tbuckley/cabot-search huggingface dataset:
HER3-EGFR score to predict clinical outcomes in triple-negative breast cancer.
Authors: Angela Ogden, Shristi Bhattarai, Andrew R. Green, Mohammed A. Aleskandarany, Emad A. Rakha, Ian O. Ellis, Xiaoxian (Bill) Li, Uma Krishnamurti, Emiel A. Janssen, Kristin Jonsdottir, Michelle D. Reid, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2017)

11612 Background: Limited preclinical evidence suggests that the ErbB family member HER3 may have prognostic value in TNBC. However, HER3 is a pseudokinase that cannot homodimerize, so in order to signal it must bind to other ErbB family members such as HER2 or EGFR. EGFR is frequently overexpressed in TNBC; consequently, it may be necessary to consider HER3 levels in the context of EGFR levels in TNBC to derive clinically meaningful insights. Methods: Towards this end, we tested the prognostic value of a combined immunohistochemical HER3-EGFR score (the sum of the individual H-scores, with the median used as a cutpoint) in a multi-institutional study of n = 510 TNBC patients using Cox proportional hazards regression. We also compared the HER3-EGFR-high and low groups in terms of 105 immunohistochemical biomarkers using Mann-Whitney U tests as well as Ingenuity canonical pathways using gene expression data from RNA-seq. Results: Among chemotherapy-treated TNBC patients, high HER3-EGFR score conferred a 2.30-fold increased risk of dying from breast cancer and a 1.78-fold increased risk of distant metastasis (p = 0.006 and p = 0.041, respectively) after adjusting for age and stage. Individual HER3 and EGFR H-scores were not associated with outcomes in simple or multivariable models. We also found that tumors from chemotherapy-treated TNBC patients with high HER3-EGFR scores exhibited higher immunohistochemical expression of luminal cytokeratins, DNA damage response proteins, and P-cadherin compared with tumors from chemotherapy-treated TNBC patients with low scores (q &lt; 0.25). The top canonical pathway whose components were overexpressed in HER3-EGFR-high TNBCs was Hepatic Fibrosis (p = 0.008), which is linked to distant metastasis, and the top upstream regulator was HNF4A (p = 0.012), a transcription factor for ERBB3 with isoforms that promote liver and gut tumorigenesis. Conclusions: Collectively, our study reveals that HER3-EGFR score may identify chemotherapy-treated TNBC patients at increased risk for distant metastases and death whose tumors may be characterized by fibrotic processes. Our immunohistochemical test thus identifies high-risk TNBCs who may benefit from agents that inhibit HER3-EGFR signaling.
Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma
Authors: Yuan Xiao Zhu, Chang-Xin Shi, Laura A. Bruins, Patrick Jedlowski, Xuewei Wang, K. Martin Kortüm, Moulun Luo, Jonathan M. Ahmann, Esteban Braggio, A. Keith Stewart
Journal: Cancer Research (2017)

FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317-27. ©2017 AACR.
Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis
Authors: Sofie L. M. Blokland, Maarten R. Hillen, Aike A. Kruize, Stephan Meller, Bernhard Homey, Glennda M. Smithson, Timothy R. D. J. Radstake, Joel A. G. van Roon
Journal: Arthritis & Rheumatology (2017)

Objective Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9‐expressing T helper cells have “Tfh‐like” characteristics and their numbers are increased at mucosa‐associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. Methods Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non‐SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. Results CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non‐SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin‐21 (IL‐21) and soluble IL‐7 receptor α‐chain (IL‐7Rα). Furthermore, the frequency of CCR9‐expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL‐7Rα and secreted higher levels of interferon‐γ, IL‐17, IL‐4, and IL‐21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL‐7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9−CXCR5− T helper cells. Conclusion Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL‐7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.
Efficacy and safety of neoadjuvant paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy in locally advanced squamous cell cervical carcinoma followed by radical surgery: A single institution experience.
Authors: Giuseppa Scandurra, Giuseppe Scibilia, Giuseppe Luigi Banna, Helga Maria Alessandra Lipari, Gabriella D'Agata, Paolo Scollo
Journal: Journal of Clinical Oncology (2013)

e16532 Background: The management of locally advanced squamous cell cervical carcinoma includes chemoradiotherapy or neoadjuvant cisplatin based chemotherapy followed by surgery, that may offer specific advantages a better potential activity. Porpouse: To evaluate efficacy and safety of TIP neoadjuvant chemoregimen in patiens affects by local advanced squamous cell cervical carcinoma. Methods: July 1997 - December 2011 were treated at our institution 165 patients with locally advanced squamous cell cervical carcinoma of whom 143 are evaluable. Regimen: Ifosfamide 5000 mg/mq ev day 1 iv in 24 h ; Mesna 5000 mg/mq ev day 1 iv in 24 h ; Paclitaxel 175 mg/mq ev day 2; Cisplatin 75 mg/mq ev day 2; every 3 weeks for a total of three courses. Tumor extension was assessed clinically and by abdominal MRI, PET WB and 3D ultrasound at baseline and after three courses.The operable patients after TIP chemoterapy underwent radical hysterectomy and pelvic lymphadenectomy. The median age 53 ( range 24-79 yrs), clinical FIGO stage Ib 2 2 pts(1%) , IIb 59 pts(41%), IIb bulky 68 pts (48%), III-IV 14 pts (10%), histological subtype SCC 138 pts (96%) and adenocarcinoma 5 pts ( 4%). Results: After neoadjuvant chemiotherapy 132 pts (92%) underwent surgery. Post-chemotherapy pathological response was pCR 25 pts (19%), PR1 16 pts (12%), PR2 80 pts (61%), SD 10 pts (7%), PD 1 pt (1%). Median numbers of courses of TIP administrated was 3 ( range 1-3). Treatments was delay or withdrawal in 22 pts ( 16%). Treament limiting toxicities were, Neutropenia 11 pts (52%) , Anemia 10 pts (45%),Thrombocytopenia 7 pts (33 %), Renal failure 3 pts (14 %), Allergic reaction 3 pts (14%), Vomiting 3 pts (14%), Febrile neutropenia 2 pts (10%), Hypopotassiemia1 pt (5%), Atrial fibrillation 1pt( 5%), Pneumonia 1 pt (5%). Conclusions: In our experience neoadjuvant TIP was feasible, effective with 92% resection rate and active in an older and higher stage disease enriched series than reported in previous clinical trials.
Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials - NSCLC meta-analyses collaborative group
Authors: S Burdett, R Stephens, L Stewart, J Tierney, A Auperin, T Le Chevalier, C Le Pechoux, JP Pignon, R Arriagada, J Higgins, D Johnson, J van Meerbeeck, M Parmar, R Souhami, Nsclc Meta-Anal Collaborat Grp
Journal: Journal of Clinical Oncology (2008)

PurposeSince our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non -small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy.MethodsSystematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs).ResultsData were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P <= .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups.ConclusionThis MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.
The Waiting Game — Why Providers May Fail to Reduce Wait Times
Authors: Jaewon Ryu, Thomas H. Lee
Journal: New England Journal of Medicine (2017)

Interview with Dr. Thomas Lee on the financial incentives that keep providers from reducing patient waiting times. (09:59)Download The financial consequences of long waiting times for appointments help explain why most health care providers have dragged their feet in cutting those delays. Redesigning care to reduce waits requires investing in systems, may reduce revenue, and irritates physicians.
Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK‐1 Inhibitor, After Short‐Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials
Authors: Frédéric Vanhoutte, Minodora Mazur, Oleksandr Voloshyn, Mykola Stanislavchuk, Annegret Van der Aa, Florence Namour, René Galien, Luc Meuleners, Gerben van 't Klooster
Journal: Arthritis & Rheumatology (2017)

JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK-1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.Treatment with filgotinib at 75-300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea.Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.
SIMILAR ADJUSTED SVR12 RATES FOR HIV CO-INFECTED AND HCV MONO-INFECTED PATIENTS AND NO DOSE OR POPULATION (TREATMENT-NAIVE/RELAPSER) EFFECT
Authors: D. Dieterich, P. Ferenci, I. M. Jacobson, F. Negro, M. Puoti, J. K. Rockstroh, M. P. Manns, K. Arasteh, C. Oliveira, J. F. Dufour, E. Zehnter, Clifford Leen, S. Bhagani, J. O. Stern, A. M. Quinson, J. Scherer, M. Manero, D. M. Jensen
Journal: Journal of Hepatology (2014)
Telomerase inhibition: Structure-activity relationships among perylene-related drugs
Authors: Krisztina Pongracz, Daria Zielinska, Nilesh Karalkar, Ellen Wunder, Queenie Lam, Denise Nazzal, Allison C. Chin, Sergei M. Gryaznov
Journal: Cancer Research (2005)

2836  A valuable approach to interfere with telomerase activity is to stabilize the G-quadruplex folded structure of telomeres. To reach this goal, compounds containing extended planar ring systems have been widely used. These compounds are effective DNA binders due to favourable stacking within the the G-quadruplex system. Among them, a prominent position from a pharmacological point of view is covered by perylenes. Many indications suggest that they stabilize G-quadruplex structures by face recognition on the terminal G-quartet of the folded telomere. With the aim to further investigate the role of drug structure in driving the DNA conformation recognition and the binding mode, we have synthesized and studied a series of perylene-related compounds. As leading compound we choose PIPER, a well known telomerase inhibitor. In this work, we modified the basicity of the nitrogens in the side chains, hence modulating the protonation state and the extent of drug aggregation at physiological conditions. Additionally, we modified the extension of the planar system, changing the number of condensed aromatic rings. Selective interaction with quadruplex vs. other DNA folded arrangements was preliminary assessed by comparing IC50s for inhibition of telomerase (TRAP assay) and TAQ polymerase respectively. To investigate in deeper detail the molecular basis for DNA-binding selectivity, the interactions of the new compounds with several DNA structures were further characterized by electrophoretic and chiroptical techniques using PIPER as a reference. Finally, cytotoxic properties of the test drugs were evaluated. The results allowed us to define structure-selective recognition-activity relationships for the examined derivatives for future rational design.
The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility
Authors: Teddy Jégu, Alaguraj Veluchamy, Juan S. Ramirez-Prado, Charley Rizzi-Paillet, Magalie Perez, Anaïs Lhomme, David Latrasse, Emeline Coleno, Serge Vicaire, Stéphanie Legras, Bernard Jost, Martin Rougée, Fredy Barneche, Catherine Bergounioux, Martin Crespi, Magdy M. Mahfouz, Heribert Hirt, Cécile Raynaud, Moussa Benhamed
Journal: Genome biology (2017)

Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored. In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome-free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms. These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions.
Drugs with FDA accelerated approval often have weak evidence, study finds
Authors: Owen Dyer
Journal: BMJ (2017)

Drugs that receive accelerated approvals from the US Food and Drug Administration often rest on a flawed evidence base, says research that evaluated over 7000 clinical studies conducted on 37 drugs that were given such approvals from 2000 to 2013.

The review, which also included researchers from the University of Pennsylvania and Stanford University, appeared in the US …
Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes
Authors: Ian Chau
Journal: Clinical Cancer Research (2017)

Gastrointestinal (GI) cancers are among the most deadly malignancies. Although serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumors of each primary anatomical site but also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumors and their interaction with the tumor microenvironment would further affect development of combination therapy, including immunotherapy. Currently, immune checkpoint blockade attracts the most intense research, and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers. Clin Cancer Res; 23(20); 6002-11. ©2017 AACR.
Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention
Authors: Raffaele Piccolo, Giuseppe Gargiulo, Anna Franzone, Andrea Santucci, Sara Ariotti, Andrea Baldo, Carlo Tumscitz, Aris Moschovitis, Stephan Windecker, Marco Valgimigli
Journal: Annals of Internal Medicine (2017)

The dual-antiplatelet therapy (DAPT) score was developed to identify patients more likely to derive harm (score <2) or benefit (score ≥2) from prolonged DAPT after percutaneous coronary intervention (PCI).To evaluate the safety and efficacy of DAPT duration according to DAPT score.Retrospective assessment of DAPT score-guided treatment duration in a randomized clinical trial. (ClinicalTrials.gov: NCT00611286).PCI patients.1970 patients undergoing PCI.DAPT (aspirin and clopidogrel) for 24 versus 6 months.Primary efficacy outcomes were death, myocardial infarction, or cerebrovascular accident. The primary safety outcome was type 3 or 5 bleeding according to the Bleeding Academic Research Consortium definition. Outcomes were assessed between 6 and 24 months.884 patients (44.9%) had a DAPT score of at least 2, and 1086 (55.1%) had a score less than 2. The reduction in the primary efficacy outcome with 24- versus 6-month DAPT was greater in patients with high scores (risk difference [RD] for score ≥2, -2.05 percentage points [95% CI, -5.04 to 0.95 percentage points]; RD for score <2, 2.91 percentage points [CI, -0.43 to 6.25 percentage points]; P = 0.030). However, the difference by score for the primary efficacy outcome varied by stent type; prolonged DAPT with high scores was effective only in patients receiving paclitaxel-eluting stents (RD, -7.55 percentage points [CI, -12.85 to -2.25 percentage points]). The increase in the primary safety outcome with 24- versus 6-month DAPT was greater in patients with low scores (RD for score ≥2, 0.20 percentage point [CI, -1.20 to 1.60 percentage points]; RD for score <2, 2.58 percentage points [CI, 0.71 to 4.46 percentage points]; P = 0.046).Retrospective calculation of the DAPT score.Prolonged DAPT resulted in harm in patients with low DAPT scores undergoing PCI but reduced risk for ischemic events in patients with high scores receiving paclitaxel-eluting stents. Whether prolonged DAPT benefits patients with high scores treated with contemporary drug-eluting stents requires further study.None.