tbuckley/cabot-search huggingface dataset:
A randomized, double-blind, multicenter phase 2 trial of denosumab in combination with chemotherapy as first-line treatment of metastatic non-small cell lung cancer.
Authors: David R. Spigel, Fred R. Hirsch, Richard H. De Boer, Ronald B. Natale, Jeffrey Crawford, Glen J. Weiss, John A. Glaspy, Amy Feng, Ada Braun, Rajul K. Jain
Journal: Journal of Clinical Oncology (2014)

TPS8130 Background: Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous disease forwhich patients (pts) may benefit from targeted therapies. RANK ligand (RANKL) and its receptor RANK are expressed in a subset of NSCLC tumors (Branstetter, 2013). Results from preclinical models show that RANKL acts directly on RANK-expressing tumor cells to promote tumor progression and metastases (Gonzalez-Suarez, 2010; Tan, 2011). Denosumab is a fully human monoclonal antibody that binds RANKL, approved for the prevention of skeletal-related events in pts with solid tumors and bone metastases. In a study of pts with solid tumors receiving standard treatment, post hoc analysis of those with stage IV NSCLC (n = 702) showed that pts who received denosumab had improved median overall survival (OS) vs those who received zoledronic acid (ZA; HR [95% CI] 0.78 [0.65–0.94], p = 0.01; Scagliotti, 2012). The current trial will correlate tumor RANK and RANKL expression and OS in pts with metastatic NSCLC receiving denosumab in combination with standard chemotherapy vs those receiving chemotherapy alone. The trial is sponsored by Amgen Inc. and registered with ClinicalTrials.gov (NCT01951586). Methods: ~216 pts with untreated stage IV NSCLC will receive 4–6 cycles of standard of care chemotherapy and be randomized (2:1) to denosumab 120 mg or placebo SC Q3W or Q4W plus a loading dose on day 8. ZA or placebo IV may be offered in a blinded manner if requested. The sample size is powered to test the interaction between treatment effect and RANK or RANKL expression under various reasonable scenarios. Pts will receive calcium and vit D daily. Randomization will be stratified based on bone metastasis (yes or no), histology (squamous vs nonsquamous), and region (North America, Western Europe/Australia, rest of world). The primary endpoint is tumor RANK expression correlated with OS. Primary analysis will occur when ~149 deaths have occurred. Eligible pts will have ECOG status 0–1 and radiographically evaluable disease. Pts with known EGFR-activating mutations, EML-4-ALK translocations, or brain metastasis will be excluded. Pt screening and enrollment is planned or underway in ~10 countries. Clinical trial information: NCT01951586.
Validation of international consensus equation for acute serum total tryptase in mast cell activation: A perioperative perspective
Authors: R. L. Baretto, S. Beck, J. Heslegrave, C. Melchior, O. Mohamed, A. Ekbote, A. P. Huissoon, M. T. Krishna
Journal: Allergy (2017)

Abstract There is no standardized method for assessing serum total mast cell tryptase ( MCT ) in anaphylaxis. The consensus equation (peak MCT should be&gt;1.2× baseline tryptase+2 mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome ( MCAS ). To validate consensus equation in a perioperative setting analyses of cases of suspected perioperative anaphylaxis during general anaesthesia ( GA ) were performed. Anaphylaxis was defined as per World Allergy Organisation ( WAO ) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic ( ROC ) curves produced. A total of 82 patients (60 females, mean age 56.5 years± SD 17.2) underwent investigation. Sixty (73%) patients fulfilled WAO criteria for anaphylaxis, and 22 patients did not. Aetiology included 59% IgE‐mediated anaphylaxis, 2% non‐IgE‐mediated anaphylaxis, 12% anaphylaxis of unknown cause and 27% deemed non‐anaphylaxis. IgE‐mediated anaphylaxis included the following: NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71 of 82 (87%) patients (60 anaphylaxis and 11 controls). The median interquartile range ( IQR ) time from reaction to peak MCT was 1.34 (0.82‐2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value ( PPV ) and negative (N) PV of 78%, 91%, 98% and 44%, respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls ( P =.0001). This equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis.
Acute hepatic porphyrias: Recommendations for evaluation and long‐term management
Authors: Manisha Balwani, Bruce Wang, Karl E. Anderson, Joseph R. Bloomer, D. Montgomery Bissell, Herbert L. Bonkovsky, John D. Phillips, Robert J. Desnick
Journal: Hepatology (2017)

The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life‐threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic attacks (&lt;4 attacks/year) or recurrent acute attacks (≥4 attacks/year), asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow‐up, and long‐term management are needed, particularly because no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific acute hepatic porphyria, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow‐up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long‐term complications. These guidelines provide a framework for monitoring patients with acute hepatic porphyrias to ensure optimal outcomes. (H epatology 2017;66:1314‐1322)
GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy
Authors: Lin Piao, Yong-Hu Fang, Kishan S. Parikh, John J. Ryan, Karen M. D'Souza, Tiju Theccanat, Peter T. Toth, Jennifer Pogoriler, Jonathan Paul, Burns C. Blaxall, Shahab A. Akhter, Stephen L. Archer
Journal: Circulation (2012)

The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein-coupled receptor kinase-2 (GRK2)-mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ-GRK2 interaction, using gallein, were tested.Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding-induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular-Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of β1-, α1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). β1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo.GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1-receptor signaling, which is impaired in RVH. Inhibiting Gβγ-GRK2 interactions has therapeutic benefit in RVH.
A memorable patient: Straight from the patient's mouth
Authors: C. Andrade
Journal: BMJ (2002)

He was a 45 year old unemployed man living in a lower middle class joint family home in an urban area. He was referred for psychiatric evaluation by a private practitioner because he was depressed and irritable, he complained of sleep disturbance, and he described a constant clicking sound arising from the middle of his head. The last mentioned symptom evoked much interest, and I, the then junior resident in the unit, was instructed to present …
A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220
Authors: Panpan Hou, Chao Wu, Yuchen Wang, Rui Qi, Dheeraj Bhavanasi, Zhixiang Zuo, Cedric Dos Santos, Shuliang Chen, Yu Chen, Hong Zheng, Hong Wang, Alexander Perl, Deyin Guo, Jian Huang
Journal: Cancer Research (2017)

Abstract Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD–positive and –negative AML patients and as maintenance therapy. To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR-pooled library to screen new genes whose loss of function confers resistance to AC220. We identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated reactivation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to AC220. We confirmed these findings in primary AML patient samples. Expression of SPRY3 and GSK3A was dramatically reduced in AC220-resistant AML samples, and SPRY3-deleted primary AML cells were resistant to AC220. Intriguingly, expression of SPRY3 was greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function conferred resistance to a selective FLT3 inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in AML. Cancer Res; 77(16); 4402–13. ©2017 AACR.
Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart
Authors: Claudia Noack, Maria P Zafiriou, Anke Renger, Hans J Schaeffer, Martin W Bergmann, Laura C Zelaráyan
Journal: Circulation Research (2012)

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.
Is the sensitivity of primary ciliary dyskinesia detection by ciliary function analysis 100%?
Authors: Mieke Boon, Mark Jorissen, Martine Jaspers, Harry Cuppens, Kris De Boeck
Journal: European Respiratory Journal (2013)

With respect to the dissociation between the risk of deep venous thrombosis and pulmonary embolism, we very much agree with D.P. Potaczek and A. Undas that this suggests that the activation of haemostasis in our population is not due to prolonged immobilisation and hospitalisations, but is the result of inflammation in the airways per se.Of course, our findings have to be replicated in larger cohorts and more studies are needed to disentangle the underlying mechanisms, in particular with respect to asthma severity, type of airway inflammation and the use of corticosteroids. @ERSpublicationsPost hoc analysis in subgroups, stratified for atopic and non-atopic asthma, reveals no differences in risk of VTE http://ow.ly/mK7BW
Is there a survival benefit in patients with advanced squamous cell carcinoma of the head and neck under chemoradiotherapy or radiotherapy alone after surgery administration: A systematic review and meta-analysis.
Authors: Jinbiao Shang, Jialei Gu, Qianbo Han, Yaping Xu, Xinmin Yu, Kejin Wang
Journal: Journal of Clinical Oncology (2014)

6052 Background: The optimal treatment strategy for patients with operable advanced squamous cell carcinoma of the head and neck is uncertain. We performed a systematic review and meta-analysis to test the hypothesis that the addition of chemotherapy to radiotherapy after surgical resection could improve the locoregional control and survival compared with postoperative radiotherapy alone. Methods: A comprehensive search of PubMed for relevant studies comparing patients with advanced squamous cell carcinoma of the head and neck undergoing chemoradiotherapy or radiotherapy alone after resection was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. The endpoints were local-regional control (LRC), disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were extracted from these studies to give pooled estimates of the effect of chemotherapy as an adjunct to postoperative radiation therapy on DFS and OS. Results: Data from a total of 1,054 patients from 5 randomized trials investigating chemoradiotherapy versus radiotherapy alone after surgery were included in a meta-analysis. The meta-analysis demonstrated significant benefits from adding chemotherapy to radiotherapy in LRC (risk ratio [RR]: 0.61, 95% confidence interval [CI]: 0.49 - 0.76, p < 0.00001), DFS (HR: 0.76, 95% CI: 0.65 - 0.88, p = 0.0003) and OS (HR: 0.77, 95% CI: 0.66 – 0.90, p = 0.001). The adverse effects occurred more frequently and severely in chemoradiation combined treatment, but there was no significant difference compared with radiotherapy alone. Conclusions: Postoperative chemotherapy adding to radiotherapy is superior to radiotherapy alone. Patients with chemoradiotherapy after surgical resection can achieve the higher LRC, longer DFS and OS. But the pronounced benefits of chemoradiation combined treatment need to be weighed against the potential toxicity of treatment.
Successful Hematopoietic Stem Cell Transplantation Using an Immunosuppressive Conditioning Regimen in Ten Patients with Severe Congenital Neutropenia: A Single-Institute Experience
Authors: Yoko Mizoguchi, Mizuka Miki, Aya Furue, Shiho Nishimura, Maiko Shimomura, Keita Tomioka, Sonoko Sakata, Ikue Chijimatsu, Shuhei Karakawa, Satoshi Okada, Takehiko Doi, Kazuhiro Nakamura, Hiroshi Kawaguchi, Masao Kobayashi
Journal: Blood (2016)
Implementation of Targeted Therapy in Denmark for Patients with Metastatic Renal Cell Carcinoma: Results from the Danish Renal Cancer Group (DARENCA) Study-2
Authors: A.V. Soerensen, F. Donskov, G.G. Hermann, N.V. Jensen, H. Spliid, E.Q. Bergan, K. Fode, P.F. Geertsen
Journal: Annals of Oncology (2012)
Precision, complexity and stigma in advanced prostate cancer terminology: it is time to move away from ‘castration-resistant’ prostate cancer
Authors: C.J. Pezaro, A. Omlin, K. Mastris, G. Attard, T.M. Beer, K.N. Chi, S. Chowdhury, I.D. Davis, C.G. Drake, J.S. de Bono, E. Efstathiou, G. Gravis, C.S. Higano, M. Hussain, N. James, C.J. Logothetis, A. Morgans, C. Parker, C.J. Ryan, F. Saad, O. Sartor, E.J. Small, C.N. Sternberg, C.J. Sweeney, I. Tannock, B. Tombal, S. Gillessen
Journal: Annals of Oncology (2017)
A novel immune biomarker <i>IFI27</i> discriminates between influenza and bacteria in patients with suspected respiratory infection
Authors: Benjamin M. Tang, Maryam Shojaei, Grant P. Parnell, Stephen Huang, Marek Nalos, Sally Teoh, Kate O'Connor, Stephen Schibeci, Amy L. Phu, Anand Kumar, John Ho, Adrienne F. A. Meyers, Yoav Keynan, Terry Ball, Amarnath Pisipati, Aseem Kumar, Elizabeth Moore, Damon Eisen, Kevin Lai, Mark Gillett, Robert Geffers, Hao Luo, Fahad Gul, Jens Schreiber, Sandra Riedel, David Booth, Anthony McLean, Klaus Schughart
Journal: European Respiratory Journal (2017)

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers. In this study, we combined an integrated genomic analysis of 1071 individuals with in vitro experiments using well-established infection models. We identified a single-gene biomarker, IFI27 , which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections. IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection.
Why We Need to Know Patients’ Education
Authors: Nancy E. Adler, M. Maria Glymour
Journal: JAMA Internal Medicine (2017)

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