tbuckley/cabot-search huggingface dataset:
Screening for a <i>BRCA2</i> Rearrangement in High-Risk Breast/Ovarian Cancer Families: Evidence for a Founder Effect and Analysis of the Associated Phenotypes
Authors: Patrícia M. Machado, Rita D. Brandão, Branca M. Cavaco, Joana Eugénio, Sandra Bento, Mónica Nave, Paula Rodrigues, Aires Fernandes, Fátima Vaz
Journal: Journal of Clinical Oncology (2007)

Purpose BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level. Patients and Methods We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed. Results Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu–positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive. Conclusion c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.
Relation between reverse sodium-calcium exchange and sarcoplasmic reticulum calcium release in guinea pig ventricular cells.
Authors: O Kohomoto, A J Levi, J H Bridge
Journal: Circulation Research (1994)

Exchange-inhibitory peptide (XIP) can inhibit sodium-calcium exchange without inhibiting L-type calcium current (ICa). We therefore used this compound to test the hypothesis that reverse sodium-calcium exchange can trigger contraction in guinea pig ventricular myocytes. When cells were dialyzed with 20 mmol/L sodium, rapid blockade of ICa with nifedipine had little effect on cell shortening. However, if reverse exchange was inhibited by first dialyzing the cells with XIP, blockade of ICa largely inhibited cell shortening. In cells dialyzed with 10 mmol/L sodium, about 51% of the maximum cell shortening remained after ICa was blocked. When both ICa and reverse exchange were significantly inhibited with nifedipine and XIP, only 24% of the cell shortening remained; ie, 27% was XIP inhibitable. Cells dialyzed with solutions deficient in sodium exhibited contractions that were largely dependent on ICa (ie, not XIP inhibitable). If the sarcoplasmic reticulum (SR) was disabled with ryanodine and thapsigargin, reverse exchange could not cause contraction. We therefore conclude that with intact SR, reverse sodium-calcium exchange activates contraction by triggering calcium release from the SR in cells dialyzed with either 10 or 20 mmol/L sodium. A scrambled sequence of XIP, sXIP, caused no measurable effect on contraction.
Antigen compartmentation and T helper cell tolerance induction.
Authors: S Oehen, L Feng, Y Xia, C D Surh, S M Hedrick
Journal: The Journal of Experimental Medicine (1996)

The process of antigen recognition depends in part on the amount of peptide antigen available and the affinity of the T cell receptor for a particular peptide-major histocompatibility complex (MHC) molecule complex. The availability of self antigen is limited by antigen processing, which is compartmentalized such that peptide antigens presented by MHC class I molecules originate in the cytoplasm, whereas peptide antigens presented by MHC class II molecules are acquired from the endocytic pathway. This segregation of the antigen-processing pathways may limit the diversity of antigens that influence the development and selection of, e.g., CD4-positive, MHC class II-specific T cells. Selection in this case might involve only a subset of self-encoded proteins, specifically those that are plasma membrane bound or secreted. To study these aspects of immune development, we engineered pigeon cytochrome for expression in transgenic mice in two forms: one in which it was expressed as a type II plasma membrane protein, and a second in which it was targeted to the mitochondria after cytoplasmic synthesis. Experiments with these mice clearly show that tolerance is induced in the thymus, irrespective of antigen compartmentation. Using radiation bone marrow chimeras, we further show that cytoplasmic/mitochondrial antigen gains access to the MHC class II pathway by direct presentation. As a result of studying the anatomy of the thymus, we show that the amount of antigen and the affinity of the TCR affect the location and time point of thymocytes under-going apoptosis.
Genome sequencing reveals fine scale diversification and reticulation history during speciation in Sus
Authors: Laurent AF Frantz, Joshua G Schraiber, Ole Madsen, Hendrik-Jan Megens, Mirte Bosse, Yogesh Paudel, Gono Semiadi, Erik Meijaard, Ning Li, Richard PMA Crooijmans, Alan L Archibald, Montgomery Slatkin, Lawrence B Schook, Greger Larson, Martien AM Groenen
Journal: Genome biology (2013)

Abstract Background Elucidating the process of speciation requires an in-depth understanding of the evolutionary history of the species in question. Studies that rely upon a limited number of genetic loci do not always reveal actual evolutionary history, and often confuse inferences related to phylogeny and speciation. Whole-genome data, however, can overcome this issue by providing a nearly unbiased window into the patterns and processes of speciation. In order to reveal the complexity of the speciation process, we sequenced and analyzed the genomes of 10 wild pigs, representing morphologically or geographically well-defined species and subspecies of the genus Sus from insular and mainland Southeast Asia, and one African common warthog. Results Our data highlight the importance of past cyclical climatic fluctuations in facilitating the dispersal and isolation of populations, thus leading to the diversification of suids in one of the most species-rich regions of the world. Moreover, admixture analyses revealed extensive, intra- and inter-specific gene-flow that explains previous conflicting results obtained from a limited number of loci. We show that these multiple episodes of gene-flow resulted from both natural and human-mediated dispersal. Conclusions Our results demonstrate the importance of past climatic fluctuations and human mediated translocations in driving and complicating the process of speciation in island Southeast Asia. This case study demonstrates that genomics is a powerful tool to decipher the evolutionary history of a genus, and reveals the complexity of the process of speciation.
Fatal acute pulmonary oedema after inhalation of fumes from polytetrafluoroethylene (PTFE)
Authors: CH Lee, YL Guo, PJ Tsai, HY Chang, CR Chen, CW Chen, TR Hsiue
Journal: European Respiratory Journal (1997)

The cases of three patients with acute pulmonary oedema caused by inhalation of fumes from heated polytetrafluoroethylene (PTFE) in a plastic factory are described. One patient died from profound hypoxaemia and shock shortly after admission, and the other two patients survived after medical treatment. This is the first report of fatal pulmonary oedema in a worker exposed to PTFE heated in a plastic extruding operation. From this observation, it appears that inhalation exposure to pyrolytic products from polytetrafluoroethylene can cause fatal respiratory complications. Special precautions are warranted in this kind of operation to prevent workers from being exposed to these substances.
Higher level influences on saccade generation in normals and patients with visual hemineglect
Authors: Wolfgang Heide, Andreas Sprenger, Detlef K&ouml;mpf
Journal: Behavioral and Brain Sciences (1999)

In this commentary we describe findings in normal human subjects and in patients with visual hemineglect that support the importance of higher-level influences on saccade generation during visual exploration. As the duration of fixations increases with increases in the cognitive demand of the task, the timing of exploratory saccades is controlled more by centers of cognitive and perceptual processing at levels 4 and 5 than by reflex-like automatic processes at level 3. In line with this, unilateral frontal eye field lesions impair systematic, intentional saccadic exploration of visual scenes, causing prolonged fixations and contralesional hemineglect, but leave visually triggered reflexive saccades largely intact.
Short intensive exercise increases the migratory activity of mesenchymal stem cells
Authors: A Schmidt, S Bierwirth, S Weber, P Platen, T Schinköthe, W Bloch
Journal: British Journal of Sports Medicine (2007)

Background: It is known that exercise increases the number of stem cells within the circulation; however, it has not been clear which cellular processes are responsible for this increase. To answer this question, we analysed the influence of athletes’ blood sera on human mesenchymal stem cells (MSC). Methods: Sera were taken before and after short intensive exercise. As cellular parameters of MSC proliferation, apoptosis and migratory activity were analysed. Results: A change in stimulation of proliferation or apoptosis was not seen after exercise. In contrast, the migratory activity of MSC was significantly increased after exercise. To identify potential factors that could be responsible for this effect, we also analysed the semiquantitative serum concentration of 120 cytokines. Of these factors brain-derived neurotrophic factor, cutaneous T-cell-attracting chemokine, epidermal growth factor receptor, glucocorticoid-induced tumour necrosis factor receptor ligand, growth-regulated oncogene-α, interleukin (IL)1a, IL6, IL8, IL15, pulmonary and activation-regulated chemokine and soluble tumour necrosis factor receptor II showed a significant increase whereas migration inhibitory factor howed a decrease in concentration after exercise. Conclusions: IL6 is known to stimulate migration in MSC. It is recognised that contracting skeletal muscles synthesise and release IL6 into the systemic circulation in response to exercise. We therefore hypothesise that there is a direct relationship between exercise, IL6 release and stem cell recruitment.
Can the redesigned NHS take flight?
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2008)

Welcome to the new-look JRSM. Our ambition was to keep it simple, clear and readable, with a dash more colour and life on the front cover. Inside, the words speak for themselves to create a unique mix of content focusing on UK medicine and healthcare.

Indeed, the JRSM has now adopted leading publication policies. Few other journals can offer open access to research articles, open peer review, declarations of competing interests and contributorship statements. These policies have met with a favourable response from authors, with more and more high quality articles submitted. We will further improve our service to authors over this year.

You may be less pleased... if so, do tell us. Is the JRSM an Ostrich, a Lame Duck, Icarus, or a Flamingo? You might consider it in those terms if you adopt the four Mont Fleur scenarios used to understand how South Africa would emerge from the end of Apartheid. Phil Hadridge and Ross Pow believe that these scenarios from 6000 miles away do resonate and provide a useful metaphor and lens to understand the National Health Service today (JRSM 2008;101:7-11).

The ambition, of course, is to achieve Flight of the Flamingos, where policies are sustainable and the service takes a path of inclusive growth and representation. NHS leaders address the failures of confidence, curiosity, connection, and compassion. But a more positive future for the NHS does not come easily, say Hadridge and Pow, since it requires involving everyone in the organisation.

Some managers would argue, though, that doctors are at the heart of the cultural problems of the NHS, exclusive, and insufficiently focused on productivity. Now that Hospital Episode Statistics have become commonly used in England to monitor activity and crude outcomes, health economists from Birmingham and York take the scrutiny of hospital consultants one step further by analysing gender and variation in activity rates (JRSM 2008;101:28-34).

Bloor et al. reach the incendiary conclusion that men have significantly higher activity rates than women, after accounting for age, specialty and hospital trust. The reasons for this gender difference are unclear but the implications for medical workforce planning are important. Feminization of the profession, suggest the authors, could lead to reduced productivity over time.

In any case, will higher productivity lead to flight of the flamingos? Are female consultants majoring on compassion and connection? Political and managerial demands for higher productivity seem to be at odds with the cry of Hadridge and Pow for more compassion and connection. Within the pages of this redesigned JRSM are arguments over the failings of our redesigned health service, which continues to create a passable impression of an Ostrich or a Lame Duck. The Flight of the Flamingos is a distant dream...
OmniPod Insulin Management System
Authors: Howard Zisser, Lois Jovanovic
Journal: Diabetes Care (2006)

This 30-day study, supported by a grant from Insulet, assessed the comfort, function, and use of the OmniPod system (Pod) compared with the use of a conventional insulin pump among subjects with type 1 diabetes.

The OmniPod system features the Pod, a lightweight, watertight, self-enclosed insulin pump with automated cannula insertion. The Pod delivers insulin according to preprogrammed instructions transmitted wirelessly from the personal diabetes manager, a hand-held device that programs the pump with customized insulin instructions, monitors the operation of the pump, performs suggested bolus calculations, and contains an integrated blood glucose meter.

Twenty subjects with type 1 …
The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid
Authors: Laetitia Dou, Marion Sallée, Claire Cerini, Stéphane Poitevin, Bertrand Gondouin, Noemie Jourde-Chiche, Karim Fallague, Philippe Brunet, Raymond Calaf, Bertrand Dussol, Bernard Mallet, Françoise Dignat-George, Stephane Burtey
Journal: Journal of the American Society of Nephrology (2014)

In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan–Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAA<3.73 µM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway.
Clinical Outcomes and Costs With the Levonorgestrel-Releasing Intrauterine System or Hysterectomy for Treatment of Menorrhagia
Authors: Ritva Hurskainen, Juha Teperi, Pekka Rissanen, Anna-Mari Aalto, Seija Grenman, Aarre Kivelä, Erkki Kujansuu, Sirkku Vuorma, Merja Yliskoski, Jorma Paavonen
Journal: JAMA (2004)

Because menorrhagia is often a reason for seeking medical attention, it is important to consider outcomes and costs associated with alternative treatment modalities. Both the levonorgestrel-releasing intrauterine system (LNG-IUS) and hysterectomy have proven effective for treatment of menorrhagia but there are no long-term comparative studies measuring cost and quality of life.To compare outcomes, quality-of-life issues, and costs of the LNG-IUS vs hysterectomy in the treatment of menorrhagia.Randomized controlled trial conducted between October 1, 1994, and October 6, 2002, and enrolling 236 women (mean [SD] age, 43 [3.4] years) referred to 5 university hospitals in Finland for complaints of menorrhagia.Participants were randomly assigned to treatment with the LNG-IUS (n = 119) or hysterectomy (n = 117) and were monitored for 5 years.Health-related quality of life (HRQL) as measured by the 5-Dimensional EuroQol and the RAND 36-Item Short-Form Health Survey, other measures of psychosocial well-being (anxiety, depression, and sexual function), and costs.After 5 years of follow-up, 232 women (99%) were analyzed for the primary outcomes. The 2 groups did not differ substantially in terms of HRQL or psychosocial well-being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS group (2817 dollars [95% confidence interval, 2222 dollars-3530 dollars] per participant) remained substantially lower than in the hysterectomy group (4660 dollars [95% confidence interval, 4014 dollars-5180 dollars]). Satisfaction with treatment was similar in both groups.By providing improvement in HRQL at relatively low cost, the LNG-IUS may offer a wider availability of choices for the patient and may decrease costs due to interventions involving surgery.
Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane
Authors: A. Guerrero, J. Gavilá, E. Folkerd, B. Ortiz, F. Martínez, A. García, M.A. Climent, V. Guillem, A. Ruíz
Journal: Annals of Oncology (2012)
Organ culture of mucosal biopsies of human small intestine
Authors: Thomas H. Browning, Jerry S. Trier
Journal: Journal of Clinical Investigation (1969)

In vitro experiments of small intestinal mucosal function and metabolism utilizing excised tissue have been limited to a few hours by rapid epithelial cell necrosis which occurs with current incubation methods. We describe a method for culturing human mucosal biopsies for up to 24 hr employing organ culture methodology and demonstrate its potential application to studies of mucosal function. Peroral biopsies were placed in organ culture plates and maintained with modified Trowell's medium in 95% O(2)-5% CO(2) at 37 degrees C for 6-24 hr. To study cell proliferation, 2 muc of thymidine-(3)H was added per ml of medium. To study fat absorption, biopsies were exposed to micellar solutions of linolenic acid, monoolein, and taurodeoxycholate in Krebs-Ringer buffer for 15 min after culture in vitro for 24 hr. After 24 hr of culture, villi were shorter and wider. Cells in the lamina were reduced in number. Light and electron microscopic morphology of epithelial cells compared favorably to those of control biopsies except in occasional areas of partial necrosis. Some absorptive cells were more cuboidal and contained more lysosomes; many appeared entirely normal. Most crypt cells appeared normal; some contained increased glycogen and lysosomes. Mitoses were present, and labeled cells were abundant in crypts of biopsies after 6 hr of incubation with thymidine-(3)H-containing medium. By 24 hr. labeled cells migrated to the base of the villi. When biopsies cultured in vitro were subsequently exposed to micellar lipid, numerous lipid droplets were identified in the cytoplasm of absorptive cells. Thus, after 24 hr in vitro under these culture conditions, many human small intestinal epithelial cells maintain near normal morphology, epithelial cell proliferation proceeds, and fat absorption occurs.
Hospital contacts for endocrine disorders in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): a population-based cohort study
Authors: Sofie de Fine Licht, Jeanette Falck Winther, Thorgerdur Gudmundsdottir, Anna Sällfors Holmqvist, Trine Gade Bonnesen, Peter Haubjerg Asdahl, Laufey Tryggvadottir, Harald Anderson, Finn Wesenberg, Nea Malila, Kirsten Holm, Henrik Hasle, Jørgen Helge Olsen
Journal: The Lancet (2014)
Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
Authors: Degui Geng, Liqin Zheng, Ratika Srivastava, Cruz Velasco-Gonzalez, Adam Riker, Svetomir N. Markovic, Eduardo Davila
Journal: Cancer Research (2010)

Abstract The efficacy of T cell–based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88–stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2−/−pmel or MyD88−/−pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88−/− mice treated with TLR2 ligand and pmel T cells, but not TLR2−/−pmel or MyD88−/−pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88–stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes. Cancer Res; 70(19); 7442–54. ©2010 AACR.