tbuckley/cabot-search huggingface dataset:
Challenges and strategies in anti-cancer nanomedicine development: An industry perspective
Authors: Jennifer I. Hare, Twan Lammers, Marianne B. Ashford, Sanyogitta Puri, Gert Storm, Simon T. Barry
Journal: Advanced Drug Delivery Reviews (2016)

Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.
P0769 : Efficacy of an eight-week regimen of grazoprevir plus elbasvir with and without ribavirin in treatment-naive, noncirrhotic HCV genotype 1B infection
Authors: J.M. Vierling, M. Kugelmas, E. Lawitz, P. Hwang, M. Robertson, J. Wahl, E. Barr, B. Haber
Journal: Journal of Hepatology (2015)
The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor‐β1 biliary secretion in mice
Authors: Nan Wu, Fanyin Meng, Pietro Invernizzi, Francesca Bernuzzi, Julie Venter, Holly Standeford, Paolo Onori, Marco Marzioni, Domenico Alvaro, Antonio Franchitto, Eugenio Gaudio, Shannon Glaser, Gianfranco Alpini
Journal: Hepatology (2016)

The secretin/secretin receptor (SR) axis is up‐regulated by proliferating cholangiocytes during cholestasis. Secretin stimulates biliary proliferation by down‐regulation of let‐7a and subsequent up‐regulation of the growth‐promoting factor, nerve growth factor (NGF). It is not known whether the secretin/SR axis plays a role in subepithelial fibrosis observed during cholestasis. Our aim was to determine the role of the secretin/SR axis in activation of biliary fibrosis in animal models and human primary sclerosing cholangitis (PSC). Studies were performed in wild‐type (WT) mice with bile duct ligation (BDL), BDL SR −/− mice, or Mdr2 −/− mouse models of cholestatic liver injury. In selected studies, the SR antagonist (Sec 5‐27) was used to block the secretin/SR axis. Biliary proliferation and fibrosis were evaluated as well as secretion of secretin (by cholangiocytes and S cells), expression of markers of fibrosis, transforming growth factor‐β1 (TGF‐β1), transforming growth factor‐β1 receptor (TGF‐β1R), let‐7a, and downstream expression of NGF. Correlative studies were performed in human control and PSC liver tissue biopsies, serum, and bile. SR antagonist reduced biliary proliferation and hepatic fibrosis in BDL WT and Mdr2 −/− mice. There was decreased expression of let‐7a in BDL and Mdr2 −/− cholangiocytes that was associated with increased NGF expression. Inhibition of let‐7a accelerated liver fibrosis was attributed to cholestasis. There was increased expression of TGF‐β1 and TGF‐β1R. Significantly higher expression of secretin, SR, and TGF‐β1 was observed in PSC patient liver samples compared to healthy controls. In addition, there was higher expression of fibrosis genes and remarkably decreased expression of let‐7a and increased expression of NGF compared to the control. Conclusion : The secretin/SR axis plays a key role in regulating the biliary contribution to cholestasis‐induced hepatic fibrosis. (H epatology 2016;64:865‐879)
High Dose Imatinib Is Effective In Children and Adolescents With Chronic Myelogenous Leukemia In Chronic Phase. The Italian Experience
Authors: Fiorina Giona, Maria Caterina Putti, Giuseppe Menna, Concetta Micalizzi, Nicola Santoro, Grazia Iaria, Saverio Ladogana, Roberta Burnelli, Caterina Consarino, Benedetta Siniscalchi, Massimiliano Rea, Deborah Marzella, Francesca Tucci, Mauro Nanni, Chiara Messina, Stefania Varotto, Daniela Diverio, Andrea Biondi, Andrea Pession, Marco Zecca, Franco Locatelli, Giuseppe Saglio, Robin Foa'
Journal: Blood (2013)
What size tumors should we detect as early-stage lung cancers in CT screening? Stage-size relationship in long-term repeated screening over 15 years.
Authors: N. Seki, K. Eguchi, M. Kaneko, H. Ohmatsu, R. Kakinuma, E. Matsui, M. Kusumoto, T. Tsuchida, H. Nishiyama, N. Moriyama
Journal: Journal of Clinical Oncology (2010)

1515 Background: We have investigated the individualized benefit of CT screening as Anti-Lung Cancer Association projects (presented at ASCO 2006-2009). However, there has not been enough data about what size of tumors we should detect as early-stage lung cancers in CT screening. Therefore, we evaluated the stage-size relationship of these asymptomatic lung cancer cases diagnosed by long-term repeated screening with low-dose helical CT. Methods: Among 2,302 participants (mean age 63 years, 87% male, and 83% smoker) at baseline screening, 2,063 underwent repeated screening from 1993 to 2009. Twenty-one (mean size 23mm) prevalence cancers and 74 (mean size 17mm) incidence cancers were detected. In relation to tumor size, the distribution of pathological stage, histology, lymph node status, distant metastases, and survival was investigated. Results: Pathological stage has a strong relationship to tumor size at baseline screening (spearman r=0.65, p=0.004) and repeated screening (r=0.66, p<0.001). In the analysis of all 95 cases, lymph node status (r=0.59, p<0.001) and distant metastases (r=0.55, p=0.005) have also a strong relationship to tumor size. The percentages of cases with no metastases (N0M0) were 100% (n=28), 96% (n=25), 76% (n=17), 77% (n=13), 50% (n=8), and 25% (n=4) for the groups of tumor size <11mm, 11-15mm, 16-20mm, 21-30mm, 31-40mm, and >40mm, respectively. Histology for the group of tumor size <16mm was bronchioloalveolar carcinoma (n=14), mixed adenocarcinoma (n=17), invasive adenocarcinoma (n=9), other non-small cell carcinoma (n=11), and small cell carcinoma (n=2). The 10-year survival rates of patients among 3 groups (tumor size; <16mm, 16-30mm, >30mm) were 84%, 61%, and 21%, respectively (p=0.001). Among 4 demographic variables, tumor size was the only significant prognostic factor. Hazard ratio increased from 1.0 (tumor size <16mm) to 2.9 (16-30mm) and 5.9 (>30mm). Conclusions: These results provide direct evidence of a stage-size relationship in long-term repeated CT screening for lung cancer. Furthermore, early detection of tumors of 15 mm or less in diameter leads to the detection of early-stage (N0M0) lung cancer in CT screening. No significant financial relationships to disclose.
Hemaexplorer 2.0: A Free Access Internet Platform For Visualization Of Gene Expression In AML Patients and The Normal Hematopoietic Hierarchy
Authors: Frederik Otzen Bagger, Nicolas Rapin, Johan Jendholm, Helena Isabel Mora-Jensen, Niels Borregaard, Ole Winther, Kim Theilgaard-Mönch, Bo Porse
Journal: Blood (2013)
The Adequacy of Individual Hospital Data to Identify High Utilizers and Assess Community Health
Authors: David Horrocks, Donna Kinzer, Scott Afzal, Jenner Alpern, Joshua M. Sharfstein
Journal: JAMA Internal Medicine (2016)

This study examined the patterns of hospital use of all patients with more than 5 emergency department visits to Maryland hospitals in 2014 to determine whether high utilizers can be identified by data from individual hospitals.
Abstract 364: Pathological Effects of Trimethylamine N-oxide (TMAO) on Pressure Overload-induced Heart Failure
Authors: Chelsea L Organ, Hiroyuki Otsuka, Jessica Bradley, Shashi Bhushan, Rishi Trivedi, W. H. Wilson Tang, Xinmin Li, Stanley Hazen, David J Lefer
Journal: Circulation Research (2015)

Rationale: Trimethylamine N-oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine, is elevated in the circulation of patients at increased risk for heart attack and adverse prognosis during heart failure. Objective: We investigated the effects of dietary choline and TMAO on the severity of heart failure following transverse aortic constriction (TAC). Methods and Results: Male C57Blk/6J mice were fed either control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) at 3 weeks prior to surgical TAC and were studied for 12 weeks. Left ventricular (LV) structure and function were monitored at 3 week intervals and myocardial tissue was collected at 12 weeks. Plasma TMAO levels were significantly (p &lt; 0.01) increased in the choline (28.64 ± 2.30 μM) and TMAO (28.18 ± 4.27 μM) compared to the control group (1.87 ± 0.26 μM). Left ventricular ejection fraction (LVEF) was significantly (p &lt; 0.05) worse in mice fed TMAO compared to control diet. LV end-diastolic and end-systolic diameters were significantly (p &lt; 0.05) increased in the TMAO group compared to control diet. Myocardial fibrosis as measured with Picrosirius Red staining was also significantly greater (p &lt; 0.01) in the TMAO and choline groups. Circulating BNP levels were significantly (p &lt; 0.05) increased in the TMAO and choline groups. Conclusions: These data demonstrate that heart failure severity is significantly enhanced in mice fed diets containing either TMAO or choline. Our results suggest that consumption of food high in dietary nutrients that increase TMAO levels such as phosphatidylcholine may increase heart failure severity.
Importance and Determinants of Comorbidities, Functional Limitations and Multiple Myeloma (MM)-Specific Risk Factors: Further Development of an Improved and Weighted MM-Risk Score (Freiburg Comorbidity Index [FCI])
Authors: Anne-Saskia Domm, Stefanie Hieke, Gabriele Ihorst, Milena Pantic, Bernd Koch, Martina Kleber, Johannes Waldschmidt, Martin Schumacher, Ralph Wäsch, Monika Engelhardt
Journal: Blood (2014)
Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results
Authors: Simon J. Harrison, Paul Mainwaring, Timothy Price, Michael J. Millward, Peeter Padrik, Craig R. Underhill, Paul K. Cannell, Steven D. Reich, Mohit Trikha, Andrew Spencer
Journal: Clinical Cancer Research (2016)

Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors.Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules.Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (∼15-416 L) and clearance (∼0.9-22 L/minutes).Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. ©2016 AACR.
Inhibition of PC-3 prostate tumor cell growth in nude mice following treatment with combination of the NO donor DETANONoate and CDDP
Authors: Sara Huerta-Yepez, Stravoula Baritaki, Mario Vega, Guillermina Baay-Guzman, Rogelio Hernandez-Pando, Cesar Gonzalez-Bonilla, Benjamin Bonavida
Journal: Cancer Research (2006)

5481   Distant metastases from malignant melanoma are known to be highly aggressive and chemoresistant, we have therefore studied the combinations of traditional and novel chemotherapy and TRAIL gene therapy in melanoma cell lines. Dacarbazine (DTIC) is the only approved treatment for metastatic malignant melanoma today, despite the modest efficacy of this treatment. New classes of drugs, such as histone deacetylase inhibitor (HDACI) are highly relevant as potential new therapy in metastatic melanoma. Moreover, TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that selectively induces apoptosis in tumor cells. However, the possibility for the use of any of these agents as monotherapy is probably limited. In the present study we have evaluated the cytotoxic effects of the combined treatments of full-length TRAIL delivered from an adenoviral vector (Ad-hTRAIL) and DTIC or the HDACI SAHA (suberoylanilide hydroxamic acid), in cell lines established from melanoma patients. Five human melanoma cell lines were treated with Ad-hTRAIL alone or in combination with DTIC or SAHA. Cell growth was measured by MTS-assay 72 hours after the treatment was added, and the results obtained for each treatment group were compared with untreated cells. The combined treatment with DTIC and Ad-hTRAIL effectively reduced the cell growth of four of the five cell lines compared to each treatment used alone. By the use of CalcuSyn software the two treatments proved to act synergistically. The HDACI also facilitated growth inhibition, as the combination of SAHA and Ad-hTRAIL was defined as additive or synergistic in all melanoma cell lines. However, the combination of DTIC and Ad-hTRAIL was more effective than the combination with SAHA and Ad-hTRAIL in the melanoma cell lines tested. Both combination therapies were accompanied by increased apoptosis assayed by increased TUNEL-staining and the effect on specific apoptotic mediators (PARP, caspases, Bid) was investigated. Caspase involvement was also observed by the rescue of the treated cells by the pan-caspase inhibitor z-VAD-fmk. In conclusion, these results suggest that treatment with DTIC and SAHA in combination with TRAIL delivered from an adenoviral vector is effective for the inhibition of melanoma cell growth  in vitro . A melanoma-targeted approach for the TRAIL gene therapy will be studied further and evaluated in relevant animal models for the possible use in melanoma patients in the future.
Erythropoietin Potentiates The Immune System Yet Induces Bone Resorption In a Myeloma Mouse Model
Authors: Naamit Deshet-Unger, Sahar Hiram-Bab, Mor Gross, Yasmin Haim-Ohana, Miriam C. Souroujon, Howard S. Oster, Moshe Mittelman, Yankel Gabet, Drorit Neumann
Journal: Blood (2013)
Systems Analysis of Thrombus Formation
Authors: Scott L. Diamond
Journal: Circulation Research (2016)

The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient-specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High-dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. In addition, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs.
Serum periostin in obstructive airways disease
Authors: James Fingleton, Irene Braithwaite, Justin Travers, Darren Bowles, Rianne Strik, Rob Siebers, Cecile Holweg, John Matthews, Mark Weatherall, Richard Beasley
Journal: European Respiratory Journal (2016)

Serum periostin is a potential biomarker of response to therapies that target type 2 inflammation in asthma. The objectives of this study were to describe: 1) the distribution of serum periostin levels in adults with symptomatic airflow obstruction; 2) its relationship with other variables, including type 2 biomarkers; and 3) the effect of inhaled corticosteroids on periostin levels. Serum periostin levels were measured in a cross-sectional study exploring phenotypes and biomarkers in 386 patients aged 18–75 years who reported wheeze and breathlessness in the past 12 months. In 49 ICS-naïve patients, periostin levels were measured again after 12 weeks of budesonide (800 μg·day −1 ). The distribution of serum periostin levels was right skewed (mean± sd 57.3±18.6 ng·mL −1 , median (interquartile range) 54.0 (45.1–65.6) ng·mL −1 , range 15.0–164.7 ng·mL −1 ). Periostin was positively associated with exhaled nitric oxide (Spearman's rho=0.22, p&lt;0.001), blood eosinophil count (Spearman's rho=0.21, p&lt;0.001), and total IgE (Spearman's rho=0.14, p=0.007). The Hodges–Lehmann estimator (95% CI) of change in periostin level after ICS therapy was −4.8 (−6.7– −3.2) ng·mL −1 (p&lt;0.001). These findings provide data on the distribution of serum periostin in adults with symptomatic airflow obstruction, the weak associations between periostin and other type 2 markers, and the reduction in periostin with inhaled corticosteroid therapy.
Potential germline relevance of tumor testing and the need for genetic referral.
Authors: Laura Virginia Barton, Christine Marie Walko, Tuya Pal, Howard L. McLeod
Journal: Journal of Clinical Oncology (2015)

e12552 Background: Recently the ability to tailor therapies to particular somatic mutations present in a patient’s tumor has grown significantly. However mutations found in a tumor may have implications if also present in the germline. Through Moffitt’s Personalized Medicine Consult Service (PMCS), we sought to find a streamlined approach to identify patients with tumor testing in whom referral to the Genetic Risk Assessment Service (GRAS) for consideration of germline testing would be appropriate. Methods: The GRAS provided the PMCS with a list of 41 genes that may have germline implications for inherited cancer predisposition, primarily encompassing genes included in multi-gene tests for inherited cancer predisposition. Genes included on currently available tumor tests were evaluated for germline relevance to inherited cancer risk using OMIM and the genereviews.org database, after which availability of clinical testing was searched using the genetests.org database. All patients consulted through the PMCS were reviewed to determine presence of alterations with relevance to inherited cancer if present in the germline. If an alteration was present, a recommendation for referral to the GRAS was included in the consult note provided to the ordering physician. When the altered gene was associated with an increased risk for the type of cancer affecting the patient, this was noted in the recommendation indicating the importance of a referral to the GRAS. Results: The PMCS was consulted on 23/111 patients with tumor sequencing from August to December of 2014. Of the 23 cases, 18 (78.3%) had alterations in genes that warranted a referral to GRAS. In 11 (61.1%) of these cases, their cancer was in the spectrum of that associated with the gene mutation, when present in the germline. Conclusions: These findings demonstrate that when conducting genetic testing of tumors to identify therapeutic targets, gene mutations with implications to inherited cancer susceptibility may be identified if they are confirmed to be present in the germline. Consequently, the process implemented by the PMCS to include GRAS members has enabled provision of input about appropriate referrals for genetic counseling and consideration of germline testing.
PWE-041 Mannose binding lectin deficiency as a predictor of severity, disease progression and outcome following paracetamol-induced acute liver failure
Authors: R Abeles, J A Underhill, M S Longhi, N J Taylor, A Gera, D L Shawcross, C G Antoniades, W Bernal, J A Wendon, D Vergani
Journal: Gut (2010)

<h3>Introduction</h3> Mannose binding lectin (MBL) plays a pivotal role in the innate immune system inflammatory response. MBL deficiency (MBLdef) is caused by three single nucleotide polymorphisms (57, 54, 52) of the MBL2 gene. MBLdef is associated with poor outcomes in severe sepsis and fulminant hepatitis B. We therefore investigated whether MBLdef is a determinant of severity, disease progression and outcome following paracetamol-induced acute liver failure (PALF). <h3>Methods</h3> 40 consecutive patients (39 Caucasian) with PALF, admitted to the liver intensive care unit of a tertiary referral centre, were recruited. Physiological, biochemical and clinical data were recorded. MBLdef was determined using polymerase chain reaction-sequence specific polymerisation. Reduced monocyte HLA-DR expression, a marker of diminished pro-inflammatory capacity, was determined by flow cytometry using dual staining with monoclonal antibodies against HLA-DR and CD14. <h3>Results</h3> 26 (65%) patients survived. 14 (35%) died or underwent emergency liver transplantation and were identifiable at admission by greater severity of liver disease and more severe organ dysfunction, but without differences in systemic inflammatory response syndrome (SIRS) scores (2 (1–3) vs 2 (1–3)) or incidence (54% vs 57%). A significantly lower proportion (6/40, 15%) of the patients were MBLdef, compared to that expected from a large (n=353) control Caucasian population (40%, p=0.001). 3/6 (50%) MBLdef patients survived vs 23/34 (68%) of the normal MBL producers (ns). The prevalence of MBLdef was 12% (3/26) in survivors and 21% (3/14) in non-survivors (ns). MBLdef was not related to any differences in organ or liver dysfunction but was associated with lower SIRS scores (1 (0–1) vs 2 (1–2), p&lt;0.05) and incidence (17% vs 62%, p&lt;0.05). On admission, MBLdef was associated with a lower AST (4049 (2245–6106) vs 7897 (5141–11 113) p&lt;0.05) and more (&gt;45%) HLA-DRneg monocytes (50% vs 6%, p=0.003). <h3>Conclusion</h3> Our data unexpectedly show that MBLdef may be underrepresented in patients who require tertiary referral centre care for PALF. However, MBLdef did not determine severity, disease progression and outcome in this small cohort. In those referred, MBLdef was associated with lower SIRS scores and lower HLA-DR monocyte expression, suggesting that a reduced pro-inflammatory capacity may be of importance.