tbuckley/cabot-search huggingface dataset:
Family Aggregation of Upper Airway Soft Tissue Structures in Normal Subjects and Patients with Sleep Apnea
Authors: Richard J. Schwab, Michael Pasirstein, Laura Kaplan, Robert Pierson, Adonna Mackley, Robert Hachadoorian, Raanan Arens, Greg Maislin, Allan I. Pack
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Sleep apnea is believed to be a genetic disorder. Thus, we hypothesized that anatomic risk factors for sleep apnea would demonstrate family aggregation.We used volumetric magnetic resonance imaging in a sib pair "quad" design to study the family aggregation of the size of upper airway soft tissue structures that are associated with increased risk for obstructive sleep apnea.We examined 55 sleep apnea probands (apnea-hypopnea index [AHI]: 43.2 +/- 26.3 events/h), 55 proband siblings (AHI: 11.8 +/- 16.6 events/h), 55 control subjects (AHI: 2.1 +/- 1.7 events/h), and 55 control siblings (AHI: 4.2 +/- 4.0 events/h). The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for visceral neck fat and craniofacial dimensions.The data support our a priori hypothesis that the volume of the important upper airway soft tissue structures is heritable. The volume of the lateral pharyngeal walls (h(2) = 36.8%; p = 0.001), tongue (h(2) = 36.5%; p = 0.0001), and total soft tissue (h(2) = 37.5%; p = 0.0001) demonstrated significant levels of heritability after adjusting for sex, ethnicity, age, visceral neck fat, and craniofacial dimensions. In addition, our data indicate that heritability of the upper airway soft tissue structures is found in normal subjects and patients with apnea. Thus, it is not simply a consequence of the prevalence of apnea.This is the first time family aggregation of size of the upper airway soft tissue structures has been demonstrated.
Signaling and Transcriptional Mechanisms in Pituitary Development
Authors: Jeremy S. Dasen, Michael G. Rosenfeld
Journal: Annual Review of Neuroscience (2001)

▪ Abstract During the development of the pituitary gland, distinct hormone-producing cell types arise from a common population of ectodermal progenitors, providing an instructive model system for elucidating the molecular mechanisms of patterning and cell type specification in mammalian organogenesis. Recent studies have established that the development of the pituitary occurs through multiple sequential steps, allowing the coordinate control of the commitment, early patterning, proliferation, and positional determination of pituitary cell lineages in response to extrinsic and intrinsic signals. The early phases of pituitary development appear to be mediated through the activities of multiple signaling gradients emanating from key organizing centers that give rise to temporally and spatially distinct patterns of transcription factor expression. The induction of these transcriptional mediators in turn acts to positionally organize specific pituitary cell lineages within an apparently uniform field of ectodermal progenitors. Ultimately, pituitary cell types have proven to be both specified and maintained through the combinatorial interactions of a series of cell-type-restricted transcription factors that dictate the cell autonomous programs of differentiation in response to the transient signaling events.
S16 Molecular profiling of the airway microbiome in COPD
Authors: K. Haldar, K. Lau, M. Bafadhel, C. Brightling, M. Barer
Journal: Thorax (2011)

<h3>Introduction</h3> It is hypothesised that bacteria are important in the pathogenesis of COPD exacerbations and clinical expression of disease. To date, most bacteriological research in COPD has been performed using culture based methods. However, novel molecular approaches offer more detailed evaluation of the airway microbiome that may better inform the role of bacteria in COPD. <h3>Aims</h3> To characterise the microbial community in COPD and examine whether detectable changes occur with serial longitudinal assessment at stable, exacerbation, follow-up and recovery visits. <h3>Methods</h3> 115 COPD patients that were part of a clinical trial had sputum samples collected at the four time points. Patients received antibiotics and / or oral corticosteroids after clinical assessment to treat exacerbations. Follow-up and recovery samples were collected 2 and 6 weeks after the exacerbation sample. Real-time quantitative PCR (qPCR) was performed on sputum DNA using universal 16S gene primers and specific gene targets to quantify total bacterial load and the specific pathogens <i>Haemophilus influenzae</i>, <i>Streptococcus pneumoniae</i>, <i>Moraxella catarrhalis</i> and <i>Staphylococcus aureus</i>. In a subgroup of 30 patients, 454 high-throughput pyrosequencing was performed at each of the 4 visits to examine changes to the global microbiome. <h3>Results</h3> Quantitative PCR identified one or more pathogens in 94% of stable samples and 97% of exacerbation samples. There was no significant difference in the total bacterial load or any specific pathogen between longitudinal stable and exacerbation samples. 454 pyrosequencing identified Proteobacteria and Firmicutes to be the dominant groups contributing &gt;80% of the sequence reads at phylum level. Haemophilus, Moraxella and Streptococcus were the dominant groups at genus level. Cluster analysis characterised three groups on the basis of the ratio of Proteobacteria to Firmicutes. No significant differences in patient characteristics were observed between microbiome clusters. There was no significant change across visits in the microbial community at either phylum or genus level. No treatment specific effects on the microbiome were observed. <h3>Conclusions</h3> Molecular profiling identifies heterogeneity in the airway microbiome of COPD patients, with dominance of pathogens routinely identified at culture. However, a precise role for bacteria in COPD remains unclear.
CD20-Directed Small Modular Immunopharmaceutical, TRU-015, Depletes Normal and Malignant B Cells
Authors: Martha S. Hayden-Ledbetter, Chuck G. Cerveny, Erik Espling, William A. Brady, Laura S. Grosmaire, Philip Tan, Robert Bader, Sonya Slater, Christy A. Nilsson, Dauphine S. Barone, Alexander Simon, Cheryl Bradley, Peter A. Thompson, Alan F. Wahl, Jeffrey A. Ledbetter
Journal: Clinical Cancer Research (2009)

CD20-directed therapy with rituximab is effective in many patients with malignant lymphoma or follicular lymphoma. However, relapse frequently occurs within 1 year, and patients become increasingly refractory to retreatment. Our purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic that could offer therapeutic advantages in the treatment of B-cell lymphoma.Rituximab is a chimeric antibody containing two heavy chains and two light chains. Here, we describe the properties of TRU-015, a small modular immunopharmaceutical specific for CD20, encoded by a single-chain construct containing a single-chain Fv specific for CD20 linked to human IgG1 hinge, CH2, and CH3 domains but devoid of CH1 and CL domains.TRU-015 mediates potent direct signaling and antibody-dependent cellular cytotoxicity but has reduced size and complement-mediated cytotoxicity activity compared with rituximab. TRU-015 is a compact dimer of 104 kDa that comigrates with albumin in size exclusion chromatography and retains a long half-life in vivo. TRU-015 induced growth arrest in multiple B lymphoma cell lines in vitro and showed effective antitumor activity against large, established subcutaneous Ramos or Daudi xenograft tumors in nude mice. TRU-015 also showed rapid, dose-dependent, and durable depletion of peripheral blood B cells following single-dose administration to nonhuman primates.These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant B cells and nonmalignant pathogenic B cells and do so with reduced complement activation.
Minimal Residual Disease Tests Provide an Independent Predictor of Clinical Outcome in Adult Acute Lymphoblastic Leukemia
Authors: Forida Y. Mortuza, Mary Papaioannou, Ilidia M. Moreira, Luke A. Coyle, Paula Gameiro, Domenica Gandini, H. Grant Prentice, Anthony Goldstone, A. Victor Hoffbrand, Letizia Foroni
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL. PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count. RESULTS: Fisher's exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P < .05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P = .005). CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.
Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial
Authors: Edith A. Perez, Amylou C. Dueck, Ann E. McCullough, Beiyun Chen, Xochiquetzal J. Geiger, Robert B. Jenkins, Wilma L. Lingle, Nancy E. Davidson, Silvana Martino, Peter A. Kaufman, Leila A. Kutteh, George W. Sledge, Lyndsay N. Harris, Julie R. Gralow, Monica M. Reinholz
Journal: Journal of Clinical Oncology (2013)

It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831.The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47).In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.
Prognostic Value of <i>LISCH7</i> mRNA in Plasma and Tumor of Colon Cancer Patients
Authors: José M. García, Cristina Peña, Vanesa García, Gemma Domínguez, Concepción Muñoz, Javier Silva, Isabel Millán, Raquel Diaz, Yolanda Lorenzo, Rufo Rodriguez, Félix Bonilla
Journal: Clinical Cancer Research (2007)

Abstract Purpose: LISCH7 is a gene potentially regulated by p53 that is up-regulated in metastasis development. Our hypothesis was that the expression of LISCH7 in primary colorectal tumors determined certain characteristics of the tumors, as well as their behavior, and that its identification in plasma could serve as a prognostic marker. Experimental Design: We tested this hypothesis in a series of 115 tumors and normal tissues and in 83 plasmas from patients with sporadic colorectal carcinomas, as well as in 20 healthy control plasmas in which the expression levels of the gene were measured by real-time PCR. The expression data were contrasted with clinicopathologic variables. Results: Although LISCH7 expression was not detected in any control plasma samples, it was positive in 25 (30.1%) plasmas from patients (P = 0.002). LISCH7 mRNA in plasma was significantly associated with the pathologic stage (P = 0.019), with lymph node metastasis (P = 0.008) and with vascular invasion (P = 0.005). Expression was not detected in any normal tissues but was detected in 80 tumor tissues, with a clear association found with vascular invasion (P = 0.027). Moreover, we show that LISCH7 was specifically expressed by the epithelial tumor cells. The adjusted overall survival study showed independent prognostic values for LISCH7 expression levels in tumor tissues (hazard ratio, 3.45; 95% confidence interval, 1.19-9.98). Conclusions: Our results suggest that LISCH7 is a good tumor marker whose expression levels could be considered as a poor prognosis factor in human colon cancer. Furthermore, plasma is suggested as a feasible source of nucleic acids for subsequent noninvasive prognostic studies.
AN INTOXICATION PSYCHOSIS ASSOCIATED WITH CIRRHOSIS OF THE LIVER
Authors: GUY H. WILLIAMS
Journal: American Journal of Psychiatry (1914)

The object of reporting the following cases of an intoxication psychosis associated with, or as a result of, cirrhosis of the liver, is to call attention to a class of cases concerning which we find very little either in works devoted entirely to mental conditions or to those devoted to pathological conditions of the liver.The search of the literature reveals practically nothing.CASE
Age and paracetamol self-poisoning
Authors: L E Schmidt
Journal: Gut (2005)

<b>Background:</b> Whereas paracetamol poisoning is predominantly seen in adolescents and young adults, the majority of paracetamol associated deaths occur in an older population. <b>Aims:</b> The aim of the present study was to evaluate age as a risk factor for fulminant hepatic failure (FHF) and death in a large population of patients with paracetamol poisoning. <b>Patients:</b> A total of 746 patients transferred to a specialised unit with severe paracetamol poisoning and 273 unselected patients admitted from the local region over a 10 year period. <b>Methods:</b> A partly retrospective study based on hospital charts. The risk associated with age was evaluated by multivariate analysis. <b>Results:</b> Paracetamol poisoning most frequently occurred in the age group 15–24 years. Transferred patients were significantly older than local patients (median age 37 years <i>v</i> 29 years; p = 0.0006). In contrast, FHF and death from paracetamol poisoning most frequently occurred in patients aged 40 years or above. In a logistic regression analysis, "age ⩾40 years" was associated with an excess risk of FHF (odds ratio (OR) 2.33 (95% confidence interval (CI) 1.50–3.64)) and death or liver transplantation (OR 4.18 (95% CI 2.17–8.05)). In addition, older age was associated with other risk factors for paracetamol hepatotoxicity such as regular alcohol abuse and late presentation. <b>Conclusions:</b> Age 40 years or above was identified as a significant independent risk factor for FHF and mortality following paracetamol overdose. Patients aged 40 years or above should be considered as high risk patients, in particular when older age appears in combination with regular alcohol abuse or late presentation.
Osler and my father
Authors: O. Wrong
Journal: Journal of the Royal Society of Medicine (2003)

William Osler was the most celebrated English-speaking physician of his day, and still excites interest though he died over 80 years ago and there can be few still living who were his patients or knew him professionally. Murray Wrong, my father, was both a family friend and a patient, and preserved his letters, which provide a personal glimpse of Osler during his last years at Oxford and also a glimpse of medical and academic practice of the time against the horrors of the First World War. The friendship began in Toronto, where Murray's father George was professor of history and Osler joined the Wrongs during summer vacations.1,2
Proteomic profiling of the tumor microenvironment: recent insights and the search for biomarkers
Authors: Sam Hanash, Mark Schliekelman
Journal: Genome Medicine (2014)

Although gain of oncogene functions and loss of tumor suppressor functions are driving forces in tumor development, the tumor microenvironment, comprising the extracellular matrix, surrounding stroma, signaling molecules and infiltrating immune and other cell populations, is now also recognized as crucial to tumor development and metastasis. Many interactions at the tumor cell-environment interface occur at the protein level. Proteomic approaches are contributing to the definition of the protein constituents of the microenvironment and their sources, modifications, interactions and turnover, as well as providing information on how these features relate to tumor development and progression. Recently, proteomic studies have revealed how cancer cells modulate the microenvironment through their secreted proteins and how they can alter their protein constituents to adapt to the microenvironment. Moreover, the release of proteins from the microenvironment into the circulatory system has relevance for the development of blood-based cancer diagnostics. Here, we review how proteomic approaches are being applied to studies of the tumor microenvironment to decipher tumor-stroma interactions and to elucidate the role of host cells in the tumor microenvironment.
Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Authors: Guillermina Girardi, Jessica Berman, Patricia Redecha, Lynn Spruce, Joshua M. Thurman, Damian Kraus, Travis J. Hollmann, Paolo Casali, Michael C. Caroll, Rick A. Wetsel, John D. Lambris, V. Michael Holers, Jane E. Salmon
Journal: Journal of Clinical Investigation (2003)

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab's. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab's. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab's or peptides that block C5a–C5a receptor interactions prevent pregnancy complications. The fact that F(ab)′2 fragments of aPL Ab's do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B–deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcγRs do not play an important role in mediating aPL Ab–induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.
Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine
Authors: Michael H. Shaw, Nobuhiko Kamada, Yun-Gi Kim, Gabriel Núñez
Journal: The Journal of Experimental Medicine (2012)

T(H)17 cells are a lineage of CD4(+) T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of T(H)17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal T(H)17 (sT(H)17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sT(H)17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sT(H)17 cells. In the absence of IL-1β-IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sT(H)17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88-deficient (MyD88(-/-)) and germ-free (GF) mice, but not IL-1R(-/-) mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R-expressing T cells to drive the generation of sT(H)17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor-related orphan receptor γt-expressing sT(H)17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sT(H)17 differentiation in the intestine, which may have therapeutic implications for T(H)17-mediated pathologies.
Validation of the Antipyrine Method for Measuring Fetal Umbilical Blood Flow
Authors: ABRAHAM M. RUDOLPH, MICHAEL A. HEYMANN
Journal: Circulation Research (1967)

Vinyl catheters were inserted into an umbilical vein, a hindlimb vein and either an umbilical or dorsalis pedis artery in 9 lamb fetuses with gestational ages of 110 to 147 days. The lambs were then delivered from the uterus, but placental flow was maintained. Cannulating electromagnetic flow transducers were inserted into both umbilical veins. Antipyrine solution was constantly infused into the hindlimb vein, and after equilibration, umbilical blood flow was calculated by the Fick method. The values for umbilical flow measured by the antipyrine technique were comparable with those recorded simultaneously with electromagnetic flowmeters. There was also no difference in antipyrine concentrations in the peripheral and main umbilical veins. The study thus validates the use of the Fick method with continuous antipyrine infusion for measuring fetal umbilical blood flow.
Analysis of Keratin Polypeptides 8 and 19 Variants in Inflammatory Bowel Disease
Authors: Guo–Zhong Tao, Pavel Strnad, Qin Zhou, Ahmad Kamal, Leilei Zhang, Nahid D. Madani, Subra Kugathasan, Steven R. Brant, Judy H. Cho, M. Bishr Omary, Richard H. Duerr
Journal: Clinical Gastroenterology and Hepatology (2007)