tbuckley/cabot-search huggingface dataset:
Promoting Organs for Transplantation
Authors: C. Everett Koop
Journal: JAMA (1984)

As a pediatric surgeon, I have special reason to be moved by appeals for organs to transplant to small children. The President has asked me to help in a number of cases, and I have done my best to respond. Like many others, however, I know that individual appeals, particularly through the mechanism of television and the other media, do not constitute a long-term resolution of the problem of organ procurement. Like others, I feel frustration (occasionally lightened when I hear of a temporary oversupply of livers for children), and wish I could command more permanent solutions to appear. Complex problems, however, surround the procurement of organs for transplantation. I can only tell myself, as I would others, "Organ transplantation is having its growing pains. Don't panic." That a single bold move will not resolve such a complex problem is illustrated by the nation's experience with the Uniform Anatomical Gift
Absolute CD3+ CD158k+ lymphocyte count is reliable and more sensitive than cytomorphology to evaluate blood tumour burden in Sézary syndrome
Authors: J.-D. Bouaziz, N. Remtoula, A. Bensussan, A. Marie-Cardine, M. Bagot
Journal: British Journal of Dermatology (2009)

Background CD158k/KIR3DL2 is a specific marker for Sézary cells which can be used to diagnose Sézary syndrome (SS) in erythrodermic patients with abnormal circulating T cells. Objectives To evaluate the suitability of CD158k/KIR3DL2 for detecting and evaluating blood tumour load during the follow up of patients with SS. Methods The absolute CD3+ CD158k+ lymphocyte count was compared with the absolute count of cytomorphological Sézary cells and was correlated with clinical flares in a cohort of patients with SS. Twenty-five patients were included in the study and 48 blood samples were analysed. Results The absolute count of CD3+ CD158k+ cells strongly correlated with the absolute count of atypical circulating cells (r = 0.97, P < 10(-15)). The CD3+ CD158k+ lymphocyte cell count was in eight cases more sensitive than cytomorphology for detecting atypical circulating cells especially for small-sized tumour cells. The tumour burden evaluated by CD3+ CD158k+ immunostaining was significantly associated with clinical flare (P < 10(-4)). Conclusions CD3+ CD158k+ phenotyping is a reliable and objective test to monitor the blood tumour burden in patients with SS under systemic therapy.
Heightened immune response to autocitrullinated<i>Porphyromonas gingivalis</i>peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
Authors: Anne-Marie Quirke, Elena Birgitta Lugli, Natalia Wegner, Bart C Hamilton, Peter Charles, Muslima Chowdhury, A Jimmy Ytterberg, Roman A Zubarev, Jan Potempa, Shauna Culshaw, Yonghua Guo, Benjamin A Fisher, Geoffrey Thiele, Ted R Mikuls, Patrick JW Venables
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking <i>Porphyromonas gingivalis</i> to RA. <i>P gingivalis</i> is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response. <h3>Objectives</h3> To examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues. <h3>Methods</h3> PPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another <i>P gingivalis</i> protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82). <h3>Results</h3> Recombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p&lt;0.05) and PD (median 60 U/ml; p&lt;0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA. <h3>Conclusions</h3> The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy.
Different spatial distribution between germinal center B and non-germinal center B primary central nervous system lymphoma revealed by magnetic resonance group analysis
Authors: M. Kinoshita, T. Sasayama, Y. Narita, F. Yamashita, A. Kawaguchi, Y. Chiba, N. Kagawa, K. Tanaka, E. Kohmura, H. Arita, Y. Okita, M. Ohno, Y. Miyakita, S. Shibui, N. Hashimoto, T. Yoshimine
Journal: Neuro-Oncology (2014)

MRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns.MR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients.A PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values <.05 (random permutation analysis with voxel-wise Fisher' exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.
Being positive about the smear
Authors: R FREEMAN
Journal: Thorax (2001)

At several points in the recently published Code of Practice 2000,1 dealing with the control and prevention of tuberculosis in the UK, a number of important actions and decisions turn on the results of sputum microscopy for acid fast bacilli (the “smear”). This simple, cheap, and rapid test is used to assess sputum infectivity and prompts decisions on isolation, initiation …
Hypoxia-inducible factor-1α polymorphisms and TSC1/2 mutations are complementary in head and neck cancers
Authors: Carla Hebert, Kathleen Norris, Pallavi Parashar, Robert A Ord, Nikolaos G Nikitakis, John J Sauk
Journal: Molecular Cancer (2006)

Abstract Background Polymorphisms or mutations in hypoxia inducible factor-1 alpha (HIF-1alpha) that increases its activity and stability under normoxia have recently been identified. Likewise, disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 has been shown to result in abnormal accumulation of HIF-1α. Here, we investigate the novel polymorphisms in exon 12, that approximate the oxygen-dependent degradation domain of HIF-1alpha in five cell lines and 28 patients with oral squamous carcinomas. Moreover, we assess for the presence of polymorphisms and mutations in TSC1 and TSC2, to ascertain if dysregulation of such might complement HIF-1alpha expression. Results Denaturing high pressure liquid chromatography (DHPLC) analysis on PCR fragments in exon 12 of HIF-1alpha from 28 patients with OSCC revealed that 6 of 28 patients had mismatched heteroduplex patterns. Genomic DNA was extracted from peripheral blood leukocytes and direct sequencing showed that in 5 of the six cases these changes represented polymorphisms while, one case was a somatic mutation. Analyses of TSC1 and TSC2 revealed heteroduplexes in exons: TSC1 exon 17; TSC2 exons 36,40, and 41. The relative levels of HIF-1alpha were significantly greater for tumors possessing a HIF-1alpha polymorphism or mutation within exon 12, whereas tumors possessing a deletion or polymorphism in TSC1/TSC2 displayed a trend for higher levels of HIF-1alpha. Western blot analyses for HIF-1alpha, TSC1 and TSC2 in five SCC cell lines revealed high levels of HIF-1alpha in SCC cells possessing TSC1 and/or TSC2 mutations. Wild-type TSC2 cells targeted with siRNA to TSC2 exhibited increased levels of HIF-1alpha. Transfection of a HIF-1alpha mutant produced higher levels of HIF-1alpha in TSC1/TSC2 mutant cell lines than in wild type cells. TSC1/TSC2 mutant cell lines administered Rapamycin blocked S6 phorphorylation and diminished the levels of HIF-1alpha to those observed in cell lines with wild type TSC1/TSC2. Conclusion Dysregulation of the TSC1/TSC2 complex by mutation compliments HIF-1α polymorphisms in the expression of HIF-1alpha in SCC of the head and neck, and may provide biomarkers to predict responses to specific therapies and overall disease prognosis.
Practical Clinical Trials
Authors: Sean R Tunis, Daniel B Stryer, Carolyn M Clancy
Journal: JAMA (2003)

Decision makers in health care are increasingly interested in using high-quality scientific evidence to support clinical and health policy choices; however, the quality of available scientific evidence is often found to be inadequate. Reliable evidence is essential to improve health care quality and to support efficient use of limited resources. The widespread gaps in evidence-based knowledge suggest that systematic flaws exist in the production of scientific evidence, in part because there is no consistent effort to conduct clinical trials designed to meet the needs of decision makers. Clinical trials for which the hypothesis and study design are developed specifically to answer the questions faced by decision makers are called pragmatic or practical clinical trials (PCTs). The characteristic features of PCTs are that they (1) select clinically relevant alternative interventions to compare, (2) include a diverse population of study participants, (3) recruit participants from heterogeneous practice settings, and (4) collect data on a broad range of health outcomes. The supply of PCTs is limited primarily because the major funders of clinical research, the National Institutes of Health and the medical products industry, do not focus on supporting such trials. Increasing the supply of PCTs will depend on the development of a mechanism to establish priorities for these studies, significant expansion of an infrastructure to conduct clinical research within the health care delivery system, more reliance on high-quality evidence by health care decision makers, and a substantial increase in public and private funding for these studies. For these changes to occur, clinical and health policy decision makers will need to become more involved in all aspects of clinical research, including priority setting, infrastructure development, and funding.
Outcome of Anorexia Nervosa: A Case-Control Study
Authors: P F Sullivan, C M Bulik, J L Fear, A Pickering
Journal: American Journal of Psychiatry (1998)

Although there have been many studies of the outcome of anorexia nervosa, methodological weaknesses limit their interpretation. The authors used a case-control design to try to improve knowledge about the outcome of anorexia nervosa.All new female patients referred to an eating disorders service between Jan. 1, 1981, and Dec. 31, 1984, who had probable or definite anorexia nervosa were eligible for inclusion. Of these women, 86.4% (N = 70) were located and agreed to participate. The comparison group (N = 98) was a random community sample. All subjects were interviewed with a structured diagnostic instrument.A minority of the patients (10%) continued to meet the criteria for anorexia nervosa a mean of 12 years after initial referral. Even among those who no longer met these criteria, relatively low body weight and cognitive features characteristic of anorexia nervosa (perfectionism and cognitive restraint) persisted. The rates of lifetime comorbid major depression, alcohol dependence, and a number of anxiety disorders were very high.In the managed care/brief treatment era, therapeutic approaches with an excessive focus on weight gain that neglect the detection and treatment of associated psychological features and comorbidity may be inappropriate. Anorexia nervosa is a serious psychiatric disorder with substantial morbidity.
Defective p38 Mitogen-Activated Protein Kinase Signaling Impairs Chemotaxic but not Proliferative Responses to Stromal-Derived Factor-1α in Acute Lymphoblastic Leukemia
Authors: Linda J. Bendall, Rana Baraz, Julius Juarez, Wei Shen, Kenneth F. Bradstock
Journal: Cancer Research (2005)

Abstract The chemokine stromal-derived factor-1α (SDF-1α) regulates leukemic cell motility and proliferation; however, the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1α–mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1α, a subset of cases did not undergo chemotaxis in response to SDF-1α, while still demonstrating dependence on SDF-1α for proliferation in stroma-supported cultures. This chemotactic defect was associated with an absence of phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by SDF-1α, and of SDF-1α–induced augmentation of β1 integrin–mediated adhesion. Signaling through phosphoinositide 3-kinase and MEK was not affected. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This study suggests that signaling through p38 MAPK is required for ALL cell chemotaxis but not for proliferation, and that the loss of a chemotactic response to SDF-1α does not impede engraftment in NOD/SCID mice.
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
Authors: Héctor Peinado, Maša Alečković, Simon Lavotshkin, Irina Matei, Bruno Costa-Silva, Gema Moreno-Bueno, Marta Hergueta-Redondo, Caitlin Williams, Guillermo García-Santos, Cyrus M Ghajar, Ayuko Nitadori-Hoshino, Caitlin Hoffman, Karen Badal, Benjamin A Garcia, Margaret K Callahan, Jianda Yuan, Vilma R Martins, Johan Skog, Rosandra N Kaplan, Mary S Brady, Jedd D Wolchok, Paul B Chapman, Yibin Kang, Jacqueline Bromberg, David Lyden
Journal: Nature Medicine (2012)
Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension
Authors: Felix Mahfoud, Christian Ukena, Roland E. Schmieder, Bodo Cremers, Lars C. Rump, Oliver Vonend, Joachim Weil, Martin Schmidt, Uta C. Hoppe, Thomas Zeller, Axel Bauer, Christian Ott, Erwin Blessing, Paul A. Sobotka, Henry Krum, Markus Schlaich, Murray Esler, Michael Böhm
Journal: Circulation (2013)

Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension.A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all <0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (-10.1/-10.2/-11.7 mm Hg, P<0.001), diastolic BP (-4.8/-4.9/-7.4 mm Hg, P<0.001), maximum SBP (-11.7/-10.0/-6.1 mm Hg, P<0.001) and minimum SBP (-6.0/-9.4/-13.1 mm Hg, P<0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response.RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension.
Biomarker Expression and Risk of Subsequent Tumors After Initial Ductal Carcinoma In Situ Diagnosis
Authors: K. Kerlikowske, A. M. Molinaro, M. L. Gauthier, H. K. Berman, F. Waldman, J. Bennington, H. Sanchez, C. Jimenez, K. Stewart, K. Chew, B. M. Ljung, T. D. Tlsty
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundStudies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.
Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors
Authors: Otto Soepenberg, Herlinde Dumez, Jaap Verweij, Dorothee Semiond, Maja J.A. deJonge, Ferry A.L.M. Eskens, Judith ter Steeg, Johan Selleslach, Sylvie Assadourian, Ger-Jan Sanderink, Alex Sparreboom, A.T. van Oosterom
Journal: Journal of Clinical Oncology (2005)

To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors.Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days.Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients.The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.
Critical Role of Ena/VASP Proteins for Filopodia Formation in Neurons and in Function Downstream of Netrin-1
Authors: Cecile Lebrand, Erik W Dent, Geraldine A Strasser, Lorene M Lanier, Matthias Krause, Tatyana M Svitkina, Gary G Borisy, Frank B Gertler
Journal: Neuron (2004)
Activation-induced Deaminase (AID)-directed Hypermutation in the Immunoglobulin Sμ Region
Authors: Hitoshi Nagaoka, Masamichi Muramatsu, Namiko Yamamura, Kazuo Kinoshita, Tasuku Honjo
Journal: The Journal of Experimental Medicine (2002)

Somatic hypermutation (SHM) and class switch recombination (CSR) cause distinct genetic alterations at different regions of immunoglobulin genes in B lymphocytes: point mutations in variable regions and large deletions in S regions, respectively. Yet both depend on activation-induced deaminase (AID), the function of which in the two reactions has been an enigma. Here we report that B cell stimulation which induces CSR but not SHM, leads to AID-dependent accumulation of SHM-like point mutations in the switch μ region, uncoupled with CSR. These findings strongly suggest that AID itself or a single molecule generated by RNA editing function of AID may mediate a common step of SHM and CSR, which is likely to be involved in DNA cleavage.
γ-Secretase gene mutations link acne inversa with Alzheimer’s disease
Authors: A V Anstey
Journal: British Journal of Dermatology (2011)

ORIGINAL ARTICLE, p 367 Acne inversa (AI, previously ‘hidradenitis suppurativa’ or HS), a common and disabling variant of acne, has been described in the past as being characterized by ‘follicular occlusion’. This issue of the BJD includes a comprehensive study of AI in which infundibular hyperkeratosis, hyperplasia of follicular epithelium and perifolliculitis were confirmed to be major histopathological features of the condition.1 von Laffert et al. from Halle‐Wittenberg in Germany analysed 485 surgical specimens from 128 patients with AI whose condition had been treated surgically. Hyperkeratosis of the terminal follicles and hyperplasia of follicular epithelium were present in 89% and 80% of specimens, respectively, suggesting, according to the authors, that these changes precede rupture of the follicle and lead to sinus formation. This study supports the long‐held concept that AI (or HS as it was then) is a disease of follicular epithelium rather than of apocrine glands.2 This histopathological research study supports important new genetic research on familial AI published in Science in November 2010. Both publications move thinking about pathogenesis of this condition away from apocrine glands, placing follicular occlusion centre stage. Using combined genome‐wide linkage scan and haplotype analysis in six Han Chinese families, Wang et al. reported that mutations in PSEN1, PSENEN and NCSTN cause AI.3 Clinical phenotype–genotype studies revealed that all of the mutations in these three genes segregated with disease with complete penetrance. Furthermore, all of the mutations were predicted to inactivate protein function.
Correlation Of Outcomes Of Allogeneic Stem Cell Transplants For Chronic Myelomonocytic Leukemia With The Mayo Prognostic Model
Authors: Michelle T Patzelt, Mark R. Litzow, William Hogan, Shahrukh K Hashmi, Michelle Elliott, Aref Al-Kali, Mrinal M. Patnaik
Journal: Blood (2013)