tbuckley/cabot-search huggingface dataset:
Integrating Clinical, Morphological, and Molecular Data to Assess Prognosis in Patients with Primary Myelofibrosis: A Practical Approach
Authors: Alessandra Iurlo, Elena Maria Elli, Francesca Palandri, Daniele Cattaneo, Anna Bossi, Ivan Cortinovis, Cristina Bucelli, Nicola Orofino, Filippo Brioschi, Giuseppe Auteri, Paola Bianchi, Sonia Fabris, Giuseppe Isimbaldi, Elena Sabattini, Agostino Cortelezzi, Umberto Gianelli
Journal: Blood (2018)
Abstract 19542: TGF-Beta 1 Receptor Antagonist Reduces the Cardiac Fibrosis and Remodeling in Npr1 Knockout Mouse Model
Authors: Umadevi Subramanian, David Chen, Venkateswara R Gogulamudi, Kailash N Pandey
Journal: Circulation (2017)

Introduction: Genetic ablation of natriuretic peptide receptor-A (NPRA) gene (Npr1) in mice provokes blood pressure and cardiac fibrosis, hypertrophy, and remodeling associated with congestive hear...
Abstract A22: Identification of gene expression differences between primary pediatric tumors and their PDX models
Authors: Jacob J. Pfeil, Alex G. Lee, Leanne C. Sayles, Ellen T. Kephart, Holly C. Beale, Lauren M. Sanders, Olena Morozova, Sofie R. Salama, Alejandro Sweet-Cordero, David Haussler
Journal: Cancer Research (2018)

Abstract Molecularly targeted therapies inhibit specific cancer pathways and have fewer harmful side effects than cytotoxic chemotherapies; however, the development of targeted therapies for childhood cancers has lagged behind that of adult cancers. Although adult and childhood cancers have different molecular mechanisms, similar druggable cancer pathways may be activated. We propose using gene expression analysis to identify opportunities to reposition FDA-approved targeted therapies for childhood cancer patients. We developed an N-of-1 gene expression approach that leverages a compendium of ~11,000 cancer gene expression profiles. To evaluate the utility of this approach for identifying cancer driver pathways, we analyzed gene expression data for 9 patient-derived xenograft (PDX) tumors. PDXs were tested for sensitivity to selected targeted therapies. Our analysis correctly predicted drug sensitivity in 8 of the 9 PDXs based on overexpression of specific cancer pathways. We also compared gene expression between PDX and matched primary tumor samples (n=7). Using TumorMap analysis, we found that PDX tumors cluster with their matched primary tumor and other samples with a similar cancer diagnosis. We also ran differential expression analysis and found 260 overexpressed genes and 630 underexpressed genes in PDX tumors. Underexpressed genes were associated with immune functions, extracellular matrix proteins, and growth factor signaling. Overexpressed genes were involved in TNF-α; signaling. This analysis confirmed expected changes in gene expression while also identifying TNF-α; signaling as a potential biologic artifact of PDX tumors. These features may influence the results of PDX experiments and should be accounted for when using this model. Overall, the PDX model recapitulates gene expression features of pediatric cancer and is a powerful tool for evaluating novel precision medicine approaches. Citation Format: Jacob J. Pfeil, Alex G. Lee, Leanne C. Sayles, Ellen T. Kephart, Holly C. Beale, Lauren M. Sanders, Olena Morozova, Sofie R. Salama, Alejandro Sweet-Cordero, David Haussler. Identification of gene expression differences between primary pediatric tumors and their PDX models [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A22.
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
Authors: Andrew J. Schork, Hyejung Won, Vivek Appadurai, Ron Nudel, Mike Gandal, Olivier Delaneau, Malene Revsbech Christiansen, David M. Hougaard, Marie Bækved-Hansen, Jonas Bybjerg-Grauholm, Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen, Benjamin M. Neale, Mark J. Daly, Naomi R. Wray, Merete Nordentoft, Ole Mors, Anders D. Børglum, Preben Bo Mortensen, Alfonso Buil, Wesley K. Thompson, Daniel H. Geschwind, Thomas Werge
Journal: Nature Neuroscience (2019)
Circulating tumor cell count from a blood sample for colorectal cancer (CRC) prevention: A 627-patient prospective study.
Authors: Wen-Sy Tsai, Drew Watson, Ying Chang, Ben Hsieh, Hung-Jen Shao, Jen-chia Wu, Jr-Ming Lai, Shih-En Chang, Mana Javey, Rui Mei, Ashish Nimgaonkar
Journal: Journal of Clinical Oncology (2019)

485 Background: Up to 25% of patients with adenomas progress to having colorectal cancer. If detected early, adenomas can be removed with a diagnostic colonoscopy procedure, preventing cancer. Invasive colonoscopy is the only screening method with the sensitivity to accurately detect adenomas, but has a low compliance rate of 38% for screening. Available non-invasive tests (including stool-based multi-analyte tests) have very limited sensitivity for adenomas. Hence, there is an unmet need for a non-invasive test for adenoma detection. Methods: IRB-approved prospective study was conducted in 627 subjects 50 years or older- recommended for routine CRC screening- 405 subjects had adenoma or CRC, confirmed by colonoscopy with tumor biopsy. Two mL peripheral blood was processed using the CellMax biomimetic platform (CMx), which uses a microfluidic biochip to enumerate circulating tumor cells (CTCs). Nominal logistic regression was used to assess performance while proportional odds logistic regression and Cuzick’s trend test were used to determine association of CTC counts with cancer stage. Results: An increase in CTC count was significantly correlated with an increase in disease burden (Cuzick’s Test p-value &lt; 0.0001). Furthermore, there was a significant association between CTC counts and stages of adenoma-carcinoma progression (Likelihood ratio p-value &lt; 0.0001). The CTC enumeration was able to differentiate between healthy and diseased patients (adenoma + cancer). Conclusions: To the best of our knowledge, these are the first reported results for a blood test that has high accuracy for adenoma detection, and truly enables colorectal cancer prevention. This test can be administered in the primary care setting and drive high compliance.[Table: see text]
Comparison Of Bronchial Response To Mite And Cat Allergen In Asthmatics Subjects in ALYATEC Environmental Exposure Chamber (EEC)
Authors: Alina Gherasim, Nicole Beck, Audrey Jacob, Florian Schoettel, Nathalie Domis, Frederic J. De Blay De Gaix
Journal: Journal of Allergy and Clinical Immunology (2019)
Phase 2 Clinical Trial Results for Bitopertin, an Oral Glycine Transporter 1 Inhibitor, in Patients with Non-Transfusion Dependent Beta-Thalassemia
Authors: Ali Taher, Vip Viprakasit, Maria Domenica Cappellini, Dominik Kraus, Patrick Cech, Volz Dietmar, Erica Winter, Norman Alan Mazer, Stephane Nave, Juergen Dukart, Franziska Schaedeli Stark, Annette Koerner, Omar Khwaja, Ricardo Hermosilla
Journal: Blood (2018)
Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology
Authors: Rudolf A. de Boer, Gilles De Keulenaer, Johann Bauersachs, Dirk Brutsaert, John G. Cleland, Javier Diez, Xiao‐Jun Du, Paul Ford, Frank R. Heinzel, Kenneth E. Lipson, Theresa McDonagh, Natalia Lopez‐Andres, Ida G. Lunde, Alexander R. Lyon, Piero Pollesello, Sanjay K. Prasad, Carlo G. Tocchetti, Manuel Mayr, Joost P.G. Sluijter, Thomas Thum, Carsten Tschöpe, Faiez Zannad, Wolfram‐Hubertus Zimmermann, Frank Ruschitzka, Gerasimos Filippatos, Merry L. Lindsey, Christoph Maack, Stephane Heymans
Journal: European Journal of Heart Failure (2019)

Abstract Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti‐fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
Abstract 19363: Liposome-Encapsulated Hemoglobin (a Novel Artificial Oxygen Carrier) Transfusion Rescues Lethal 85% Hemorrhagic Rats: Its Anti-Arrhythmogenic Effect on Myocardium
Authors: Bonpei Takase, Kenichi Hashimoto, Nobuyuki Masaki
Journal: Circulation (2017)

Liposome-encapsulated hemoglobin (HbV) can serve as blood substitutes of oxygen-carrying capacity comparable to human blood. To investigate the resuscitation effect of HbV on lethal hemorrhage and its efficacy on myocardial arrhythmogenesis, optical mapping analysis (OMP) and electrophysiological study (EPS) were performed in graded blood exchange up to 85% blood loss in rats. Six rats were gradually exchanged blood with 5% albumin (Alb-group) while 4 rats exchanged with washed rat erythrocyte (washed RBC-group) and 5 rats with HbV (HbV-group). Survival effects over 24 hours were examined in 5 rats in each group. After excising the heart, OMP and EPS were performed. All rats died in Alb-group whereas all survived for following 24-hours in washed RBC-group and HbV-group (Figure 1). OMP revealed impaired (prolonged) action potential duration (APD) dispersion in LV in Alb-group. In contrast, myocardial APD dispersions in LV were substantially attenuated in HbV-group and washed RBC-group (Figure 2). Lethal ar...
Pharmacokinetic and Pharmacodynamic Properties of l-Ornithine l-Aspartate (LOLA) in Hepatic Encephalopathy
Authors: Gerald Kircheis, Stefan Lüth
Journal: Drugs (2019)

l-Ornithine l-aspartate (LOLA), a stable salt of l-ornithine and l-aspartate, readily dissociates into its constituent amino acids that are readily absorbed by active transport, distributed, and metabolized. l-ornithine serves as an intermediary in the urea cycle in periportal hepatocytes in the liver and as an activator of carbamoyl phosphate synthetase, and, like l-aspartate, by transamination to glutamate via glutamine synthetase in perivenous hepatocytes as well as by skeletal muscle and brain. By way of these metabolic pathways, both amino acids participate in reactions whereby the ammonia molecule is incorporated into urea and glutamine and it is the nature, cellular, and biological location of these pathways that underpins the application of LOLA as an effective ammonia-lowering strategy widely used for the management and treatment of hepatic encephalopathy. These metabolic pathways were elucidated based upon studies in experimental animals and were confirmed by studies in patients with severe liver diseases. More recent studies suggest that LOLA may have additional direct hepatoprotective properties. Moreover, its use may result in improvements in skeletal muscle function in cirrhosis.
Meta-analysis Illustrates the Genetic Signature Underlying Allergic Rhinitis Pathophysiology and Potential Therapeutic Targets
Authors: Jihad Aljabban, Sean McDermott, Ross A. Wanner, Hussam Salhi, Nabeal Aljabban, Mohamad Mukhtar, Zhraa Mohammed, Hisham Aljabban, Maryam Panahiazar, Dexter Hadley
Journal: Journal of Allergy and Clinical Immunology (2019)
The Impact of the Cellular Origin in Acute Myeloid Leukemia: Learning From Mouse Models
Authors: James Neil Fisher, Natarajaswamy Kalleda, Vaia Stavropoulou, Juerg Schwaller
Journal: HemaSphere (2019)

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous disease driven by a limited number of cooperating mutations. There is a long‐standing debate as to whether AML driver mutations occur in hematopoietic stem or in more committed progenitor cells. Here, we review how different mouse models, despite their inherent limitations, have functionally demonstrated that cellular origin plays a critical role in the biology of the disease, influencing clinical outcome. AML driven by potent oncogenes such as mixed lineage leukemia fusions often seem to emerge from committed myeloid progenitors whereas AML without any major cytogenetic abnormalities seem to develop from a combination of preleukemic initiating events arising in the hematopoietic stem cell pool. More refined mouse models may serve as experimental platforms to identify and validate novel targeted therapeutic strategies.
On-treatment changes of plasma protein biomarkers in CALGB/SWOG 80405 (Alliance).
Authors: Ace Joseph Hatch, Fang-Shu Ou, Tyler Zemla, Mark D. Starr, John C. Brady, Yingmiao Liu, Federico Innocenti, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly, Heinz-Josef Lenz, Herbert Hurwitz, Alan P. Venook, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2019)

588 Background: CALGB/SWOG 80405 found no difference in overall survival (OS) or progression-free survival (PFS) in 1137 patients with KRAS wild-type metastatic colorectal cancer (mCRC) treated with either the anti-VEGF agent bevacizumab (Bev) or the anti-EGFR agent cetuximab (Cet) in combination with chemotherapy (FOLFOX or FOLFIRI) as first-line therapy. Additional molecular biomarkers are required for the optimization of treatment choices for patients with mCRC. Methods: Levels of 24 proteins were assayed in EDTA-plasma samples using multiplex ELISA techniques. Plasma samples were collected at baseline and cycle 2 day 1 (C2D1). Analyses of baseline markers have been presented previously. Changes from baseline to C2D1 were expressed as an L-ratio (LR, log 2 of C2D1 divided by baseline measure). LRs dichotomized at 0 were analyzed for potential prognostic and predictive effects on OS and PFS using Cox models while adjusting for confounders (post-hoc optimized cutpoints were used for PLGF, TIMP1, VCAM1, and VEGFR3 due to skew in the distributions of these markers). P-values are not corrected for multiple testing. Results: Baseline and matched C2D1 samples from 446 patients (212 Bev/234 Cet) were available for analysis. Thirteen markers were differentially modulated between arms (p &lt; 0.05). Early increases in CD73 (p = 0.001), ICAM1 (p = 0.022), TIMP1 (p = 0.001), TSP2 (p = 0.024), and VEGFR3 (p = 0.006) were prognostic for shorter OS. Increases in ICAM1 (p = 0.008), TIMP1 (p = 0.042), and TGFB1 (p = 0.039) were prognostic for shorter PFS. Changes in VEGFR3 (p int = 0.097) and TGFBR3 (p int = 0.052) were predictive for OS and PFS, respectively. No other markers were predictive for OS or PFS (p &lt; 0.1). Conclusions: Changes in circulating plasma protein biomarkers observed in patients enrolled in CALGB/SWOG 80405 were both prognostic and predictive for OS and PFS and warrant further study. Such changes could provide valuable information and help guide treatment decisions. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180830; ClinicalTrials.gov: NCT00265850. [Table: see text]
Endoscopic therapy of sclerosing cholangitis*1
Authors: J LEE
Journal: Hepatology (1995)

The efficacy of endoscopic treatment in primary sclerosing cholangitis has not been clearly established. This report presents endoscopic intervention in 53 consecutive patients with this disorder. Pertinent data were abstracted from the GI-TRAC database, medical records, and cholangiograms, and clinical follow-up was obtained by telephone interview of the subjects. Assessed treatment outcomes were clinical symptom, liver function test, and cholangiographic appearance. Between 1986 and 1993, 85 patients with primary sclerosing cholangitis underwent successful ERCP, of which 36 men and 17 women underwent 100 therapeutic endoscopic procedures. Forty-three of 50 dilations, 37 of 38 stentings, 8 of 8 nasobiliary tube placements, and 11 of 17 stone extractions were technically successful. These treatments were complicated by cholangitis or pancreatitis in 15 patients. Clinical follow-up was obtained in 50 of 53 patients who had undergone 85 procedures (median follow-up of 31 months): 28 patients felt better, 21 felt the same, and 1 felt worse. Liver function tests obtained within 3 months of the endoscopic treatment were significantly improved compared with pretreatment values (P < .001). Cholangiograms showed improvement in 36% of the patients, no change in 51%, and the effect of therapy could not be assessed in 13%. Overall, 41 of 53 patients (77%) had improvements of their clinical symptoms, liver function tests, or cholangiograms.
Platelet microRNAs and vascular injury
Authors: Elena V. Dolmatova, Kathy K. Griendling
Journal: Journal of Clinical Investigation (2019)

Vascular smooth muscle cell (VSMC) phenotype switching from a contractile state to a synthetic phenotype has been implicated in intimal remodeling during vascular injury. While multiple studies have focused on dedifferentiation of VSMCs, prevention of VSMC-mediated excessive repair remains poorly understood. In this issue of the JCI, Zeng et al. identified a mechanism by which platelet-derived microRNA-223 (miRNA-223) reverses VSMC dedifferentiation. The authors show that suppression of proliferation occurs after platelet internalization by VSMCs. Moreover, they demonstrate that miRNA-223 inhibits dedifferentiation and intimal hyperplasia in diabetic mice by decreasing PDGFRβ expression in VSMCs. Together, these results identify platelet-derived miRNA-223 as a potential therapeutic target in vascular injury.
Genetic polymorphisms of vascular endothelial growth factor (VEGF) associated with gastric cancer recurrence after curative resection with adjuvant chemotherapy.
Authors: Ik Hyun Jo, Yeon Ji Kim, Woo Chul Chung
Journal: Journal of Clinical Oncology (2019)

9 Background: The relationship between polymorphisms in vascular endothelial growth factor (VEGF) and gastric cancer is still inconclusive. We investigated whether there is an association between VEGF genetic polymorphisms and risk of gastric cancer, and evaluated the recurrence of advanced gastric cancer after curative resection with adjuvant chemotherapy according to VEGF genetic polymorphisms. Methods: The association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene (+936C &gt; T, -634G &gt; C, -2578C &gt; A, +1612G &gt; A) were evaluated. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A total of 151 patients with gastric cancer were enrolled, and the control group consisted of 413 individuals with esophago-gastroduodenoscopy who were randomly selected through health screening. All of the enrolled patients had curative resections with completion of adjuvant capecitabine and oxaliplatin combination chemotherapy and the initial metastatic cases were excluded. During the regular follow-up protocol, the episodes of the recurrence were documented and the specific genotype and allelic frequencies were evaluated. Results: As for the cancer risk, there were no significant differences in specific genotypes and allelic frequencies. The mean follow-up period was 28.82 ± 30.92 (12 ~ 72) months and the recurrence rate was 28.3%. In the patients carrying the 936-C allele, the recurrence rate of gastric cancer was high ( P = 0.02). Disease-free interval was significantly different between the patients carrying the 936-CC and 936-CT/TT genotype ( P = 0.02). Conclusions: VEGF +936 C &gt; T genetic polymorphism is associated with poor prognosis, but not risk of gastric cancer. In the patients carrying the 936-C allele, more potent adjuvant treatment would be considered.
MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate
Authors: Sara Abdelfatah, Angela Berg, Qi Huang, Li Jun Yang, Sami Hamdoun, Anette Klinger, Henry J. Greten, Edmond Fleischer, Thorsten Berg, Vincent K.W. Wong, Thomas Efferth
Journal: Acta Pharmaceutica Sinica B (2019)

Polo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethyl-benzofuran-2-carboxylic acid ethyl ester (designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis. This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest-a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.