tbuckley/cabot-search huggingface dataset:
50 Years of Preclinical Anticancer Drug Screening: Empirical to Target-Driven Approaches
Authors: Marie Suggitt, Michael C. Bibby
Journal: Clinical Cancer Research (2005)

Abstract The number of anticancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of molecules into the clinic requires improvement. The value of any preclinical model will ultimately depend on its ability to accurately predict clinical response. This review focuses on the major contributions of preclinical screening models to anticancer drug development over the past 50 years. Over time, a general transition has been observed from the empirical drug screening of cytotoxic agents against uncharacterized tumor models to the target-orientated drug screening of agents with defined mechanisms of action. New approaches to anticancer drug development involve the molecular characterization of models along with an appreciation of the pharmacodynamic and pharmacokinetic properties of compounds [e.g., the US National Cancer Institute (NCI) in vitro 60-cell line panel, hollow fiber assay, and s.c. xenograft]. Contributions of other potentially more clinically relevant in vivo tumor models including orthotopic, metastatic, and genetically engineered mouse models are also reviewed. Although this review concentrates on the preclinical screening efforts of the NCI, European efforts are not overlooked. Europe has played a key role in the development of new anticancer agents. The two largest academic drug development groups, the European Organisation for Research and Treatment of Cancer and Cancer Research UK, have been collaborating with the NCI in the acquisition and screening of compounds since the 1970s. As with the drug development process internationally, rational pharmacodynamic approaches have more recently been adopted by these two groups.
Phylogenetic relationship of the kingdoms Animalia, Plantae, and Fungi, inferred from 23 different protein species.
Authors: N Nikoh, N Hayase, N Iwabe, K Kuma, T Miyata
Journal: Molecular Biology and Evolution (1994)

The phylogenetic relationship among the kingdoms Animalia, Plantae, and Fungi remains uncertain, because of lack of solid fossil evidence. In spite of the extensive molecular phylogenetic analyses since the early report, this problem is a longstanding controversy; the proposed phylogenetic relationships differ for different authors, depending on the molecules and methods that they use. To settle this problem, we have accumulated 23 different protein species from the three kingdoms and have inferred the phylogenetic trees by three different methods--the maximum-likelihood method, the neighbor-joining method, and the maximum-parsimony method--for each data set. Although inferred tree topologies differ for different protein species and methods used, both the maximum-likelihood analysis based on the difference (delta l) between the total log-likelihood of a tree and that of the maximum-likelihood tree and bootstrap probability (P) of 23 proteins consisting of 10,051 amino acid sites in total have shown that a tree ((A,F),P), in which Plantae (P) is an outgroup to an Animalia (A)-Fungi (F) clade, is the maximum-likelihood tree; the delta l (= 0.0) and P (94%) of ((A,F),P) are significantly larger than those of ((A,P),F) (delta l = -54.4 +/- 36.3; and P = 6%) and ((F,P),A) (delta l = -141.1 +/- 30.9; and P = 0%).(ABSTRACT TRUNCATED AT 250 WORDS)
Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer.
Authors: K Kubota, Y Nishiwaki, R Kakinuma, F Hojo, T Matsumoto, H Ohmatsu, I Sekine, M Yokozaki, K Goto, N Ebi, T Kodama
Journal: Journal of Clinical Oncology (1997)

PURPOSE This study was undertaken to determine the activity and toxicity of dose-intensive weekly chemotherapy (cisplatin, vincristine, doxorubicin, and etoposide [CODE] regimen) for previous treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS The 17 patients with relapsed SCLC entered onto the study were to receive intensive weekly chemotherapy with the CODE regimen. All 17 patients had been heavily pretreated with some form of cisplatin-based combination chemotherapy. Six patients had received previous chemotherapy with CODE and one patient with cisplatin and etoposide (PE) as induction therapy. Nine patients had been treated with concurrent or sequential PE plus thoracic irradiation (TRT). The median time off chemotherapy was 6.7 months (range, 3.3 to 72). Patients were treated with 9 weeks of the CODE regimen. Response, survival, and toxicity data were noted. RESULTS All 17 patients were assessable for response, survival, and toxicity. Fifteen of 17 patients (88.2%) had an objective response, with five complete responses (CRs; 29%) and 10 partial responses (PRs; 58.8%). The median durations of response and survival were 156 days and 245 days, respectively. Myelosuppression was significant, with 76% of patients developing grade 4 leukopenia. No treatment-related death was observed. CONCLUSION The CODE regimen is highly active in the treatment of relapsed SCLC with an encouraging survival outcome.
Multicentre longitudinal analysis of body mass index, lung function and sputum microbiology in primary ciliary dyskinesia
Authors: Marco Maglione, Andrew Bush, Kim Nielsen, Claire Hogg, Silvia Montella, June Marthin, Angela Di Giorgio, Francesca Santamaria
Journal: European Respiratory Journal (2013)

BACKGROUND: No studies have longitudinally assessed paired body mass index (BMI) and lung function in primary ciliary dyskinesia (PCD). Data about the relationship between sputum pathogens and spirometric evolution are also lacking.

METHODS: We aimed to determine longitudinal BMI and spirometry changes in 162 PCD patients from London, UK (n=75), Naples, Italy (n=24) and Copenhagen, Denmark (n=63). Annual BMI and FEV1 were analyzed over blocks of 2, 4 and 6 consecutive years. Isolation of P. aeruginosa (PA) from sputum was recorded in order to assess impact on lung function progression.

RESULTS: Median age at first spirometry was 9 years (range, 4.2-27.2). Mean Z scores of first measured BMI and FEV1, were -0.02, and -1.37, respectively. There were no significant changes in BMI and FEV1 slopes, over any time block. During the follow-up PA was not related to lung function evolution, even though patients with at least one isolation of PA showed a trend towards worse lung function at 2 years.

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CONCLUSIONS: PCD subjects receiving centralized care show steady BMI and stable spirometry over medium term follow-up. Evolution of lung function could not be significantly correlated to PA isolation, although a trend was found towards decline of FEV1 after 2 years of follow-up.
Risk of atrial fibrillation with bisphosphonate treatment
Authors: Shahid A Kausar
Journal: BMJ (2015)

Maraka and Kennel discussed the adverse effects associated with bisphosphonate treatment in detail but failed to mention the risk of atrial fibrillation.1 2

The risk of new onset atrial fibrillation is increased by the use of both oral and intravenous bisphosphonates, although the risk may be greater with …
Noninvasive quantitative tissue characterization and two-dimensional color-coded map of human atherosclerotic lesions using ultrasound integrated backscatter
Authors: Masanori Kawasaki, Hisato Takatsu, Toshiyuki Noda, Yoko Ito, Akihisa Kunishima, Masazumi Arai, Kazuhiko Nishigaki, Genzou Takemura, Norihiko Morita, Shinya Minatoguchi, Hisayoshi Fujiwara
Journal: Journal of the American College of Cardiology (2001)
Non-invasive evaluation in prediction of pulmonary hypertension in patients with idiopathic pulmonary fibrosis
Authors: František Salajka, Vladimír Bartoš, Jakub Novosad, Josef Štásek, Josef Bis, Miroslav Brtko, Pavel Polanský, Vladimír Koblízek, Vratislav Sedlák
Journal: European Respiratory Journal (2011)

Pulmonary hypertension (PH) occurs rather frequently in patients with advanced idiopathic pulmonary fibrosis (IPF). However, no reliable non-invasive screening method of detection is available so far. Recently, new formula allowing to detect the patients with PH among patients with IPF and, also, to assess the mean pulmonary artery pressure (MPAP) in individual patients was published: –11.9 + 0.272 × SpO 2  + 0.0659 × (100 – SpO 2 ) 2  + 3.06 × FVC%/TLCO% [1]. The aim of our study was to confirm the usefulness of this formula in our group of IPF patients.  In a prospective study, lung function tests and right heart catheterization examinations were performed in a group of 27 patients with IPF. In total, pulmonary hypertension (MPAP > 20 mm Hg) was detected by catheterization in 17 patients (63%). Compared with the results of the formula, the significant correlation was not reached either for the PH defined according to the recent recommendation (MPAP > 20 mm Hg, r=0.135, p=0.502). or when the border level criterion for PH was heightened to 25 mm Hg, similar to the originally published data (r= -0.043, p=0.833). Also, the use of the tested formula to calculate the level of MPAP in individual patients was not helpful. We found only a non-significant correlation between the level of the mean cMPAP and the calculated MPAP in individual patients (r= -0.148, p=0.461).  In conclusion, our study did not confirm the possibility of using the published formula to predict with sufficient accuracy either the presence or the level of PH in patients with IPF.   Reference:   1Zisman DA et al. Prediction of pulmonary hypertension in idiopathic pulmonary fibrosis.  Respir Med  2007;101(10):2153–2159.
A Dutch web-survey on management of malignant pleural effusions
Authors: Rogier Boshuizen, Andrew Vincent, Peter Kunst, Sjaak Burgers, Michel vd Heuvel
Journal: European Respiratory Journal (2011)

Background:  Malignant pleural effusion (MPE) is a major problem in patients with advanced cancer. Pleural approximation is necessary for a successful pleurodesis. The decision to perform a pleurodesis is made by the pulmonologist. Inter-physician variances in the assessment of the Chest X-ray might have impact on the final outcome of the pleurodesis procedure.   Aims and objectives:  To describe decision variability among physicians regarding pleurodesis.   Methods:  A series of 50 consecutive chest X-rays made during MPE drainage with clinical data were sent to all active Dutch pulmonologists, together with a questionnaire on the MPE management. The following questions were asked for all of these X-rays: (1) Do you report this lung to be expanded? (2) Would you install a sclerotic agent?; (3) What would be the estimated chance on a successful pleurodesis?   Results:  Pulmonologists of 30% of the Dutch hospitals responded. All pulmonologists were aware of the national guideline. The overall probability of recommending a pleurodesis was higher in the expanded lung group than in the not expanded lungs (90 vs 39%; p   Conclusion:  Pulmonologists9s experience influences decisions regarding MPE management.
Characteristics of a stable and satisfactory condition in long term survivors of pulmonary arterial hypertension
Authors: Marielle van de Veerdonk, Tim Marcus, Frances de Man, Harm-Jan Bogaard, Anco Boonstra, Nico Westerhof, Anton Vonk Noordegraaf
Journal: European Respiratory Journal (2013)

Introduction  The aim of the study is to perform a longitudinal data comparison between long term stable and unstable patients with pulmonary arterial hypertension (PAH).  Methods  Included patients were 9 long term stable (stable survivors during 10 year follow-up), 12 long term unstable (died after 8 years) and 9 short term non-survivors (died ≤1.5 years) with idiopathic PAH diagnosed between 1999-2003 and followed to 2013. All patients underwent baseline right heart catheterization, cardiac magnetic resonance and 6 minute walk testing (6MWT). Unstable patients had additional measurements after 1, 3 and 7 years and stable patients underwent further evaluation at 10 years.  Results  Although baseline parameters identified short term non-survivors, these characteristics did not discriminate between long term stable and unstable patients (Fig 1). During follow-up, hemodynamics and 6MWT were similar in both long term follow-up groups (Fig 1A-C). Despite similar baseline values, long term stable patients had unchanged right ventricular (RV) volumes over time whereas unstable patients showed progressive dilatation (p int: 0.03; Fig 1D). Stable patients showed a higher RV ejection fraction (RVEF) than non-stable patients at baseline and over time (p  Conclusions  The absence of progressive RV dilatation and preserved RVEF predict a long term stable, satisfactory condition in PAH patients.
Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated <i>MuRF1</i> Expression
Authors: Philipp Du Bois, Cristina Pablo Tortola, Doerte Lodka, Melanie Kny, Franziska Schmidt, Kunhua Song, Sibylle Schmidt, Rhonda Bassel-Duby, Eric N. Olson, Jens Fielitz
Journal: Circulation Research (2015)

Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1).To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting.A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting.We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia
Authors: Aditya Sarvaria, Zheng Topp, Alan Saven
Journal: JAMA Oncology (2015)

Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.
Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers
Authors: Sarah Voisin, Markus Sällman Almén, Galina Y. Zheleznyakova, Lina Lundberg, Sanaz Zarei, Sandra Castillo, Fia Ence Eriksson, Emil K. Nilsson, Matthias Blüher, Yvonne Böttcher, Peter Kovacs, Janis Klovins, Mathias Rask-Andersen, Helgi B. Schiöth
Journal: Genome Medicine (2015)
Therapeutic potential of CPL-407-105 – Novel potent JAK/STAT pathway inhibitor for the treatment of asthma
Authors: Pawel Gunerka, Barbara Dymek, Daria Zdzalik, Michal Mroczkiewicz, Joanna Lipner, Bartosz Stypik, Anna Bujak, Paulina Grygielewicz, Olga Musielak, Monika Skupinska, Joanna Hucz-Kalitowska, Krzysztof Dubiel, Monika Lamparska-Przybysz, Maciej Wieczorek, Aleksandra Stanczak
Journal: European Respiratory Journal (2014)

INTRODUCTION  Cytokines and chemokines are key modulators of immunological system, playing essential role in inflammation-related diseases, e.g. asthma. Janus kinases (JAKs) are main part of signaling pathways responsible for signal transduction from immune receptors and activation of downstream cytokines9 expression. Therefore, selective JAK inhibitors emerge as an attractive strategy in asthma.   METHODS AND RESULTS  We have designed CPL-407-105 (9105)– a novel small molecule JAK2 inhibitor with high  in vitro  inhibitory potency (IC 50 =3nM in recombinant kinase activity assay). Compound exhibited good selectivity versus JAK1 and JAK3 kinases (12- and 25-fold, respectively), as well as versus additional panel of diverse kinases. In cell-based proliferation assays 9105 inhibited JAK2-dependent SET-2 cells with IC 50  of 320nM, without significant inhibition of JAK-independent HEK293 cells (up to 2,5μM). Western Blot analysis revealed almost complete abrogation of pSTAT3 in HEL cells following treatment with 100nM of 9105. Additionally, flow cytometry analysis showed that 9105 efficiently decreased pSTAT1 level in IFNγ-stimulated CD14 +  cells (IC 50 =86nM). 9105 also reduced pSTAT5 level in GM-CSF-stimulated CD14 +  cells and IL-2-stimulated CD3 +  cells (IC 50  of 430nM and 400nM, respectively). Finally, 9105 lowered secretion of IFNγ, IL-5, IL-6, IL-9, and IL-13 by CD4 + T cells with IC 50  of 100, 10, 500, 30 and 50nM, respectively.   CONCLUSION  CPL-407-105 exerts anti-inflammatory effect by suppressing cytokine signaling in selected cellular models. Collected data rationalize further evaluation of 9105 in advanced  in vitro  and  in vivo  models of inflammation-mediated diseases, including asthma.
Changes in Plasma Gastrointesitinal Peptide Levels After Platinum-Based Chemotherapy in Esophageal Cancer Patients
Authors: Yuko Ono, Yuhki Sato, Tomotaka Shibata, Yosuke Suzuki, Ryosuke Tatsuta, Takashi Fujioka, Tsuyoshi Noguchi, Hiroki Itoh
Journal: Annals of Oncology (2014)
Abstract 3916: Hematopoietic Sphingosine-1-phosphate Receptor 4 Affects Inflammation, Migration And Atherosclerotic Lesion Formation
Authors: Danielle M Curfs, Marion J Gijbels, Ingeborg van der Made, Monique N Vergouwe, Anneke M Sijbers, Dianne M Delsing, Darcy Black, Marten H Hofker, Menno P de Winther
Journal: Circulation (2008)
Changes in respiratory mechanics following surgical repair of mitral valve insufficiency in children
Authors: Iliona Malaspinas, Anne-Laure Martin, Anne Perrin, Maurice Beghetti, Ferenc Petak, Walid Habre
Journal: European Respiratory Journal (2012)

RATIONALE: Postcapillary pulmonary hypertension (PHT) such as observed with mitral valve insufficiency (MVI) is associated with lung function impairment. We assessed airway resistance (Raw) and total respiratory elastance (Ers) before and after surgical repair of MVI in children to verify whether vascular engorgement is responsible for the increase in airway tone and stiffness of the respiratory tissues.

METHODS: The input impedance of the respiratory system during spontaneous breathing was measured in 16 children, aged 12.3±2.5 years (mean±SD), with congenital or post rheumatic mitral valve insufficiency preoperatively, and within 5 days and 3 weeks after mitral valve repair surgery. Raw was estimated by calculating the average resistance values between 4 and 26 Hz, while Ers was assessed from the respiratory reactance data by model fitting.

RESULTS: Raw decreased significantly 5 days after the surgery (5.5±1.6 to 4.3±1.0 cmH2O.s/l, p<0.001). It remained lowered 3 weeks later in 8 children (4.5±1.4 cmH2O.s/l, p=0.003). Conversely, Ers exhibited no significant changes postoperatively (70±10, 58±6 and 77±9 cmH2O/l, before and 5 and 21 days after the surgery, respectively, p=0.4)

CONCLUSIONS: Decreasing vascular engorgement after surgical reparation of MVI in children results in a fast and sustained improvement in airway function. The lack of concomitant beneficial changes in the Ers suggests that mechanical interdependence between the airways and pulmonary vasculature is responsible for this finding.

Supported by SNSF grant 3200B0-118231.
Clinical evaluation of recombinant interferon alfa-2a (Roferon-A) in metastatic melanoma using two different schedules .
Authors: S S Legha, N E Papadopoulos, C Plager, S Ring, S P Chawla, L M Evans, R S Benjamin
Journal: Journal of Clinical Oncology (1987)

Based on the reports of activity of interferons against metastatic melanomas, we conducted a phase II study of recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) in 66 patients with disseminated melanoma. All patients had excellent Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1), and no evidence of brain metastases. Thirty patients had previously received chemotherapy and the remainder were untreated. The first 35 patients were treated on a daily schedule starting with a Roferon-A dose of 3 X 10(6) U/d and escalating to a maximum of 36 X 10(6) U/d over a period of 12 days. Because of excessive toxicity, the second group of 31 patients were treated on a fixed dose of 18 X 10(6) U/d [corrected] three times weekly (TIW). Among the 62 evaluable patients, five achieved an objective response for a response rate of 8% (95% confidence limits, 3% to 18%). Four patients had minor regressions and eight patients had stability of disease. The responses were evenly distributed between the two dose schedules. The major toxicity of interferon consisted of a constitutional syndrome of anorexia, fever, weight loss, and fatigue, which required a dose reduction in 75% of the patients on the daily schedule. Our data revealed a modest level of activity, which was not influenced by prior treatment or by the dose or schedule of interferon. Because of substantial toxicity with the daily schedule, we recommend a dose of 18 X 10(6) U/d [corrected] if interferon is used in the treatment of patients with melanoma.
Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study
Authors: D. M. Nathan, E. Barrett-Connor, J.P. Crandall, S. L. Edelstein, R.B. Goldberg, E. S. Horton, W.C. Knowler, K. J. Mather, T. J. Orchard, X. Pi-Sunyer, D. Schade, M. Temprosa
Journal: The Lancet Diabetes & Endocrinology (2015)
Extra radiation to lymph nodes reduces breast cancer recurrence, studies show:
Authors: Susan Mayor
Journal: BMJ (2015)

Giving radiotherapy to the lymph nodes in addition to standard treatment with whole breast irradiation after breast conserving surgery significantly reduces breast cancer recurrence but has no effect on overall survival, two studies in the New England Journal of Medicine have shown.1 2

The first study1 randomised 1832 women with early stage breast cancer to treatment with whole breast irradiation plus irradiation of regional lymph nodes, including the internal mammary, supraclavicular, and axillary lymph nodes, or to whole breast irradiation alone.

All of the women had axillary node positive breast cancer or high risk node negative disease, with …