tbuckley/cabot-search huggingface dataset:
High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients.
Authors: U Magriples, F Naftolin, P E Schwartz, M L Carcangiu
Journal: Journal of Clinical Oncology (1993)

PURPOSE Several reports have associated tamoxifen administration with endometrial carcinoma. A retrospective study of the histologic features of uterine cancer in patients with a history of breast carcinoma was undertaken to determine the effect of treatment with tamoxifen. MATERIALS AND METHODS A computer search of the Yale-New Haven Hospital Tumor Registry from 1980 to 1990 identified 53 patients with a history of breast carcinoma who subsequently developed a malignant tumor of the uterine corpus. RESULTS Fifteen patients received tamoxifen for breast carcinoma and 38 did not. The mean ages of the two groups were not significantly different. The mean interval between detection of breast and endometrial cancers was 5 years in the tamoxifen group and 12 years in the nontreated group (P = .0023). Sixty-seven percent of patients in the tamoxifen group had poorly differentiated endometrioid carcinomas (including adenosquamous carcinoma) or carcinomas associated with poor outcome (eg, uterine papillary serous carcinoma, clear-cell carcinoma, or mixed müllerian tumor), as compared with 24% in the nontreated group (P = .03). Patients in the tamoxifen group were much more likely to die of endometrial cancer (33.3% v 2.6% of the nontreated group, P = .005). CONCLUSION From this retrospective study, it appears that women receiving tamoxifen as treatment for breast cancer who subsequently develop uterine cancer are at risk for high-grade endometrial cancers that have a poor prognosis. These findings also indicate that tamoxifen-associated uterine cancers may have a different basis from those associated with steroidal estrogen treatment.
Platelet von willebrand factor abnormalities in myeloproliferative syndromes
Authors: Giancarlo Castaman, Antonella Lattuada, Marco Ruggeri, Alberto Tosetto, Pier Mannuccio Mannucci, Francesco Rodeghiero
Journal: American Journal of Hematology (1995)

Plasma and platelet von Willebrand factor (vWF) measurements, multimeric pattern and subunit composition of plasma vWF were obtained in 29 consecutive patients with chronic myeloproliferative syndromes. In the 8 patients with chronic myelogenous leukemia (CML), plasma vWF was significantly higher than in the 11 patients with essential thrombocythemia (ET) and in the 10 patients with polycythemia vera (PV). The RiCof/vWF:Ag ratio was low in all these groups of patients (mean 0.64 +/- 0.1, 0.66 +/- 0.2, and 0.61 +/- 0.2; normal 0.97 +/- 0.2). Bleeding time was prolonged (> 7.5 min) in 1/8 CML patients, 1/10 with PV, and 3/11 with ET. Plasma vWF multimers showed a minor loss of the largest multimers in 3/8 patients with CML, 4/10 with PV, and a more severe reduction in 9/11 ET patients. The latter pattern correlated with an abnormal proteolysis of vWF, expressed by a major increase of the 140-Kd fragment and decrease of the intact 225-Kd subunit in ET patients, whereas the 176-Kd fragment was significantly increased in all the subgroups of patients. Platelet vWF was significantly higher in CML patients in comparison to ET and normal controls. However, minor losses of the larger multimers were evident in all the subsets of patients. In ET patients also the intermediate forms were lacking in platelets, accompanied by a significant decrease of platelet RiCof. This abnormality was significantly correlated with the occurrence of bleeding symptoms in PV and ET patients (P = 0.007; Fisher's exact test). In conclusion, plasma and platelet vWF abnormalities are common findings in myeloproliferative syndromes and are more severe in ET. The more pronounced platelet vWF abnormalities in ET may reflect the more frequent bleeding symptoms observed in this disorder.
Comparison of Medial Growth of Human Thoracic and Abdominal Aortas
Authors: HARVEY WOLINSKY
Journal: Circulation Research (1970)

Recent morphologic studies of adult mammalian thoracic and abdominal aortic segments have shown that the adult human abdominal aorta deviates significantly from the usual pattern of medial lamellar architecture. In the present study medial growth of these two aortic segments from prenatal life to adulthood was compared in terms of medial architecture and calculated tangential tension levels. During prenatal life, these parameters were very similar in the two segments. However, the postnatal increase in the medial thickness of the thoracic segment was due mainly to the addition of lamellar units which increased in number from 35 to 56; only a minor contribution was made by increased thickness of each unit which changed from 0.012 to 0.017 mm. The converse was true for the abdominal segment; the number of lamellar units increased only from 25 to 28, but lamellar unit thickness increased strikingly from 0.012 to 0.026 mm. Calculated wall stress was similar in the two segments throughout growth, but tension per lamellar unit became disparate in the segments during the first decade of life, culminating in unusually elevated values in the adult human abdominal aortic media.
T Cell Activation and the Cytoskeleton
Authors: Oreste Acuto, Doreen Cantrell
Journal: Annual Review of Immunology (2000)

Ligation of the T cell antigen receptor (TCR) stimulates protein tyrosine kinases (PTKs), which regulate intracellular calcium and control the activity of protein kinase C (PKC) isozymes. PTKs activated by antigen receptors and costimulatory molecules also couple to phosphatidylinositol-3 kinase (PI3K) and control the activity of Ras- and Rho-family GTPases. T cell signal transduction is triggered physiologically by antigen in the context of antigen presenting cells (APC). The formation of stable and prolonged contacts between T cells and APCs is not neccessary to initiate T cell signaling but is required for effective T cell proliferation and differentiation. The stabilization of the T cell/ APC conjugate is regulated by intracellular signals induced by antigen receptors and costimulators. These coordinate the regulation of the actin and microtubule cytoskeleton and organize a specialized signaling zone that allows sustained TCR signaling.
Tumor-Infiltrating Lymphocyte Grade Is an Independent Predictor of Sentinel Lymph Node Status and Survival in Patients With Cutaneous Melanoma
Authors: Farhad Azimi, Richard A. Scolyer, Pavlina Rumcheva, Marc Moncrieff, Rajmohan Murali, Stanley W. McCarthy, Robyn P. Saw, John F. Thompson
Journal: Journal of Clinical Oncology (2012)

To determine whether density and distribution of tumor-infiltrating lymphocytes (TILs; TIL grade) is an independent predictor of sentinel lymph node (SLN) status and survival in patients with clinically localized primary cutaneous melanoma.From the Melanoma Institute Australia database, 1,865 patients with a single primary melanoma ≥ 0.75 mm in thickness were identified. The associations of clinical and pathologic factors with SLN status, recurrence-free survival (RFS), and melanoma-specific survival (MSS) were analyzed.The majority of patients had either no (TIL grade 0; 35.4%) or few (TIL grade 1; 45.1%) TILs, with a minority showing moderate (TIL grade 2; 16.3%) or marked (TIL grade 3; 3.2%) TILs. Tumor thickness, mitotic rate, and Clark level were inversely correlated with TIL grade (each P < .001). SLN biopsy was performed in 1,138 patients (61.0%) and was positive in 252 (22.1%). There was a significant inverse association between SLN status and TIL grade (SLN positivity rates for each TIL grade: 0, 27.8%; 1, 20.1%; 2, 18.3%; 3, 5.6%; P < .001). Predictors of SLN positivity were decreasing age (P < .001), decreasing TIL grade (P < .001), ulceration (P = .003), increasing tumor thickness (P = .01), satellitosis (P = .03), and increasing mitoses (P = .03). The 5-year MSS and RFS rates were 83% and 76%, respectively (median follow-up, 43 months). Tumor thickness (P < .001), ulceration (P < .001), satellitosis (P < .001), mitotic rate (P = .003), TIL grade (P < .001), and sex (P = .01) were independent predictors of MSS. Patients with TIL grade 3 tumors had 100% survival.TIL grade is an independent predictor of survival and SLN status in patients with melanoma. Patients with a pronounced TIL infiltrate have an excellent prognosis.
Characterisation and transplantation of enteric nervous system progenitor cells
Authors: S. Almond, R. M Lindley, S. E Kenny, M G. Connell, D. H Edgar
Journal: Gut (2006)

<b>Aims:</b> Enteric nervous system (ENS) progenitor cells have been postulated to be an appropriate source of cells for the treatment of Hirschsprung's disease. In order for this to be successful, the techniques previously used for the isolation of rodent ENS progenitor cells need to be adapted for postnatal human tissue. In this paper, we describe a method suitable for the preparation of both mouse and human postnatal ENS progenitor cells and assess their transplantation potential. <b>Method:</b> Single cell suspensions were isolated from 11.5 days post-coitum embryonic mouse caecum and postnatal human myenteric plexus. These cells were cultured under non-adherent conditions to generate neurospheres which were implanted into aganglionic embryonic mouse hindgut explants. Cell proliferation, migration and differentiation were observed using immunofluorescence microscopy. <b>Results:</b> Neurospheres generated from both mouse and human tissues contained proliferating neural crest-derived cells that could be expanded in tissue culture to generate both glial cells and neurons. When implanted into aganglionic murine gut, cells migrated from the neurospheres using pathways appropriate for cells derived from the neural crest, and differentiated to become glia and neurons expressing neuronal phenotypic markers characteristic of the ENS including nitric oxide synthase and vasoactive intestinal polypeptide. <b>Conclusion:</b> We have developed a technique for the isolation and expansion of ENS progenitor cells from human neonates. These cells have the ability to differentiate into neurons and glia when transplanted into aganglionic gut, this demonstration being a necessary first step for their autologous transplantation in the treatment of Hirschsprung's disease.
Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitisAn unusual case of ascites
Authors: M C Wapenaar, A J Monsuur, A A van Bodegraven, R K Weersma, M R Bevova, R K Linskens, P Howdle, G Holmes, C J Mulder, G Dijkstra, D A van Heel, C Wijmenga
Journal: Gut (2007)

Coeliac disease (gluten-sensitive enteropathy; GSE) and inflammatory bowel disease (IBD) are common gastrointestinal disorders. Both display enhanced intestinal permeability, initiated by gluten exposure (GSE) or bacterial interactions (IBD). Previous studies showed the association of both diseases with variants in MYO9B, presumably involved in epithelial permeability.It was hypothesised that genetic variants in tight junction genes might affect epithelial barrier function, thus contributing to a shared pathogenesis of GSE and IBD.This hypothesis was tested with a comprehensive genetic association analysis of 41 genes from the tight junction pathway, represented by 197 tag single nucleotide polymorphism (SNP) markers.Two genes, PARD3 (two SNPs) and MAGI2 (two SNPs), showed weak association with GSE in a Dutch cohort. Replication in a British GSE cohort yielded significance for one SNP in PARD3 and suggestive associations for two additional SNPs, one each in PARD3 and MAGI2. Joint analysis of the British and Dutch data further substantiated the association for both PARD3 (rs10763976, p = 6.4 x 10(-5); OR 1.23, 95% CI 1.11 to 1.37) and MAGI2 (rs6962966, p = 7.6 x 10(-4); OR 1.19, 95% CI 1.08 to 1.32). Association was also observed in Dutch ulcerative colitis patients with MAGI2 (rs6962966, p = 0.0036; OR 1.26, 95% CI 1.08 to 1.47), and suggestive association with PARD3 (rs4379776, p = 0.068).These results suggest that coeliac disease and ulcerative colitis may share a common aetiology through tight junction-mediated barrier defects, although the observations need further replication.
Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age
Authors: D.J. Purvis, J.M.D. Thompson, P.M. Clark, E. Robinson, P.N. Black, C.J. Wild, E.A. Mitchell
Journal: British Journal of Dermatology (2005)

Journal Article Risk factors for atopic dermatitis in New Zealand children at 3·5 years of age Get access D.J. Purvis, D.J. Purvis Department of Paediatrics, School of Population Health Search for other works by this author on: Oxford Academic Google Scholar J.M.D. Thompson, J.M.D. Thompson Department of Paediatrics, School of Population Health Search for other works by this author on: Oxford Academic Google Scholar P.M. Clark, P.M. Clark Department of Paediatrics, School of Population Health Search for other works by this author on: Oxford Academic Google Scholar E. Robinson, E. Robinson Department of Paediatrics, School of Population Health Search for other works by this author on: Oxford Academic Google Scholar P.N. Black, P.N. Black Department of Medicine Search for other works by this author on: Oxford Academic Google Scholar C.J. Wild, C.J. Wild Department of Statistics, University of Auckland, Private Bag 92019, Auckland, New Zealand Search for other works by this author on: Oxford Academic Google Scholar E.A. Mitchell E.A. Mitchell Department of Paediatrics, School of Population Health E. A. Mitchell. E‐mail: e.mitchell@auckland.ac.nz Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 4, 1 April 2005, Pages 742–749, https://doi.org/10.1111/j.1365-2133.2005.06540.x Published: 01 April 2005 Article history Accepted: 05 November 2004 Published: 01 April 2005
De Novo Uroplakin IIIa Heterozygous Mutations Cause Human Renal Adysplasia Leading to Severe Kidney Failure
Authors: Dagan Jenkins, Maria Bitner-Glindzicz, Sue Malcolm, Chih-Chi A. Hu, Jennifer Allison, Paul J.D. Winyard, Ambrose M. Gullett, David F.M. Thomas, Rachel A. Belk, Sally A. Feather, Tung-Tien Sun, Adrian S. Woolf
Journal: Journal of the American Society of Nephrology (2005)

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.
Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant <i>GNAQ-</i> and <i>GNA11</i>-Dependent Manner
Authors: Jahan S. Khalili, Xiaoxing Yu, Ji Wang, Brendan C. Hayes, Michael A. Davies, Gregory Lizee, Bita Esmaeli, Scott E. Woodman
Journal: Clinical Cancer Research (2012)

Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in approximately 80% of uveal melanomas. Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key down-stream effectors of GNAQ/11 represents a rational therapeutic approach for uveal melanomas that harbor these mutations. The mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/MAPK) and PI3K/AKT pathways are activated in uveal melanoma. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on uveal melanoma cells with different GNAQ/11 mutation backgrounds.We use the largest set of genetically annotated uveal melanoma cell lines to date to carry out in vitro cellular signaling, cell-cycle regulation, growth, and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were used to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was done to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition.GNAQ/11 mutation status was not a determinant of whether cells would undergo cell-cycle arrest or growth inhibition to MEK and/or phosphoinositide 3-kinase (PI3K) inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment resulted in the marked induction of apoptosis in a GNAQ/11 mutant-dependent manner.MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma, given the inherent reciprocal activation of these pathways within these cells.
Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults
Authors: Douwe F. Postma, Cornelis H. van Werkhoven, Leontine J.R. van Elden, Steven F.T. Thijsen, Andy I.M. Hoepelman, Jan A.J.W. Kluytmans, Wim G. Boersma, Clara J. Compaijen, Eva van der Wall, Jan M. Prins, Jan J. Oosterheert, Marc J.M. Bonten
Journal: New England Journal of Medicine (2015)

The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy.In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval.A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies.Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).
Desmond John Green
Authors: A. M. D. Rose
Journal: BMJ (2013)

Desmond Green (“Des”) was born and educated in Gainsborough , Lincolnshire. He studied medicine at Birmingham University , where he was active in the soccer team. After several medical posts in Birmingham—where he met his wife, Cath , a radiographer—he entered the radiology training scheme in Oxford.

In 1986 he was appointed to Nottingham City Hospital as consultant radiologist with an interest …
Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection
Authors: Shivani Srivastava, Meghan A. Koch, Marion Pepper, Daniel J. Campbell
Journal: The Journal of Experimental Medicine (2014)

Regulatory T (T reg) cells play an essential role in preventing autoimmunity but can also impair clearance of foreign pathogens. Paradoxically, signals known to promote T reg cell function are abundant during infection and could inappropriately enhance T reg cell activity. How T reg cell function is restrained during infection to allow the generation of effective antiviral responses remains largely unclear. We demonstrate that the potent antiviral type I interferons (IFNs) directly inhibit co-stimulation–dependent T reg cell activation and proliferation, both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). Loss of the type I IFN receptor specifically in T reg cells results in functional impairment of virus-specific CD8+ and CD4+ T cells and inefficient viral clearance. Together, these data demonstrate that inhibition of T reg cells by IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection.
Taking ion channel degradation to heart
Authors: J EHRLICH
Journal: Cardiovascular Research (2007)

See article by Jespersen et al.  [5]  (pages 64–74) in this issue. 

A balance between synthesis and degradation of cellular proteins is of natural importance to regulation of protein levels and necessary to retain viability of living cells. Protein degradation often occurs via targeting through ubiquitination and subsequent decomposition in the cellular proteasome [1]. Some other pathways may either not utilize ubiquitination or degrade proteins via lysosomal catalysis. Ligation of proteins to ubiquitin (a small reusable 8.5-kDa protein) requires a sequential three-step action of specific enzymes (termed E1 to E3). Through this process a C-terminal glycine residue of ubiquitin is activated in an energy (i.e. ATP)-requiring step by an activating enzyme (E1) binding ubiquitin to a cysteine residue of E1. Ubiquitin is then transferred to a cysteine residue of an ubiquitin-carrier protein, E2. In the third step, catalysed by ubiquitin-protein ligases (E3), ubiquitin is linked by its C-terminus to an e-amino group of the substrate protein's lysine residues [2].

Several families of E3 enzymes exist … 

*Tel.: +49 (69) 6301 83661; fax: +49 (69) 6301 4387. Email address: j.ehrlich{at}em.uni-frankfurt.de