tbuckley/cabot-search huggingface dataset:
Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1
Authors: Brandon F. Keele, Hui Li, Gerald H. Learn, Peter Hraber, Elena E. Giorgi, Truman Grayson, Chuanxi Sun, Yalu Chen, Wendy W. Yeh, Norman L. Letvin, John R. Mascola, Gary J. Nabel, Barton F. Haynes, Tanmoy Bhattacharya, Alan S. Perelson, Bette T. Korber, Beatrice H. Hahn, George M. Shaw
Journal: The Journal of Experimental Medicine (2009)

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was &amp;gt;2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research.
Zero deaths from tuberculosis: progress, reality, and hope
Authors: Alimuddin Zumla, Peter Kim, Markus Maeurer, Marco Schito
Journal: The Lancet Infectious Diseases (2013)

To commemorate World TB Day 2013, The Lancet Infectious Diseases is publishing a Series of articles on tuberculosis, a disease that has long plagued human beings and was declared a global emergency in 1993 by WHO. At that time, most Mycobacterium tuberculosis strains were susceptible to first-line tuberculosis drugs, and global control of the disease seemed a realistic goal. However, tuberculosis persists as one of the main causes of death from infectious disease: in 2011, 8·7 million incident cases causing 1·4 million deaths were estimated.
Measurements of disordered flows distal to subtotal vascular stenoses in the thoracic aortas of dogs.
Authors: D P Giddens, R F Mabon, R A Cassanova
Journal: Circulation Research (1976)

Instantaneous blood velocity measurements employing a constant temperature hot film anemometer were obtained in the region distal to externally enforced, subtotal vascular stenoses in the descending thoracic aortas of anesthetized dogs. Our objectives were to determine alterations in velocity waveforms and energy spectra as the degree of stenosis was increased. We paid particular attention to distinguishing features of the flow which were characteristic of turbulence. Our results indicate that, for the vessels studied, disturbances in the velocity waveforms occur for very minor localized constrictions. The energy spectra follow certain similarity parameters within a restricted region of the distal velocity field. For severe stenoses relatively high levels of energy exist in frequency ranges which previously have been found to produce poststenotic dilation. The measurements suggest that velocity waveforms and energy spectra provide a very early clue to the existence of localized occlusive vascular disease in larger vessels and that, within a limited region distal to a stenosis, the degree of constriction may be estimated by similarity analysis of the energy spectra.
Common Cancer Biomarkers
Authors: Christopher F. Basil, Yingdong Zhao, Katia Zavaglia, Ping Jin, Monica C. Panelli, Sonia Voiculescu, Susanna Mandruzzato, Hueling M. Lee, Barbara Seliger, Ralph S. Freedman, Phil R. Taylor, Nan Hu, Paola Zanovello, Francesco M. Marincola, Ena Wang
Journal: Cancer Research (2006)

Abstract There is an increasing interest in complementing conventional histopathologic evaluation with molecular tools that could increase the sensitivity and specificity of cancer staging for diagnostic and prognostic purposes. This study strove to identify cancer-specific markers for the molecular detection of a broad range of cancer types. We used 373 archival samples inclusive of normal tissues of various lineages and benign or malignant tumors (predominantly colon, melanoma, ovarian, and esophageal cancers). All samples were processed identically and cohybridized with an identical reference RNA source to a custom-made cDNA array platform. The database was split into training (n = 201) and comparable prediction (n = 172) sets. Leave-one-out cross-validation and gene pairing analysis identified putative cancer biomarkers overexpressed by malignant lesions independent of tissue of derivation. In particular, seven gene pairs were identified with high predictive power (87%) in segregating malignant from benign lesions. Receiver operator characteristic curves based on the same genes could segregate malignant from benign tissues with 94% accuracy. The relevance of this study rests on the identification of a restricted number of biomarkers ubiquitously expressed by cancers of distinct histology. This has not been done before. These biomarkers could be used broadly to increase the sensitivity and accuracy of cancer staging and early detection of locoregional or systemic recurrence. Their selective expression by cancerous compared with paired normal tissues suggests an association with the oncogenic process resulting in stable expression during disease progression when the presently used differentiation markers are unreliable. (Cancer Res 2006; 66(6): 2953-61)
Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, Part 1
Authors: J Sieper, J Lenaerts, J Wollenhaupt, M Rudwaleit, V I Mazurov, L Myasoutova, S Park, Y Song, R Yao, D Chitkara, N Vastesaeger
Journal: Annals of the Rheumatic Diseases (2013)

To assess whether combination therapy with infliximab (IFX) plus nonsteroidal anti-inflammatory drugs (NSAIDs) is superior to NSAID monotherapy for reaching Assessment of SpondyloArthritis international Society (ASAS) partial remission in patients with early, active axial spondyloarthritis (SpA) who were naïve to NSAIDs or received a submaximal dose of NSAIDs.Patients were randomised (2 : 1 ratio) to receive naproxen (NPX) 1000 mg daily plus either IFX 5 mg/kg or placebo (PBO) at weeks 0, 2, 6, 12, 18 and 24. The primary efficacy measure was the percentage of patients who met ASAS partial remission criteria at week 28. Several other measures of disease activity, clinical symptoms and patient-rated outcomes were evaluated. Treatment group differences were analysed with Fisher exact tests or analysis of covariance.A greater percentage of patients achieved ASAS partial remission in the IFX+NPX group (61.9%; 65/105) than in the PBO+NPX group (35.3%; 18/51) at week 28 (p=0.002) and at all other visits (p<0.05, all comparisons). Results of most other disease activity and patient-reported endpoints (including Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, multiple quality of life measures and pain measures) showed greater improvement in the IFX+NPX group than the PBO+NPX group, with several measures demonstrating early and consistent improvement over 28 weeks of treatment.Patients with early, active axial SpA who received IFX+NPX combination treatment were twice as likely to achieve clinical remission as patients who received NPX alone. NPX alone led to clinical remission in a third of patients.
Stem Cells and Transplant Arteriosclerosis
Authors: Qingbo Xu
Journal: Circulation Research (2008)

Stem cells can differentiate into a variety of cells to replace dead cells or to repair damaged tissues. Recent evidence indicates that stem cells are involved in the pathogenesis of transplant arteriosclerosis, an alloimmune initiated vascular stenosis that often results in transplant organ failure. Although the pathogenesis of transplant arteriosclerosis is not yet fully understood, recent developments in stem cell research have suggested novel mechanisms of vascular remodeling in allografts. For example, stem cells derived from the recipient may repair damaged endothelial cells of arteries in transplant organs. Further evidence suggests that stem cells or endothelial progenitor cells may be released from both bone marrow and non-bone marrow tissues. Vascular stem cells appear to replenish cells that died in donor vessels. Concomitantly, stem/progenitor cells may also accumulate in the intima, where they differentiate into smooth muscle cells. However, several issues concerning the contribution of stem cells to the pathogenesis of transplant arteriosclerosis are controversial, eg, whether bone marrow-derived stem cells can differentiate into smooth muscle cells that form neointimal lesions of the vessel wall. This review summarizes recent research on the role of stem cells in transplant arteriosclerosis, discusses the mechanisms of stem cell homing and differentiation into mature endothelial and smooth muscle cells, and highlights the controversial issues in the field.
Luminal Expression of <i>PIK3CA</i> Mutant H1047R in the Mammary Gland Induces Heterogeneous Tumors
Authors: Dominique S. Meyer, Heike Brinkhaus, Urs Müller, Matthias Müller, Robert D. Cardiff, Mohamed Bentires-Alj
Journal: Cancer Research (2011)

The phosphoinositide 3-kinase (PI3K) signaling cascade, a key mediator of cellular survival, growth, and metabolism, is frequently altered in human cancer. Activating mutations in PIK3CA, which encodes the α-catalytic subunit of PI3K, occur in approximately 30% of breast cancers. These mutations result in constitutive activity of the enzyme and are oncogenic, but it is not known whether they are sufficient to induce mammary carcinomas in mice. In the present study, we show that the expression of mutant PIK3CA H1047R in the luminal mammary epithelium evokes heterogeneous tumors that express luminal and basal markers and are positive for the estrogen receptor. Our results suggest that the PIK3CA H1047R oncogene targets a multipotent progenitor cell and, furthermore, show that this model recapitulates features of human breast tumors with PIK3CA H1047R.
Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome
Authors: Julien Ratelade, Tiphaine Aguirre Lavin, Andrea Onetti Muda, Ludivine Morisset, Ge[Combining Acute Accent]raldine Mollet, Olivia Boyer, Deborah S. Chen, Anna Henger, Matthias Kretzler, Norbert Hubner, Clotilde The[Combining Acute Accent]ry, Marie-Claire Gubler, Xavier Montagutelli, Corinne Antignac, Ernie L. Esquivel
Journal: Journal of the American Society of Nephrology (2008)

Mutations in the NPHS2 gene, which encodes podocin, are responsible for some cases of sporadic and familial autosomal recessive steroid-resistant nephrotic syndrome. Inter- and intrafamilial variability in the progression of renal disease among patients bearing NPHS2 mutations suggests a potential role for modifier genes. Using a mouse model in which the podocin gene is constitutively inactivated, we sought to identify genetic determinants of the development and progression of renal disease as a result of the nephrotic syndrome. We report that the evolution of renal disease as a result of nephrotic syndrome in Nphs2-null mice depends on genetic background. Furthermore, the maternal environment significantly interacts with genetic determinants to modify survival and progression of renal disease. Quantitative trait locus mapping suggested that these genetic determinants may be encoded for by genes on the distal end of chromosome 3, which are linked to proteinuria, and on the distal end of chromosome 7, which are linked to a composite trait of urea, creatinine, and potassium. These loci demonstrate epistatic interactions with other chromosomal regions, highlighting the complex genetics of renal disease progression. In summary, constitutive inactivation of podocin models the complex interactions between maternal and genetically determined factors on the progression of renal disease as a result of nephrotic syndrome in mice.
Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma
Authors: L.D. Piro, C.A. White, A.J. Grillo-López, N. Janakiraman, A. Saven, T.M. Beck, C. Varns, S. Shuey, M. Czuczman, J.W. Lynch, J.E. Kolit, V. Jain
Journal: Annals of Oncology (1999)
Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors
Authors: Derek A. Wainwright, Sadhak Sengupta, Yu Han, Maciej S. Lesniak
Journal: Neuro-Oncology (2011)

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an average survival time of 15 months. Previously, we and others demonstrated that CD4+FoxP3+ regulatory T cells (Tregs) infiltrate human GBM as well as mouse models that recapitulate malignant brain tumors. However, whether brain tumor-resident Tregs are thymus-derived natural Tregs (nTregs) or induced Tregs (iTregs), by the conversion of conventional CD4+ T cells, has not been established. To investigate this question, we utilized the i.c. implanted GL261 cell-based orthotopic mouse model, the RasB8 transgenic astrocytoma mouse model, and a human GBM tissue microarray. We demonstrate that Tregs in brain tumors are predominantly thymus derived, since thymectomy, prior to i.c. GL261 cell implantation, significantly decreased the level of Tregs in mice with brain tumors. Accordingly, most Tregs in human GBM and mouse brain tumors expressed the nTreg transcription factor, Helios. Interestingly, a significant effect of the brain tumor microenvironment on Treg lineage programming was observed, based on higher levels of brain tumor-resident Tregs expressing glucocorticoid-induced tumor necrosis factor receptor and CD103 and lower levels of Tregs expressing CD62L and CD45RB compared with peripheral Tregs. Furthermore, there was a higher level of nTregs in brain tumors that expressed the proliferative marker Ki67 compared with iTregs and conventional CD4+ T cells. Our study demonstrates that future Treg-depleting therapies should aim to selectively target systemic rather than intratumoral nTregs in brain tumor-specific immunotherapeutic strategies.
Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-α Compared with Immune Effector Cells
Authors: Gregory B. Lesinski, John Trefry, Melanie Brasdovich, Sri Vidya Kondadasula, Korkor Sackey, Jason M. Zimmerer, Abhik Ray Chaudhury, Lianbo Yu, Xiaoli Zhang, Tim R. Crespin, Michael J. Walker, William E. Carson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: IFN-α is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-α. Experimental Design: Tyr701-phosphorylated STAT1 (P-STAT1) was measured by flow cytometry in IFN-α–stimulated human melanoma cell lines, melanoma cells derived from patient tumors, and peripheral blood mononuclear cells (PBMC). Expression of other Janus-activated kinase (Jak)-STAT intermediates (STAT1, STAT2, Jak1, tyrosine kinase 2, IFN-α receptor, STAT3, and STAT5) was evaluated by flow cytometry, immunoblot, or immunohistochemistry. Results: Significant variability in P-STAT1 was observed in human melanoma cell lines following IFN-α treatment (P &amp;lt; 0.05) and IFN-α–induced P-STAT1 correlated with the antiproliferative effects of IFN-α (P = 0.042). Reduced formation of P-STAT1 was not explained by loss of Jak-STAT proteins or enhanced STAT5 signaling as reported previously. Basal levels of P-STAT3 were inversely correlated with IFN-α–induced P-STAT1 in cell lines (P = 0.013). IFN-α–induced formation of P-STAT1 was also variable in melanoma cells derived from patient tumors; however, no relationship between P-STAT3 and IFN-α–induced P-STAT1 was evident. Because IFN-α acts on both tumor and immune cells, we examined the ability of IFN-α to induce P-STAT1 in patient-derived melanoma cells and PBMCs. IFN-α induced significantly lower levels of P-STAT1 in melanoma cells compared with matched PBMCs (P = 0.046). Melanoma cells and human melanocytes required 10-fold higher IFN-α doses to exert P-STAT1 levels comparable with PBMCs. Conclusions: Melanoma cells are variable in their IFN-α responsiveness, and cells of the melanocytic lineage exhibit a lower capacity for IFN-α–induced Jak-STAT signaling compared with immune cells.
Lymphocytes and the Adventitial Immune Response in Atherosclerosis
Authors: Kirsti A. Campbell, Michael J. Lipinski, Amanda C. Doran, Marcus D. Skaflen, Valentin Fuster, Coleen A. McNamara
Journal: Circulation Research (2012)

Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.
Cutaneous manifestations of methylmalonic and propionic acidaemia: a description based on 38 cases
Authors: C. BODEMER, Y. DE PROST, B. BACHOLLET, F. POGGI, D. TEILLAC-HAMEL, S. FRAITAG, J.M. SAUDUBRAY
Journal: British Journal of Dermatology (1994)

Summary Methylmalonic and propionic acidaemias are rare metabolic disorders with an autosomal recessive mode of inheritance. A number of aminoacidopathies may have cutaneous manifestations, but these are usually absent in methylmalonic and propionic acidaemia. We have studied 38 children with propionic and methylmalonic acidaemia in the last 10 years at the Hôpital Necker-Enfants Malades. Thirteen had cutaneous manifestations: acute superficial scalded skin and superficial desquamation, bilateral and periorificial dermatitis, psoriasiform eruptions, and alopecia. The relative uniformity of these manifestations (scalded skin and desquamation after metabolic decompensation, chronic bilateral and periorificial dermatitis) suggests that methylmalonic and propionic acidaemias should be included in the category of aminoacidopathies with cutaneous manifestations. All these patients were suffering from severe forms of these diseases, with no residual enzyme activity, and they were all subjected to a very severe natural protein-restricted diet. These cutaneous manifestations may therefore either be part of a complex multideficiency syndrome, or be due to the enzyme deficiency itself.
A review of electromyographic activation levels, timing differences, and increased anterior cruciate ligament injury incidence in female athletes
Authors: T E Hewett, B T Zazulak, G D Myer, K R Ford
Journal: British Journal of Sports Medicine (2005)

Deficits in dynamic neuromuscular control of the knee may contribute to the higher incidence of anterior cruciate ligament (ACL) injury in female athletes. There is evidence that neuromuscular training alters muscle firing patterns, as it decreases landing forces, improves balance, and reduces ACL injury incidence in female athletes. The purpose of this review is to summarise the evidence for altered muscular activation and timing relative to ACL injury risk in female athletes.
Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease
Authors: K Yamamoto
Journal: Gut (2005)

A characteristic feature of Crohn's disease (CD) is mesenteric adipose tissue hypertrophy. Mesenteric adipocytes or specific proteins secreted by them may play a role in the pathogenesis of CD. We recently identified adiponectin as an adipocyte specific protein with anti-inflammatory properties. Here we report on expression of adiponectin in mesenteric adipose tissue of CD patients.Mesenteric adipose tissue specimens were obtained from patients with CD (n = 22), ulcerative colitis (UC) (n = 8) and, for controls, colon carcinoma patients (n = 28) who underwent intestinal resection. Adiponectin concentrations were determined by enzyme linked immunosorbent assay, and adiponectin mRNA levels were determined by real time quantitative reverse transcription-polymerase chain reaction. Tissue concentrations and release of adiponectin were significantly increased in hypertrophied mesenteric adipose tissue of CD patients compared with normal mesenteric adipose tissue of CD patients (p = 0.002, p = 0.040, respectively), UC patients (p = 0.002, p = 0.003), and controls (p<0.0001, p<0.0001). Adiponectin mRNA levels were significantly higher in hypertrophied mesenteric adipose tissue of CD patients than in paired normal mesenteric adipose tissue from the same subjects (p = 0.024). Adiponectin concentrations in hypertrophied mesenteric adipose tissue of CD patients with an internal fistula were significantly lower than those of CD patients without an internal fistula (p = 0.003).Our results suggest that adipocytes in hypertrophied mesenteric adipose tissue produce and secrete significant amounts of adiponectin, which could be involved in the regulation of intestinal inflammation associated with CD.
Effects of inspiratory resistance, inhaled beta-agonists and histamine on canine tracheal blood flow
Authors: WT Kelly, EM Baile, A Brancatisano, PD Pare, LA Engel
Journal: European Respiratory Journal (1992)

Tracheobronchial blood flow is potentially important in asthma as it could either influence the clearance of mediators from the airways, thus affecting the duration and severity of bronchospasm, or enhance oedema formation with a resultant increase in airflow obstruction. In anaesthetized dogs, spontaneously breathing via a tracheostomy, we investigated the effects of three interventions which are relevant to acute asthma attacks and could potentially influence blood flow and its distribution to the mucosa and remaining tissues of the trachea: 1) increased negative intrathoracic pressure swings (-25 +/- 1 cmH2O) induced by an inspiratory resistance; 2) variable inhaled doses of a beta-adrenoceptor-agonist (terbutaline); and 3) aerosolized histamine sufficient to produce a threefold increase in pulmonary resistance. Microspheres labelled with different radioisotopes were used to measure blood flow. Resistive breathing did not influence tracheobronchial blood flow. Following a large dose of terbutaline, mucosal blood flow (Qmb) increased by 50%. After inhaled histamine, Qmb reached 265% of the baseline value. We conclude that, whereas increased negative pressure swings do not influence tracheobronchial blood flow or its distribution, inhalation of aerosolized terbutaline, corresponding to a conventionally nebulized dose, increases mucosal blood flow. Our results also confirm that inhaled histamine, in a dose sufficient to produce moderate bronchoconstriction, increases tracheal mucosal blood flow in the area of deposition.