tbuckley/cabot-search huggingface dataset:
CS-03 * UTILIZING COLLAGEN AND DISCOIDIN DOMAIN RECEPTOR SIGNALING AS A NEWTHERAPEUTIC STRATEGY IN HUMAN MALIGNANT GLIOMA
Authors: S.-M. Chen, C. Wu, Y.-Y. Li, L. Feun, M. Wangpaichitr, R. J. Benveniste, N. Savaraj
Journal: Neuro-Oncology (2014)

We have previously shown that certain gliomas expressed procollagen type1 alpha1(1α1). Procollagen is synthesized in the endoplasmic reticulum, modified and packaged in the Golgi body and transported out of the cells. Once exited, the N-and C-terminal are cleaved by peptidase and fibril is formed. The collagen can interact with integrin, Endo180, or discoindin domain receptor(DDR). DDR is a class of receptor tyrosine kinase. The binding to collagen triggers autophosphorylation of DDR and initiation of other signaling cascades which are poorly understood, but have been implicated for cellular proliferation and invasion. DDR is comprised of 2 members(DDR1 and DDR2). Thus far, the clinical relevance of this pathway is not known. However, DDR1 has been reported in glioblastoma multiforme, both in cell lines and tissue and correlates with poor prognosis. In this report, we investigated the expression of procollagen1α1, DDR1 and DDR2 in 6 glioma cell lines. Silencing procollagen1α1, DDR1 or DDR2 resulted in impairment of cell migration. Silencing procollagen1α1 resulted in cell cycle arrest at G2/M. This effect is less when silencing DDR1 or DDR2. However, silencing DDR1 or DDR2 resulted in attenuation of pERK and pAKT. Since there is no inhibitor of collagen or DDRs, we have used Brefeldin A, which can block procollagen secretion out of the cell. Treatment with Brefeldin A resulted in retention of procollagen in the ER. Thus, less procollagen was secreted and hence there was less ligand to bind DDRs. As a result, less DDRs were activated. Our data suggest that there is a definite relationship between collagen and DDRs in gliomas which can affect cellular proliferation and migration. The downstream of this signaling is not yet understood but it can be explored for future treatment of glioma which possess both the ligand and receptor.
The Penile Prosthesis and Diabetic Impotence: Some Caveats
Authors: Wayne M Sotile
Journal: Diabetes Care (1979)

Literature published as of January 1978 contains reports of 103 diabetic men who have undergone implantation of a penile prosthesis as treatment for sexual impotence. Two forms of prosthesis have been used. One procedure involves the use of semi-rigid silicone rods. The other procedure uses inflatable silicone rubber cylinders. Both devices have yielded very high success rates within diabetic populations. Prospective recipients of a penile prosthesis should undergo extensive evaluation geared toward discrimination of organic versus psychogenic factors contributing to the sexual dysfunction. Before recommending prosthesis implantation, the physician should assess the expectations of the patient and his regular sex partner regarding the effects of the procedure. The stability of the patient's relationship with his regular sex partner should be considered an important determinant of response to implantation. Controlled investigations regarding the short- and long-term effects of this procedure are still needed.
Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways
Authors: Masahiko Igarashi, Hisao Wakasaki, Noriko Takahara, Hidehiro Ishii, Zhen-Y Jiang, Teruaki Yamauchi, Koji Kuboki, Matthias Meier, Christopher J. Rhodes, George L. King
Journal: Journal of Clinical Investigation (1999)

Hyperglycemia can cause vascular dysfunctions by multiple factors including hyperosmolarity, oxidant formation, and protein kinase C (PKC) activation. We have characterized the effect of hyperglycemia on p38 mitogen-activated protein (p38) kinase activation, which can be induced by oxidants, hyperosmolarity, and proinflammatory cytokines, leading to apoptosis, cell growth, and gene regulation. Glucose at 16.5 mM increased p38 kinase activity in a time-dependent manner compared with 5.5 mM in rat aortic smooth muscle cells (SMC). Mannitol activated p38 kinase only at or greater than 22 mM. High glucose levels and a PKC agonist activated p38 kinase, and a PKC inhibitor, GF109203X, prevented its activation. However, p38 kinase activation by mannitol or tumor necrosis factor-α was not inhibited by GF109203X. Changes in PKC isoform distribution after exposure to 16.5 mM glucose in SMC suggested that both PKC-β2 and PKC-δ isoforms were increased. Activities of p38 kinase in PKC-δ– but not PKC-β1–overexpressed SMC were increased compared with control cells. Activation of p38 kinase was also observed and characterized in various vascular cells in culture and aorta from diabetic rats. Thus, moderate hyperglycemia can activate p38 kinase by a PKC-δ isoform–dependent pathway, but glucose at extremely elevated levels can also activate p38 kinase by hyperosmolarity via a PKC-independent pathway.
Erratum: Corrigendum: Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice
Authors: S L Gilbert, L Zhang, M L Forster, J R Anderson, T Iwase, B Soliven, L R Donahue, H O Sweet, R T Bronson, M T Davisson, R L Wollmann, B T Lahn
Journal: Nature Genetics (2006)
Axillary Lymph Node Ratio Revisited
Authors: Khaled M. Musallam, Faek R. Jamali, Hassan A. Hatoum, Muhieddine Seoud, Nagi S. El-Saghir, Ali I. Shamseddine
Journal: Journal of Clinical Oncology (2009)

We read with interest the article by Vinh-Hung et al 1 examining the superiority of the lymph node ratio (LNR) to the absolute number of positive lymph nodes (pN) as a prognostic indicator in patients with lymph node-positive breast cancer.The authors conclude that LNR cut-offs (0.2 and 0.65) provide better patient separation into low, intermediate, and high risk groups than pN.This was mostly evident as patients with pN2 (four to nine positive nodes) and pN3 (Ն 10 positive nodes) involvement showed an imbalance in prognostic separation, with survival curves crossing after 15 years.Although the authors described several limitations to their work, they still failed to mention some very pertinent shortcomings.The study did not take into consideration or document if any patients received neoadjuvant chemotherapy.There was no mention in the methodology section if such patients were excluded from the analysis.This is relevant as neoadjuvant systemic treatments may modify the nodal yield in an axillary dissection. 2 In other words, patients who were classified as belonging to the pN2 category may truly belong to pN3, and thus, have a similar overall survival to the latter group.Moreover, the authors failed to mention the pathological method used to confirm nodal involvement.During the primary era of the study, it is likely that the majority of cases of micrometastatic disease were diagnosed using hematoxylin-eosin (H&E) staining, rather than immunohistochemistry (IHC) or molecular studies.Most centers have continued to use H&E staining as a minimum standard in nodal assessment.4][5] Again this may also explain a crossover in diagnosis and eventually in survival between pN2 and pN3 patients.Lastly, tumor receptor status (estrogen and progesterone) and HER2 overexpression were not included in survival analysis.These variables may not have an established role in overall survival, yet they remain significant predictors of adjuvant treatment response. 6onsequently, since adjuvant treatment was a significant predictor of survival on multivariate analysis in Vinh-Hung et al's study, 1 a confounding effect of tumor receptor status on overall survival cannot be ruled out.The statistical superiority of LNR, as a global variable, to pN is so far well documented.This may offer a great clinical advantage as it takes into consideration the total number of retrieved nodes, and thus, may help neutralize interinstitutional differences in axillary dissection techniques.The study by Vinh-Hung et al provides a well appreciated contribution by defining LNR cut-offs with significant separation in survival.However, the superiority of the assigned cut-offs to the pN system categories may not be clearly established based on this study.
Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome
Authors: Kyu-Ho Park, Julien Piron, Shehrazade Dahimene, Jean Mérot, Isabelle Baró, Denis Escande, Gildas Loussouarn
Journal: Circulation Research (2005)

Nearly a hundred different KCNQ1 mutations have been reported as leading to the cardiac long QT syndrome, characterized by prolonged QT interval, syncopes, and sudden death. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP2) regulates the KCNQ1-KCNE1 complex. In the present study, we show that PIP2 affinity is reduced in three KCNQ1 mutant channels (R243H, R539W, and R555C) associated with the long QT syndrome. In giant excised patches, direct application of PIP2 on the cytoplasmic face of the three mutant channels counterbalances the loss of function. Reintroduction of a positive charge by application of methanethiosulfonate ethylammonium on the cytoplasmic face of R555C mutant channels also restores channel activity. The channel affinity for a soluble analog of PIP2 is decreased in the three mutant channels. By using a model that describes the KCNQ1-KCNE1 channel behavior and by fitting the relationship between the kinetics of deactivation and the current amplitude obtained in whole-cell experiments, we estimated the PIP2 binding and dissociation rates on wild-type and mutant channels. The dissociation rate of the three mutants was higher than for the wild-type channel, suggesting a decreased affinity for PIP2. PIP2 binding was magnesium-dependent, and the PIP2-dependent equilibrium constant in the absence of magnesium was higher with the wild-type than with the mutant channels. Altogether, our data suggest that a reduced PIP2 affinity of KCNQ1 mutants can lead to the long QT syndrome.
Renin-Angiotensin System Blockade Is Renoprotective in Immune Complex–Mediated Glomerulonephritis
Authors: Shunhua Guo, Jolanta Kowalewska, Tomasz A. Wietecha, Masayuki Iyoda, Li Wang, Kenneth Yi, Min Spencer, Miriam Banas, Sanda Alexandrescu, Kelly L. Hudkins, Charles E. Alpers
Journal: Journal of the American Society of Nephrology (2008)

Blockade of the renin-angiotensin system is renoprotective in a variety of chronic nephropathies, but the direct effect of such treatment in active, immune complex-mediated glomerulonephritis is unknown. This study investigated the short- and long-term effects of an angiotensin-converting enzyme inhibitor (enalapril) and an angiotensin II type 1 receptor blocker (losartan) in thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop mixed cryoglobulinemia and severe cryoglobulinemia-associated membranoproliferative glomerulonephritis. Enalapril and losartan each reduced hypertension, proteinuria, glomerular extracellular matrix deposition, and mesangial cell activation in TSLPtg mice. These renoprotective effects were not observed with hydralazine treatment, despite a similar antihypertensive effect. Treatment with enalapril or losartan also decreased renal plasminogen activator inhibitor-1 in TSLPtg mice, assessed by immunohistochemistry and quantitative real-time reverse transcriptase-PCR. None of the treatments affected immune complex deposition or macrophage infiltration. Overall, enalapril- and losartan-treated TSLPtg mice survived significantly longer than untreated TSLPtg mice. These studies demonstrate that angiotensin blockade may provide renoprotective benefits, independent of its BP-lowering effect, in the treatment of active immune complex-mediated glomerulonephritis.
Compliance With Consensus Recommendations for Systemic Therapy Is Associated With Improved Survival of Women With Node-Negative Breast Cancer
Authors: Nicole Hébert-Croteau, Jacques Brisson, Jean Latreille, Michèle Rivard, Nadia Abdelaziz, Ginette Martin
Journal: Journal of Clinical Oncology (2004)

The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer.The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses.Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P <.0005) and compliance with guidelines (P <.0005) were independent significant predictors of survival.Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control.
Gynecologic Surgeries and Risk of Ovarian Cancer in Women With BRCA1 and BRCA2 Ashkenazi Founder Mutations: An Israeli Population-Based Case-Control Study
Authors: J. L. Rutter, S. Wacholder, A. Chetrit, F. Lubin, J. Menczer, S. Ebbers, M. A. Tucker, J. P. Struewing, P. Hartge
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: In the general population, the risk of developing ovarian cancer is reduced in women who have undergone tubal ligation, hysterectomy, or oophorectomy, although peritoneal cancer can arise after bilateral oophorectomy. In studies from genetic screening clinics, women with mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2 have been found to have a low risk of peritoneal carcinoma in the first years after bilateral oophorectomy. We assessed the level and persistence of reduction of ovarian (including peritoneal) cancer risk after gynecologic surgeries for women who carry BRCA1/2 mutations but were not selected from high-risk clinics. Methods: We identified 1124 Israeli women with incident ovarian cancer or primary peritoneal cancer and tested 847 of them for the three Ashkenazi founder mutations. We compared gynecologic surgery history among all case patients, BRCA1 (n = 187) and BRCA2 (n = 64) carrier case patients, and the non-carrier case patients (n = 598) with that in control subjects drawn from a population registry (n = 2396). We estimated ovarian cancer risk (odds ratios [ORs] with 95% confidence intervals [CIs]) after gynecologic surgery in mutation carriers and non-carriers with logistic regression models. Results: Eight women with primary peritoneal cancer and 128 control subjects reported a previous bilateral oophorectomy (OR = 0.12, 95% CI = 0.06 to 0.24). Other gynecologic surgeries were associated with a 30%–50% reduced risk of ovarian cancer, depending on the type of surgery, with surgery to remove some ovarian tissue associated with the most risk reduction (OR = 0.34, 95% CI = 0.16 to 0.74). Reduced risks were seen in BRCA1/2 carriers and non-carriers. Age at surgery and years since surgery did not affect risk reductions. Conclusion: Both BRCA1/2 mutation carriers and non-carriers have reduced risk of ovarian or peritoneal cancer after gynecologic surgery. The magnitude of the reduction depends upon the type and extent of surgery.
Common variants at 6p21.1 are associated with large artery atherosclerotic stroke
Authors: Elizabeth G Holliday, Jane M Maguire, Tiffany-Jane Evans, Simon A Koblar, Jim Jannes, Jonathan W Sturm, Graeme J Hankey, Ross Baker, Jonathan Golledge, Mark W Parsons, Rainer Malik, Mark McEvoy, Erik Biros, Martin D Lewis, Lisa F Lincz, Roseanne Peel, Christopher Oldmeadow, Wayne Smith, Pablo Moscato, Simona Barlera, Steve Bevan, Joshua C Bis, Eric Boerwinkle, Giorgio B Boncoraglio, Thomas G Brott, Robert D Brown, Yu-Ching Cheng, John W Cole, Ioana Cotlarciuc, William J Devan, Myriam Fornage, Karen L Furie, Sólveig Grétarsdóttir, Andreas Gschwendtner, M Arfan Ikram, W T Longstreth, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Eugenio A Parati, Bruce M Psaty, Pankaj Sharma, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Matthew Traylor, Benjamin F J Verhaaren, Kerri L Wiggins, Bradford B Worrall, Cathie Sudlow, Peter M Rothwell, Martin Farrall, Martin Dichgans, Jonathan Rosand, Hugh S Markus, Rodney J Scott, Christopher Levi, John Attia
Journal: Nature Genetics (2012)
Plasticity in the Vestibulo-Ocular Reflex: A New Hypothesis
Authors: F A Miles, S G Lisberger
Journal: Annual Review of Neuroscience (1981)

The vestibulo-ocular reflex functions to prevent head movements from disturbing retinal images by generating compensatory eye movements to offset the head movements. In the monkey--the species mainly under consideration here--this reflex is machine-like and very effective. In the short-term, the VOR operates as an open-loop control system without the benefit of feedback and its performance is fixed and immutable: No matter what pattern of eye-head coordination the animal uses to view external objects, there is a continuing need for the VOR and it continues to operate; however, should the VOR consistently fail to stabilize the retinal images during head turns, it will gradually undergo long-term adaptive gain changes that restore, that stability. This adaptive capability is ultimately dependent upon vision, and a variety of optical devices that disturb the visual input normally associated with lead turns have been used to induce large changes in the reflex. Insofar as the monkey is concerned, all of the available evidence suggests to us that the modifiable elements underlying these long-term adjustments are located in the brainstem vestibular pathways and not, as previously suggested by others, in the floccular lobes of the cerebellum. However, the flocculus does appear to have an important, inductive role in the adaptive process providing at least part of the error signal guiding the long-term adjustments in the brainstem. In our view, the VOR is a particularly well-defined example of a plastic system and promises to be a most useful model for studying the cellular mechanisms underlying memory and learning the central nervous system.
Major histocompatibility complex (MHC) restriction of foreign transplantation antigens in rats rendered tolerant at birth.
Authors: H Kimura, L Desquenne-Clark, M Miyamoto, W K Silvers
Journal: The Journal of Experimental Medicine (1986)

Evidence is presented that MHC restriction of foreign transplantation antigens occurs when tolerance is induced. Whereas PVG and F344 rats rendered tolerant at birth with (DA X PVG)F1 and (DA X F344)F1 hybrid bone marrow cells (BMC), respectively, accept ACI skin grafts, presumably because the foreign transplantation antigens of these third party grafts, which are MHC-compatible with DA, are recognized only in association with the MHC of the hosts, DA rats rendered tolerant with (DA X PVG)F1 or (DA X F344)F1 hybrid BMC usually reject ACI skin. Further support that MHC restriction accompanies the induction of tolerance is provided by the observation that Lewis.1N rats rendered tolerant at birth with athymic (nude) Wag BMC are much more likely to accept BN.B2 (MHC-compatible with Wag) skin grafts, than BN (MHC-compatible with Lewis.1N) grafts.
Antibody Concentration and Clinical Protection After Hib Conjugate Vaccination in the United Kingdom
Authors: Paul T. Heath
Journal: JAMA (2000)

The schedule for Haemophilus influenzae type b (Hib) vaccination of infants in the United Kingdom consists of 3 doses given at 2, 3, and 4 months of age. Many countries include a fourth dose (booster) of Hib vaccine in the second year of life on the basis of declining Hib antibody concentrations after the primary series. Few data are available to show that this fourth dose is actually necessary.To evaluate long-term clinical protection against Hib disease and Hib antibody concentrations following primary Hib vaccination without a booster dose.Clinical protection study conducted between October 1992 and March 1999 in the United Kingdom, in which children developing invasive Hib disease despite vaccination in infancy with 3 doses of Hib conjugate vaccine were reported by pediatricians through an active, prospective, national survey. Separate antibody studies were conducted among 2 cohorts of children (n = 153 and n = 107) vaccinated at 2, 3, and 4 months of age with Hib conjugate vaccine and followed up to 43 and 72 months of age.Age-specific vaccine effectiveness, derived from the observed number of true vaccine failures after 3 Hib vaccine doses compared with the number of cases expected based on the age-specific rates of invasive Hib disease obtained prior to the introduction of Hib vaccines; and proportion of children in the 2 cohorts with Hib antibody concentrations of less than 0.15 and less than 1.0 microg/mL.Ninety-six true vaccine failures occurring after 3 vaccine doses were detected. During the study period, an estimated 4,368,200 infants in the United Kingdom received 3 doses of vaccine; therefore, the vaccine failure rate was 2.2 per 100,000 vaccinees (95% confidence interval, 1.8-2.7 per 100,000). Although vaccine effectiveness declined significantly after the first year of life (P<.001), it remained high until the sixth year of life (99.4% in children aged 5-11 months vs 97.3% in those aged 12-71 months). The proportion of cohorts 1 and 2 with anti-PRP antibody levels of less than 0.15 microg/mL increased between 12 and 72 months of age (6% at 12 months, 8% at 43 months, and 32% at 72 months; chi(2)(1) = 18.25; P<.001 for trend).Our results suggest that anti-PRP antibody levels and clinical protection against Hib disease wane over time after Hib vaccination at 2, 3, and 4 months of age without a booster dose at 2 years of age. The decline in clinical protection is minimal, however, suggesting that a booster dose of Hib vaccine following infant vaccination is not essential. JAMA. 2000;284:2334-2340.