tbuckley/cabot-search huggingface dataset:
Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury
Authors: Brittany L. Rocque, Sima Babayeva, Jane Li, Vicki Leung, Lisa Nezvitsky, Andrey V. Cybulsky, Philippe Gros, Elena Torban
Journal: Journal of the American Society of Nephrology (2014)

The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane. Podocyte cell protrusions (foot processes) are critical for glomerular permselectivity; loss of foot process architecture results in proteinuria and FSGS. Previously, we showed a profound effect of PCP signaling on podocyte shape, actin rearrangement, cell motility, and nephrin endocytosis. To test our hypothesis that the PCP pathway is involved in glomerular development and function and circumvent lethality of the ubiquitous Vangl2 mutation in the Looptail mouse, we generated a mouse model with a podocyte-specific ablation of the Vangl2 gene. We report here that podocyte-specific deletion of Vangl2 leads to glomerular maturation defects in fetal kidneys. In adult mice, we detected significantly smaller glomeruli, but it did not affect glomerular permselectivity in aging animals. However, in the context of glomerular injury induced by injection of antiglomerular basement membrane antibody, deletion of Vangl2 resulted in exacerbation of injury and accelerated progression to chronic segmental and global glomerular sclerosis. Our results indicate that Vangl2 function in podocytes is important for glomerular development and protects against glomerular injury in adult animals.
Gold Nanorods Based Platforms for Light-Mediated Theranostics
Authors: Zhenjiang Zhang, Jing Wang, Chunying Chen
Journal: Theranostics (2013)

Due to their tunable surface plasmon and photothermal effects, gold nanorods (AuNRs) have proved to be promising in a wide range of biomedical applications such as imaging, hyperthermia therapy and drug delivery.All these applications can be remotely controlled by near infrared (NIR) light which can penetrate deep into human tissues with minimal lateral invasion.AuNRs thus hold the potential to combine both imaging diagnosis and therapeutic treatment into one single system and function as a NIR light-mediated theranostic platform.Herein we review recent progress in diagnostic and therapeutic applications of AuNRs with a highlight on combined applications for theranostic purposes.
Normal and Abnormal Biology of the beta-Amyloid Precursor Protein
Authors: D J Selkoe
Journal: Annual Review of Neuroscience (1994)

Few macromolecules have become the object of more intense chemical and biological scrutiny in recent years than has the l3-amyloid precursor protein. This highly conserved and widely expressed integral membrane protein is the focus of a rapidly growing number of studies aimed at its characterization by protein chemical, molecular biological , cell biological , and neuroanatomical methods. The principal reason for this attention is clear. The early promise that a 39-43 residue fragment of I3APP, the amyloid l3-protein (AI3), might play a central role in the pathogenesis of Alzheimer's disease has increasingly been borne out. Although there is still substantial debate about exactly when AI3 becomes involved in Alzheimer's disease and how attractive a therapeutic target it represents , accumulating evidence now points to an early and sometimes causative role in the pathogenetic cascade. I3APP has become a compelling example of the phenomenon of research that begins with a strictly disease-oriented focus giving rise to novel insights about the normal biology of a whole family of macromolecules, in this case about the processing of certain cell surface, single membrane-spanning polypeptides. Here, I review recent information about the normal structure and function of I3APP and how its AI3 fragment contributes to Alzheimer's disease. Such
A Phase I Study of Samarium Lexidronam/Bortezomib Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma
Authors: James R. Berenson, Ori Yellin, Ravi Patel, Herb Duvivier, Youram Nassir, Russell Mapes, Christina DiLauro Abaya, Regina A. Swift
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This open-label, phase I dose-escalation study assessed the safety, tolerability, and initial efficacy of Samariam 153 (153Sm)-lexidronam/bortezomib combination therapy for patients with relapsed/refractory multiple myeloma. Experimental Design: Patients were enrolled in six cohorts and given bortezomib (1.0 or 1.3 mg/m2) on days 1, 4, 8, and 11 and 153Sm-lexidronam (0.25, 0.5, or 1.0 mCi/kg) on day 3 of a 56-day cycle (maximum of four cycles). The primary endpoints were safety and tolerability of the 153Sm-lexidronam/bortezomib regimen. Results: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm3 and 98,500/mm3, respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg 153Sm-lexidronam in combination with 1.3 mg/m2 bortezomib. The maximum tolerated dose for 153Sm-lexidronam in combination with the 1.0 mg/m2 bortezomib was not reached. No nonhematologic dose-limiting toxicities were observed; both the incidence and the severity of peripheral neuropathy were low. Responses occurred in 5 (21%) patients, including 3 (12.5%) complete and 2 (8.3%) minimal responses. Conclusions: Bortezomib combined with 153Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.
Role of Adiponectin in Matching of Fetal and Placental Weight in Mothers With Type 1 Diabetes
Authors: Scott M. Nelson, Dilys J. Freeman, Naveed Sattar, Robert S. Lindsay
Journal: Diabetes Care (2008)

To assess the association of fetal hormones with placental growth and fetal weight-to-placental weight ratio index (FPI) in pregnancies complicated by maternal diabetes.We conducted a prospective study using umbilical venous blood samples taken at birth from 122 offspring of mothers with type 1 diabetes (OT1D) and 46 control subjects.Placental weight (P = 0.009) and gestation-adjusted birth weight (P < 0.001) were increased in OT1D, but FPI was unaltered (P = 0.33). Placental weight correlated with birth weight (P < 0.001) and cord leptin (P < 0.001) in control subjects and OT1D, with further relationships with cord insulin, IGF-1, IGF-binding protein-3 (IGFBP-3), and triceps and subscapular thickness in OT1D. FPI was associated with adiponectin in both groups, even after adjustment for confounders.Placental and fetal growth show a parallel increase in mothers with type 1 diabetes. The possible role of adiponectin in matching of fetal and placental growth merits further study.
IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway
Authors: Dongki Yang, Qin Li, Insuk So, Chou-Long Huang, Hideaki Ando, Akihiro Mizutani, George Seki, Katsuhiko Mikoshiba, Philip J. Thomas, Shmuel Muallem
Journal: Journal of Clinical Investigation (2011)

Fluid and HCO(3)(-) secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and HCO(3)(-) in secretory glands is fueled by Na(+)/HCO(3)(-) cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by Cl(-)/HCO(3)(-) exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and HCO(3)(-) secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis.
Phosphorylation of ABCB4 impacts its function: Insights from disease-causing mutations
Authors: Julien Gautherot, Danièle Delautier, Marie-Anne Maubert, Tounsia Aït-Slimane, Gérard Bolbach, Jean-Louis Delaunay, Anne-Marie Durand-Schneider, Delphine Firrincieli, Véronique Barbu, Nicolas Chignard, Chantal Housset, Michèle Maurice, Thomas Falguières
Journal: Hepatology (2014)

The ABCB4 transporter mediates phosphatidylcholine (PC) secretion at the canalicular membrane of hepatocytes and its genetic defects cause biliary diseases. Whereas ABCB4 shares high sequence identity with the multidrug transporter, ABCB1, its N-terminal domain is poorly conserved, leading us to hypothesize a functional specificity of this domain. A database of ABCB4 genotyping in a large series of patients was screened for variations altering residues of the N-terminal domain. Identified variants were then expressed in cell models to investigate their biological consequences. Two missense variations, T34M and R47G, were identified in patients with low-phospholipid–associated cholelithiasis or intrahepatic cholestasis of pregnancy. The T34M and R47G mutated proteins showed no or minor defect, respectively, in maturation and targeting to the apical membrane, in polarized Madin-Darby Canine Kidney and HepG2 cells, whereas their stability was similar to that of wild-type (WT) ABCB4. By contrast, the PC secretion activity of both mutants was markedly decreased. In silico analysis indicated that the identified variants were likely to affect ABCB4 phosphorylation. Mass spectrometry analyses confirmed that the N-terminal domain of WT ABCB4 could undergo phosphorylation in vitro and revealed that the T34M and R47G mutations impaired such phosphorylation. ABCB4-mediated PC secretion was also increased by pharmacological activation of protein kinases A or C and decreased by inhibition of these kinases. Furthermore, secretion activity of the T34M and R47G mutants was less responsive than that of WT ABCB4 to protein kinase modulators. Conclusion : We identified disease-associated variants of ABCB4 involved in the phosphorylation of its N-terminal domain and leading to decreased PC secretion. Our results also indicate that ABCB4 activity is regulated by phosphorylation, in particular, of N-terminal residues. (Hepatology 2014;60:610–621)
Molecular cloning and characterization of tropomyosin, a major allergen of chironomus kiiensis, a dominant species of non-biting midges in Korea
Authors: Kyoung Young Jeong, Hye-Yung Yum, In-Yong Lee, Han-Il Ree, Chein Soo Hong, Dong Soo Kim, Tai-Soon Yong
Journal: Journal of Allergy and Clinical Immunology (2002)
The Time-Resolved Fluorescence-Based PCA3 Test on Urinary Sediments after Digital Rectal Examination; a Dutch Multicenter Validation of the Diagnostic Performance
Authors: Martijn P.M.Q. van Gils, Daphne Hessels, Onno van Hooij, Sander A. Jannink, W. Pim Peelen, Suzanne L.J. Hanssen, J. Alfred Witjes, Erik B. Cornel, Herbert F.M. Karthaus, Geert A.H.J. Smits, Gerhard A. Dijkman, Peter F.A. Mulders, Jack A. Schalken
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To improve the specificity in prostate cancer diagnosis and to prevent unnecessary prostate biopsies, especially in the serum prostate-specific antigen (PSA) “gray zone” between 3 and 15 ng/mL, the implementation of prostate cancer–specific markers is urgently needed. The recently discovered prostate cancer antigen 3 (PCA3) is such a promising prostate cancer marker. In a previous single institution study, the PCA3 urine test clearly proved to be of diagnostic value. Therefore, the diagnostic performance of the PCA3 urine test was validated in a multicenter study. Experimental Design: The first voided urine after digital rectal examination was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/mL who were to undergo prostate biopsies. We determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies. Results: A total of 534 men (92%) had an informative sample. The area under the receiver-operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65%, the specificity was 66% (versus 47% for serum PSA), and the negative predictive value was 80%. Conclusions: In this multicenter study, we validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test. This study shows that the PCA3 urine test, when used as a reflex test, can improve the specificity in prostate cancer diagnosis and could prevent many unnecessary prostate biopsies.
On Mice, Rabbits, and Human Heart Failure
Authors: A.J. Marian
Journal: Circulation (2005)

arcomeres, bundled into thick and thin filaments, are the units of contraction in the striated muscle.The thick filaments comprise several hundred hexameric myosin molecules, composed of 2 myosin heavy chain (MyHC) proteins, the molecular motor of contraction, and 2 regulatory and 2 essential light chains.The globular head of MyHC contains the binding domains for cardiac ␣-actin and adenosine triphosphate (ATP) and is attached to a hinge region, which when flexed, moves the globular head over the thin filaments.The thin filaments comprise the cardiac troponin C (cTnC), T (cTnT), and I (cTnI) complex, ␣-tropomyosin dimers, and cardiac ␣-actin, maintained in a tight 1:1:7 stoichiometry.Several additional sarcomeric proteins, such as myosin-binding protein C, titin, obscurin, and telethonin contribute to the stabilization and function of the sarcomeres.
Dynamic Imaging of Emerging Resistance during Cancer Therapy
Authors: Kuei C. Lee, Daniel E. Hall, Benjamin A. Hoff, Bradford A. Moffat, Surabhi Sharma, Thomas L. Chenevert, Charles R. Meyer, Wilbur R. Leopold, Timothy D. Johnson, Richard V. Mazurchuk, Alnawaz Rehemtulla, Brian D. Ross
Journal: Cancer Research (2006)

Abstract One of the greatest challenges in developing therapeutic regimens is the inability to rapidly and objectively assess tumor response due to treatment. Moreover, tumor response to therapeutic intervention in many cases is transient, and progressive alterations within the tumor may mask the effectiveness of an initially successful therapy. The ability to detect these changes as they occur would allow timely initiation of alternative approaches, maximizing therapeutic outcome. We investigated the ability of diffusion magnetic resonance imaging (MRI) to provide a sensitive measure of tumor response throughout the course of treatment, possibly identifying changes in sensitivity to the therapy. Orthotopic 9L gliomas were subjected to two separate therapeutic regimens, with one group receiving a single 5-day cycle (1ω) of low-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and a second group receiving two cycles at the same dose, bisected with 2 days of rest (2ω). Apparent diffusion coefficient maps were acquired before and throughout treatment to observe changes in water mobility, and these observations were correlated to standard measures of therapeutic response and outcome. Our results showed that diffusion MRI was indeed able to detect the emergence of a drug-resistant tumor subpopulation subsequent to an initially successful cycle of BCNU therapy, leading to minimal gains from a second cycle. These diffusion MRI findings were highly correlated with tumor growth delay, animal survival, and ex vivo growth inhibition assays showing emerging resistance in excised tumors. Overall, this study highlights the ability of diffusion MRI to provide sensitive dynamic assessment of therapy-induced response, allowing early opportunities for optimization of therapeutic protocols. (Cancer Res 2006; 66(9): 4687-92)
Role of paraoesophageal collaterals and perforating veins on outcome of endoscopic sclerotherapy for oesophageal varices: an endosonographic study.
Authors: R K Dhiman, G Choudhuri, V A Saraswat, D K Agarwal, S R Naik
Journal: Gut (1996)

BACKGROUND--Endoscopic sclerotherapy (EST) is an established method for controlling and preventing bleeding from oesophageal varices. However, oesophageal varices sclerose easily and require less sessions of EST in some patients while few fail to respond. This study therefore looked at changes in the vascular anatomy of the lower oesophagus and upper stomach that accompany successful sclerotherapy of oesophageal varices. METHODS--Endoscopic ultrasonography was performed in 50 patients with cirrhotic portal hypertension before (control, 20 patients) and after successful obliteration of varices with endoscopic sclerotherapy in a group of responders (EST-R, 20 patients) and in a group of non-responders (EST-NR, 10 patients). RESULTS--The median number and size of submucosal veins at the gastrooesophageal junction and in the lower oesophagus were significantly less in the EST-R group compared with control and EST-NR groups (p values between &lt; 0.00001 and &lt; 0.000001). Concomitantly, the number and size of paraoesophageal collaterals were significantly less in the EST-R group compared with the other two groups (p values between 0.02 and 0.00007). Perforating veins were identified in 14 (70%) patients in the control group, nine (90%) in the EST-NR group and in none in the EST-R group (p &lt; 0.001 for both controls v EST-R and EST-R v EST-NR, and p = NS, control v EST-NR). CONCLUSION--Oesophageal variceal sclerosis is associated with significant reduction in the number and size of paraoesophageal collaterals and disappearance of perforating veins in the lower oesophagus.
Expression of Angiogenesis-Related Genes and Progression of Human Ovarian Carcinomas in Nude Mice
Authors: Junya Yoneda, Hiroki Kuniyasu, Janet E. Price, Corazon D. Bucana, Isaiah J. Fidler, Marta A. Crispens
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice. Methods: Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies. Results: Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery. Conclusions: The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.
The Impact of Temperature on Mortality in Tianjin, China: A Case-Crossover Design with a Distributed Lag Nonlinear Model
Authors: Yuming Guo, Adrian G Barnett, Xiaochuan Pan, Weiwei Yu, Shilu Tong
Journal: Environmental Health Perspectives (2011)

Background: Although interest in assessing the impacts of temperature on mortality has increased, few studies have used a case-crossover design to examine nonlinear and distributed lag effects of temperature on mortality. Additionally, little evidence is available on the temperature–mortality relationship in China or on what temperature measure is the best predictor of mortality.Objectives: Our objectives were to use a distributed lag nonlinear model (DLNM) as a part of case-crossover design to examine the nonlinear and distributed lag effects of temperature on mortality in Tianjin, China and to explore which temperature measure is the best predictor of mortality.Methods: We applied the DLNM to a case-crossover design to assess the nonlinear and delayed effects of temperatures (maximum, mean, and minimum) on deaths (nonaccidental, cardiopulmonary, cardiovascular, and respiratory).Results: A U-shaped relationship was found consistently between temperature and mortality. Cold effects (i.e., significantly increased mortality associated with low temperatures) were delayed by 3 days and persisted for 10 days. Hot effects (i.e., significantly increased mortality associated with high temperatures) were acute and lasted for 3 days and were followed by mortality displacement for nonaccidental, cardiopulmonary, and cardiovascular deaths. Mean temperature was a better predictor of mortality (based on model fit) than maximum or minimum temperature.Conclusions: In Tianjin, extreme cold and hot temperatures increased the risk of mortality. The effects of cold last longer than the effects of heat. Combining the DLNM and the case-crossover design allows the case-crossover design to flexibly estimate the nonlinear and delayed effects of temperature (or air pollution) while controlling for season.