside of the neonatal regenerative window, EZH1 but not EZH2 likewise improved heart function and stimulated cardiac myocyte proliferation. Mechanistically, EZH1 occupied and activated genes related to cardiac growth. Conclusions: Our work unravels divergent mechanisms of EZH1 in heart development and regeneration, which will empower efforts to overcome epigenetic barriers to heart regeneration.
<i>Aspergillus fumigatus</i> in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis
Authors: A. Carsin, T. Romain, S. Ranque, M. Reynaud‐Gaubert, J.‐C. Dubus, J.‐L. Mège, J. Vitte
Journal: Allergy (2017)

A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%-10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis.
Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis
Authors: Timothy E. McAlindon, Michael P. LaValley, William F. Harvey, Lori Lyn Price, Jeffrey B. Driban, Ming Zhang, Robert J. Ward
Journal: JAMA (2017)

<h3>Importance</h3> Synovitis is common and is associated with progression of structural characteristics of knee osteoarthritis. Intra-articular corticosteroids could reduce cartilage damage associated with synovitis but might have adverse effects on cartilage and periarticular bone. <h3>Objective</h3> To determine the effects of intra-articular injection of 40 mg of triamcinolone acetonide every 3 months on progression of cartilage loss and knee pain. <h3>Design, Setting, and Participants</h3> Two-year, randomized, placebo-controlled, double-blind trial of intra-articular triamcinolone vs saline for symptomatic knee osteoarthritis with ultrasonic features of synovitis in 140 patients. Mixed-effects regression models with a random intercept were used to analyze the longitudinal repeated outcome measures. Patients fulfilling the American College of Rheumatology criteria for symptomatic knee osteoarthritis, Kellgren-Lawrence grades 2 or 3, were enrolled at Tufts Medical Center beginning February 11, 2013; all patients completed the study by January 1, 2015. <h3>Interventions</h3> Intra-articular triamcinolone (n = 70) or saline (n = 70) every 12 weeks for 2 years. <h3>Main Outcomes and Measures</h3> Annual knee magnetic resonance imaging for quantitative evaluation of cartilage volume (minimal clinically important difference not yet defined), and Western Ontario and McMaster Universities Osteoarthritis index collected every 3 months (Likert pain subscale range, 0 [no pain] to 20 [extreme pain]; minimal clinically important improvement, 3.94). <h3>Results</h3> Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm (between-group difference, −0.11 mm; 95% CI, −0.20 to −0.03 mm); and no significant difference in pain (−1.2 vs −1.9; between-group difference, −0.6; 95% CI, −1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A<sub>1c</sub>levels (between-group difference, −0.2%; 95% CI, −0.5% to −0.007%). <h3>Conclusions and Relevance</h3> Among patients with symptomatic knee osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline, resulted in significantly greater cartilage volume loss and no significant difference in knee pain. These findings do not support this treatment for patients with symptomatic knee osteoarthritis. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01230424