tbuckley/cabot-search huggingface dataset:
Deregulated TGF-β/BMP Signaling in Vascular Malformations
Authors: Sara I. Cunha, Peetra U. Magnusson, Elisabetta Dejana, Maria Grazia Lampugnani
Journal: Circulation Research (2017)

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.
Covered TIPS versus endoscopic band ligation plus propranolol for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: a randomised controlled trial
Authors: Yong Lv, Xingshun Qi, Chuangye He, Zhengyu Wang, Zhanxin Yin, Jing Niu, Wengang Guo, Wei Bai, Hongbo Zhang, Huahong Xie, Liping Yao, Jianhong Wang, Tao Li, Qiuhe Wang, Hui Chen, Haibo Liu, Enxing Wang, Dongdong Xia, Bohan Luo, Xiaomei Li, Jie Yuan, Na Han, Ying Zhu, Jielai Xia, Hongwei Cai, Zhiping Yang, Kaichun Wu, Daiming Fan, Guohong Han
Journal: Gut (2017)

Objective Limited data are available on the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis (PVT). This study aimed to compare transjugular intrahepatic portosystemic shunt (TIPS) with covered stents versus endoscopic band ligation (EBL) plus propranolol for the prevention of variceal rebleeding among patients with cirrhosis and PVT. Design Consecutive cirrhotic patients (94% Child-Pugh class A or B) with PVT who had variceal bleeding in the past 6 weeks were randomly assigned to TIPS group (n=24) or EBL plus propranolol group (EBL+drug, n=25), respectively. Primary endpoint was variceal rebleeding. Secondary endpoints included survival, overt hepatic encephalopathy (OHE), portal vein recanalisation and rethrombosis, other complications of portal hypertension and adverse events. Results During a median follow-up of 30 months in both groups, variceal rebleeding was significantly less frequent in the TIPS group (15% vs 45% at 1 year and 25% vs 50% at 2 years, respectively; HR=0.28, 95% CI 0.10 to 0.76, p=0.008), with a significantly higher portal vein recanalisation rate (95% vs 70%; p=0.03) and a relatively lower rethrombosis rate (5% vs 33%; p=0.06) compared with the EBL+drug group. There were no statistically significant differences in survival (67% vs 84%; p=0.152), OHE (25% vs 16%; p=0.440), other complications of portal hypertension and adverse events between groups. Conclusion Covered TIPS placement in patients with PVT and moderately decompensated cirrhosis was more effective than EBL combined with propranolol for the prevention of rebleeding, with a higher probability of PVT resolution without increasing the risk of OHE and adverse effects, but this benefit did not translate into improved survival. Trial registration number ClinicalTrials.gov: NCT01326949 .
A composite of exhaled <scp>LTB</scp><sub>4</sub>, <scp>LXA</scp><sub>4</sub>, Fe<scp>NO</scp>, and <scp>FEV</scp><sub>1</sub> as an “asthma classification ratio” characterizes childhood asthma
Authors: L.‐C. Chen, H.‐M. Tseng, M.‐L. Kuo, C.‐Y. Chiu, S.‐L. Liao, K.‐W. Su, M.‐H. Tsai, M.‐C. Hua, S.‐H. Lai, T.‐C. Yao, K.‐W. Yeh, A.‐H. Wu, J.‐L. Huang, S.‐K. Huang
Journal: Allergy (2017)

Abstract Background Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates ( EBC s) were assessed as candidate markers for childhood asthma. Methods Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model‐building and validation phases. Results Exhaled LTB 4 , LTE 4 , PGE 2, and LXA 4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic ( ROC ) analyses of the training subset revealed the level of exhaled LTB 4 to be the most discriminative among all parameters, including Fe NO , and a composite of exhaled LTB 4 , LXA 4 , together with Fe NO and FEV 1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as “asthma classification ratio” was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively. Conclusions In a pediatric study population in Taiwan, the levels of exhaled LTB 4 , LTE 4 , LXA 4, and PGE 2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB 4 and LXA 4 , together with Fe NO and FEV 1 , best characterized childhood asthma.
Minimal neonatal transfer of certolizumab pegol in a Japanese patient with rheumatoid arthritis
Authors: Takayoshi Morita, Kosuke Fujimoto, Yoshihito Shima, Atsushi Ogata, Atsushi Kumanogoh
Journal: Annals of the Rheumatic Diseases (2017)

Clowse et al 1 have reported minimal to no transfer of certolizumab pegol (CZP) into breast milk, and their findings have supported the continuation of CZP treatment during breast milk feeding. Rheumatoid arthritis (RA) often develops in women of childbearing age. It is generally difficult to treat these patients with methotrexate, which is the anchor drug for RA. Therefore, biologics, such as tumour necrosis factor (TNF) inhibitors, are often considered for active RA during pregnancy. However, the biologics cross the placenta from mother to fetus and transfer into breast milk during lactation. Although a meta-analysis report indicated that anti-TNF-α therapy did not increase the risks, such as congenital malformation or abortion during pregnancy, in patients with inflammatory …
Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults
Authors: Danni Li, Angela Radulescu, Rupendra T. Shrestha, Matthew Root, Amy B. Karger, Anthony A. Killeen, James S. Hodges, Shu-Ling Fan, Angela Ferguson, Uttam Garg, Lori J. Sokoll, Lynn A. Burmeister
Journal: JAMA (2017)

<h3>Importance</h3> Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. <h3>Objective</h3> To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. <h3>Design, Setting, and Participants</h3> Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory <h3>Exposure</h3> Administration of 10 mg/d of biotin supplementation for 7 days. <h3>Main Outcomes and Measures</h3> Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. <h3>Results</h3> Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion–associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (<i>P</i> = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. <h3>Conclusions and Relevance</h3> In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT03034707
A phase I/pilot study of CPX-351 for children, adolescents and young adults with recurrent or refractory hematologic malignancies.
Authors: Michael Absalon, Maureen Megan O'Brien, Christine L. Phillips, Karen Cristly Burns, Jennifer Mangino, Benjamin Mizukawa, Erin Haag Breese, Rachana Shah, John Peter Perentesis
Journal: Journal of Clinical Oncology (2016)

10541 Background: CPX-351, a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio, has demonstrated pre-clinical activity against AML and ALL cell lines and is currently under phase-III investigation in adults with AML and high risk features. A phase I trial evaluating this agent in children with relapsed or refractory hematologic malignancies was conducted. Methods: Children and young adults age 12 months to 21 years with relapsed or refractory leukemia were enrolled in the dose exploration phase of the study in which participants received a single course of CPX-351. Using a rolling 6 design, CPX-351 was administered once on days 1, 3, and 5. Enrollment was initiated at the recommended dose for study in adults (dose Level 1: 100 Units/m2/dose) with provisions to explore either a single dose escalation to 134 Units/m2/dose (dose level 2) or de-escalation to 67 Units/m2/dose. Results: Nine patients [median age 8 y (range 1-17y)] with AML (n = 6) or ALL (n = 3) were enrolled and evaluable for toxicity. All participants experienced Grade 3 or 4 hematologic toxicity including 8 with fever with neutropenia or infection. Grade 3-4 non-hematologic toxicity included rash (n = 2), anorexia (n = 2), colitis (n = 1), and elevated GGT (n = 1). There were no DLTs observed in the 4 patients enrolled at level 1. Two of the 5 participants accrued at dose level 2 experienced dose limiting toxicity: Grade 3 pain lasting greater than 48 hours. One patient with AML was unevaluable due to removal from protocol therapy to receive bone marrow transplantation. All others were evaluable for response: 1 patient with ALL had stable disease, 2 with AML achieved a complete remission, and 1 with AML achieved a MRD negative marrow but developed low level CNS disease (CNS status 2). The study continues to accrue to the expansion phase using dose level 1. Conclusions: CPX-351 is well tolerated in children with relapsed leukemia and has demonstrated clinically meaningful responses. The recommended dose of CPX-351 for further study in pediatrics is 100 Units/m2/dose administered on Days 1, 3, and 5.
Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target
Authors: Jacob New, Levi Arnold, Megha Ananth, Sameer Alvi, Mackenzie Thornton, Lauryn Werner, Ossama Tawfik, Hongying Dai, Yelizaveta Shnayder, Kiran Kakarala, Terance T. Tsue, Douglas A. Girod, Wen-Xing Ding, Shrikant Anant, Sufi Mary Thomas
Journal: Cancer Research (2017)

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679-91. ©2017 AACR.
Abstract 18608: Low Appendicular Skeletal Muscle Mass Predicts the Future Cadiovascular Events in Patients With Acute Decompensated Heart Failure
Authors: Eiichi Akiyama, Masaaki Konishi, Yasushi Matsuzawa, Mitsuaki Endo, Chika Kawashima, Hiroyuki Suzuki, Naoki Nakayama, Nobuhiko Maejima, Noriaki Iwahashi, Kengo Tsukahara, Kiyoshi Hibi, Masami Kosuge, Toshiaki Ebina, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2015)

Introduction: Heart failure (HF) is a clinical syndrome associated with diverse metabolic disturbances. Recent studies suggest that failing heart through secretion of soluble myostatin may induce skeletal muscle wasting in HF patients and skeletal muscle plays an important role in pathogenesis of exercise intolerance in patients with chronic HF. However, the clinical significance of skeletal muscle mass in patients with acute decompensated HF (ADHF) remains unclear. Hypothesis: We hypothesized that low appendicular skeletal muscle mass could predict the occurrence of future cardiovascular (CV) events in patients with ADHF. Methods: We assessed lean body mass by dual energy X-ray absorptiometry in 96 patients with ADHF (age 72±11, left ventricular ejection fraction (LVEF) 38±15%, B-type natriuretic peptide (BNP) levels on admission 752 [377-1398] pg/ml). Low appendicular skeletal muscle mass index (ASMI, appendicular skeletal muscle mass/height 2 ) was defined according to the Asia Working Group for Sarcopenia criteria (&lt;7.0kg/m 2 in male, &lt;5.4kg/m 2 in female). ADHF patients were followed until occurring CV events (CV death, nonfatal myocardial infarction, ischemic stroke, or HF re-hospitalization). Results: ASMI significantly correlated with age (r=-0.51, P&lt;0.001), male sex (r=0.53, P&lt;0.001), body mass index (r=0.63, P&lt;0.001), systolic blood pressure on admission (r=0.21, P=0.04), and BNP levels on admission (r=-0.39, P=0.04). ADHF patients with low ASMI (n=54, 56%) had higher BNP levels (968 [552-1773] versus 498 [273-943], p=0.001) and higher rate of clinical scenario 2-3 (48% versus 12%, p=0.001) than those with normal ASMI. 42 patients developed CV events (median follow-up, 16months). Kaplan-Meier analysis demonstrated a significantly higher probability of CV events in the low ASMI group than those in the normal ASMI group (54% vs. 29%, log-rank test, P=0.02). Multivariate Cox hazard analysis identified low ASMI as an independent predictor of the CV events in patients with ADHF (hazard ratio 2.1, 95%-confidence interval 1.1-4.2, P=0.03). Conclusions: Low ASMI could predict the future CV events in patients with ADHF, irrespective of LV systolic function and other clinical profile.
Molecular haplotyping vs. statistical inference: Example of paraoxonase 1 (PON1)
Authors: James G. Wetmur, Mahdu Kumar, Li Zhang, Sylvan Wallenstein, Wendy Chan, Gertrud Berkowitz, Jia Chen
Journal: Cancer Research (2005)

4067   Paraoxonase 1 (PON1) is an enzyme with multiple activities, including detoxification of organophosphates. It is believed to be important in preventing neurotoxic damage, and has also been implicated in atherosclerosis. The PON1 gene contains three common promoter polymorphisms, three in the promoter (-909G>C, -162A>G, -108C>T) and two in the coding region (M55L, Q192R) with varying but incomplete linkage disequilibrium. In a previous study, we have imputed PON1 haplotypes using two widely used programs, PHASE and tagSNPs, which yielded very similar results. In this study, we have developed a molecular approach, linking emulsion PCR (LE-PCR), to physically determine the PON1 haplotypes; results from this determination can be used to test the accuracy of the statistical inference of haplotypes. Linking emulsion PCR (LE-PCR) enables formation of minichromosomes preserving phase information of two polymorphic loci, thus the haplotype. Emulsion PCR confines amplicons of two linked polymorphic sites on a single template molecule to one aqueous-phase droplet. Linking PCR uses external primers in excess over biotinylated, overlapping linking primers to connect these amplicons. Unlinked amplicons are removed on streptavidin-coated magnetic beads, and runoff products are capped by primer extension on partially complementary 3’-blocked oligonucleotides. Quantitative allele-specific PCR can then be used to ascertain the haplotypes of the two polymorphic loci on the minichromosomes. In a total population of 378 individuals, we determined PON1 molecular haplotypes at three loci (-909g>c, L55M, Q192R) in 165 individual who were compound heterozygotes for -909g>c/L55M (n=89), -909g>c/Q192R (n=77) or L55M/Q192R (n=68). Twenty-four of the 165 individuals showed different molecular haplotypes than the inferred haplotypes (15% disconcordancy); 14 of these were -909g>c/Q192R compound heterozygotes, possibly due the lower degree of linkage between the two loci. We also observed a strong association between PON1 substrate specificity (measured as paraoxon/phenylacetate substrate activity ratios) and 909g>c/Q192R haplotype. We have demonstrated here a powerful molecular haplotyping technology that can be applied in population studies. Meanwhile, a ∼15% “error rate” suggests caution in the use of statistical inference for haplotypes.
Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy
Authors: Adeolu Oluwasanmi, Wejdan Al-Shakarchi, Ayesha Manzur, Mohammed H. Aldebasi, Rayan S. Elsini, Malek K. Albusair, Katherine J. Haxton, Anthony D.M. Curtis, Clare Hoskins
Journal: Journal of Controlled Release (2017)
Liver dysfunction in chronic lymphocytic leukemia: Prevalence, outcomes, and pathological findings
Authors: Paul J. Hampel, Kari G. Chaffee, Rebecca L. King, Douglas Simonetto, Melissa C. Larson, Sara Achenbach, Timothy G. Call, Wei Ding, Saad S. Kenderian, Jose F. Leis, Asher A. Chanan‐Khan, Deborah A. Bowen, Michael J. Conte, Susan M. Schwager, Curtis A. Hanson, Susan L. Slager, Neil E. Kay, Tait D. Shanafelt, Sameer A. Parikh
Journal: American Journal of Hematology (2017)

Abstract The prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (&lt;12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed. An abnormal LFT was present in 82/2336 (3.5%) patients at diagnosis and was associated with advanced Rai stage (Rai III–IV) (21% vs. 6%; P &lt; .001), lower hemoglobin (13.1 g/dL vs. 13.9 g/dL; P &lt; .001), and lower platelet count (187 × 109/L vs. 200 × 109/L; P = .03). Additionally, 236 patients with normal LFTs at diagnosis developed acquired liver dysfunction during follow‐up. Patients with abnormal LFTs at diagnosis had a shorter OS compared to those with normal LFTs (HR 1.80 95% CI 1.13‐2.87; P = .014, adjusted for age, sex, Rai stage, and treatment), although TTFT was not different. Of 52 patients who underwent a liver biopsy, CLL was present in liver tissue in 39/52 (73%) patients, with the portal tracts the most common region involved. Histopathology findings of liver involvement by CLL had limited correlation with choice of CLL therapy. In conclusion, approximately 1 of 25 newly diagnosed CLL patients has abnormal LFTs at diagnosis. Although the TTFT was not different among patients with abnormal LFTs, these patients have a shorter OS compared to those with normal LFTs.