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#34130349   2021/06/15 To Up

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

 Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation.
Bibian M E Tullemans, Delia I Fernández, Alicia Veninga, Constance C F M J Baaten, Linsey J F Peters, Maureen J B Aarts, Johannes A Eble, Elena Campello, Luca Spiezia, Paolo Simioni, Emiel P C van der Vorst, Paola E J van der Meijden, Johan W M Heemskerk, Marijke J E Kuijpers

1591 related Products with: Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

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#34130115   2021/06/12 To Up

Novel autoantibodies to the β-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by autoimmune destruction of insulin-producing β-cells in pancreatic islets. Seroconversions to islet autoantibodies (IAbs) precede the disease onset by many years, but the role of humoral autoimmunity in the disease initiation and progression are unclear. In the present study, we identified a new IAb directed to the extracellular epitopes of ZnT8 (ZnT8ec) in newly diagnosed patients with T1D, and demonstrated immunofluorescence staining of the surface of human β-cells by autoantibodies to ZnT8ec (ZnT8ecA). With the assay specificity set on 99th percentile of 336 healthy controls, the ZnT8ecA positivity rate was 23.6% (74/313) in patients with T1D. Moreover, 30 children in a longitudinal follow up of clinical T1D development were selected for sequential expression of four major IAbs (IAA, GADA, IA-2A and ZnT8icA). Among them, 10 children were ZnT8ecA positive. Remarkably, ZnT8ecA was the earliest IAb to appear in all 10 children. The identification of ZnT8ec as a cell surface target of humoral autoimmunity in the earliest phase of IAb responses opens a new avenue of investigation into the role of IAbs in the development of β-cell autoimmunity.
Yong Gu, Chengfeng Merriman, Zheng Guo, Xiaofan Jia, Janet Wenzlau, Hua Li, Huilin Li, Marian Rewers, Liping Yu, Dax Fu

1271 related Products with: Novel autoantibodies to the β-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes.

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#34129395   2021/06/15 To Up

Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

Pancreatitis accounts for more than $2.5 billion of healthcare costs and remains the most common gastrointestinal (GI) admission. Few contemporary studies have assessed temporal trends of incidence, complications, management, and outcomes for acute pancreatitis in hospitalized patients at the national level. We used data from one of the largest hospital-based databases available in the United States, the Healthcare Cost and Utilization Project's (HCUP) State Inpatient Database, from 10 states between 2008 and 2015. We included patients with a diagnosis of acute pancreatitis (ICD-9 CM 577.0). Patient- and hospital-level data were used to estimate incidence and inpatient mortality rates. From 80,736,256 hospitalizations, 929,914 (1.15%) cases of acute pancreatitis were identified, 186,226 (20.2%) of which were caused by gallbladder disease). The median age was 53 years (interquartile range [IQR], 41-67) and 50.8% were men. In-hospital mortality was 2.5% and crude mortality rates declined from 2.9% to 2.0% over the study period. Admission year remained significant after adjusting for patient demographics and comorbidities (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.89-0.90; p < 0.001). Gallbladder disease was associated with decreased odds of mortality (OR, 0.60; 95% CI, 0.57-0.62). Median length of stay was four days (IQR, 2-7) and decreased over time. The rates of surgical and endoscopic interventions were highest in 2011 (peak incidence of 16.1% and 9.5%, respectively) and have been decreasing since. Surgical providers were, on average, more likely than medical providers to perform surgery in both those with and without gallbladder disease etiology (gallbladder disease OR, 7.11; 95% CI, 5.46-9.25; non-gallbladder disease OR, 20.50; 95% CI, 16.81-25.01), endoscopy (gallbladder disease OR, 1.22; 95% CI, 0.87-1.72; non-gallbladder disease OR, 1.60; 95% CI, 1.18-2.16), or both (gallbladder disease OR, 7.00; 95% CI, 5.22-9.37; non-gallbladder disease OR, 8.85; 95% CI, 5.61-13.96). The incidence of pancreatitis, from 2008 to 2015, has increased whereas inpatient mortality (i.e., case fatality) has decreased. Understanding temporal trends in outcomes and management along with provider, hospital, and regional variation can better identify areas for future research and collaboration in managing these patients.
Nicholas E Ingraham, Samantha King, Jennifer Proper, Lianne Siegel, Emily J Zolfaghari, Thomas A Murray, Victor Vakayil, Adam Sheka, Ruoying Feng, Gabriel Guzman, Samit Sunny Roy, Dhannanjay Muddappa, Michael G Usher, Jeffrey G Chipman, Christopher J Tignanelli, Kathryn M Pendleton

1257 related Products with: Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

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#34129156   2021/06/15 To Up

Quercetin improves oxidative stress-induced pancreatic beta cell alterations via mTOR-signaling.

Citrus flavonoids particularly quercetin which is abundant in grapefruit, onion, green tea, berries etc. are known to have a protective effect on oxidative stress. Pancreatic β cells which synthesize and secrete insulin are prone to oxidative stress induced damage because of low cellular antioxidant enzymes. To delineate the effects of quercetin on pancreatic β cells we evaluated the protective effect of quercetin on TC6 insulinoma cells subjected to oxidative stress induced by tert-butyl-hydrogen-peroxide (TBHP). Quercetin was found to reduce TBHP induced apoptosis and trigger insulin secretion in response to glucose, in a dose-dependent manner. Quercetin treatment increased mitochondrial biogenesis, caused hypertrophy in pancreatic β cells and activated mTOR signaling with a transient change in mitochondrial membrane potential and AMP/ATP. Activation of mTOR signaling resulted in enhanced insulin secretion in TC6 cells.
R Dhanya, C C Kartha

1074 related Products with: Quercetin improves oxidative stress-induced pancreatic beta cell alterations via mTOR-signaling.

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#34129114   2021/06/15 To Up

Relationship between hepatic venous anatomy and hepatic venous blood loss during hepatectomy.

Predicting increased blood loss based on anatomical intervascular relationships is essential in major hepatectomy.
Atsushi Nanashima, Yukinori Tanoue, Tatefumi Sakae, Isao Tsuneyoshi, Masahide Hiyoshi, Naoya Imamura, Takeomi Hamada, Koichi Yano, Takahiro Nishida, Mitsutoshi Ishii, Takeshi Nagayasu, Kunihide Nakamura

2132 related Products with: Relationship between hepatic venous anatomy and hepatic venous blood loss during hepatectomy.

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#34128834   2021/06/15 To Up

Dysregulation of mannose-6-phosphate dependent cholesterol homeostasis in acinar cells mediates pancreatitis.

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding for a key enzyme in M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of non-esterified cholesterol in lysosomes/autolysosomes, its' depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.
Olga A Mareninova, Eszter T Vegh, Natalia Shalbueva, Carli Jm Wightman, Dustin L Dillon, Sudarshan Malla, Yan Xie, Toshimasa Takahashi, Zoltan Rakonczay, Samuel W French, Herbert Y Gaisano, Frederick Sanford Gorelick, Stephen J Pandol, Steven J Bensinger, Nicholas O Davidson, David W Dawson, Ilya Gukovsky, Anna S Gukovskaya

2965 related Products with: Dysregulation of mannose-6-phosphate dependent cholesterol homeostasis in acinar cells mediates pancreatitis.

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#34128828   2021/06/01 To Up

Targeted inhibition of the WEE1 kinase as novel therapeutic strategy in neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2-dimensional and 3-dimensional spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA-double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.
Lena Weindl, Lena Weindl, Imke Atreya, Peter Dietrich, Sabine Neubeck, Markus F Neurath, Marianne E Pavel

1620 related Products with: Targeted inhibition of the WEE1 kinase as novel therapeutic strategy in neuroendocrine neoplasms.

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