tbuckley/cabot-search huggingface dataset:
Contrast Magnetic Resonance Imaging in the Assessment of Myocardial Viability in Patients With Stable Coronary Artery Disease and Left Ventricular Dysfunction
Authors: Kishin Ramani, Robert M. Judd, Thomas A. Holly, Todd B. Parrish, Vera H. Rigolin, Michele A. Parker, Cathy Callahan, Steven W. Fitzgerald, Robert O. Bonow, Francis J. Klocke
Journal: Circulation (1998)

Background —The utility of contrast MRI for assessing myocardial viability in stable coronary artery disease (CAD) with left ventricular dysfunction is uncertain. We therefore performed cine and contrast MRI in 24 stable patients with CAD and regional contractile abnormalities and compared MRI findings with rest-redistribution 201 Tl imaging and dobutamine echocardiography. Methods and Results —Delayed MRI contrast enhancement patterns were examined from 3 to 15 minutes after injection of 0.1 mmol/kg IV gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). Comparable MRI and 201 Tl basal and midventricular short-axis images were subdivided into 6 segments. Segments judged nonviable by quantitative and qualitative assessment of 201 Tl scans showed persistent, systematically greater MRI contrast signal intensity than segments judged viable ( P ≤0.002). Delayed contrast hyperenhancement also occurred in segments judged nonviable by dobutamine echocardiography ( P ≤0.03). The presence or absence of hyperenhancement correlated most closely with nonviability and viability, respectively, in segments that were akinetic or dyskinetic under resting conditions (83% concordance with 201 Tl in both cases). In segments with resting hypokinesis, 58% of segments showing hyperenhancement were judged viable by 201 Tl and may have represented an admixture of scar tissue and viable myocardium. Conclusions —Delayed (by 3 to 15 minutes) hyperenhancement of Gd-DTPA contrast–enhanced MRI images occurs frequently in dysfunctional areas of the left ventricle in patients with stable CAD. Hyperenhancement is associated with nonviability by rest-redistribution 201 Tl scintigraphy and dobutamine echocardiography, particularly in regions exhibiting resting akinesis/dyskinesis. The absence of hyperenhancement correlates with radionuclide and echocardiographic determinations of viability, regardless of resting contractile function.
Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs.
Authors: G Y Koh, M H Soonpaa, M G Klug, H P Pride, B J Cooper, D P Zipes, L J Field
Journal: Journal of Clinical Investigation (1995)

This report documents the formation of stable fetal cardiomyocyte grafts in the myocardium of dystrophic dogs. Preliminary experiments established that the dystrophin gene product could be used to follow the fate of engrafted cardiomyocytes in dystrophic mdx mice. Importantly, ultrastructural analyses revealed the presence of intercalated discs consisting of fascia adherens, desmosomes, and gap junctions at the donor-host cardiomyocyte border. To determine if isolated cardiomyocytes could form stable intracardiac grafts in a larger species, preparations of dissociated fetal canine cardiomyocytes were delivered into the hearts of adult CXMD (canine X-linked muscular dystrophy) dogs. CXMD dogs, like Duchenne muscular dystrophy patients and mdx mice, fail to express dystrophin in both cardiac and skeletal muscle. Engrafted fetal cardiomyocytes, identified by virtue of dystrophin immunoreactivity, were observed to be tightly juxtaposed with host cardiomyocytes as long as 10 wk after engraftment, the latest date analyzed. Confocal laser scanning microscopy revealed the presence of connexin43, a major constituent of the gap junction, at the donor-host cardiomyocyte border. The presence of intracardiac grafts was not associated with arrhythmogenesis in the CXMD model. These results indicate that fetal cardiomyocyte grafting can successfully augment cardiomyocyte number in larger animals.
Physicochemical basis for formation of renal stones of calcium phosphate origin: calculation of the degree of saturation of urine with respect to brushite
Authors: Charles Y. C. Pak
Journal: Journal of Clinical Investigation (1969)

Brushite (CaHPO(4).2H(2)O) was considered to govern the formation of renal calculus of calcium phosphate origin. The degree of saturation of urine with respect to this phase was therefore calculated. This value was obtained from the ratio of the activity product of Ca(++) and HPO(4) (m) (K(sp)) before and after incubation of urine with brushite. The errors in the calculation of K(sp) were largely eliminated by this procedure.The urine of patients with idiopathic hypercalciuria and recurrent calcium-containing renal calculi was supersaturated with respect to brushit largely because of the high urinary concentration of Ca(++). The urine of normocalciuric subjects was undersaturated except at high urinary pH. This technique of estimating the degree of saturation of urine should allow a quantitative assessment of the various therapeutic regimens recommended for patients with nephrolithiasis.
LAPCs promote follicular helper T cell differentiation of Ag-primed CD4+ T cells during respiratory virus infection
Authors: Jae-Kwang Yoo, Eleanor N. Fish, Thomas J. Braciale
Journal: The Journal of Experimental Medicine (2012)

The humoral immune response to most respiratory virus infections plays a prominent role in virus clearance and is essential for resistance to reinfection. T follicular helper (Tfh) cells are believed to support the development both of a potent primary antibody response and of the germinal center response critical for memory B cell development. Using a model of primary murine influenza A virus (IAV) infection, we demonstrate that a novel late activator antigen-presenting cell (LAPC) promotes the Tfh response in the draining lymph nodes (dLNs) of the IAV-infected lungs. LAPCs migrate from the infected lungs to the dLN “late,” i.e., 6 d after infection, which is concomitant with Tfh differentiation. LAPC migration is CXCR3-dependent, and LAPC triggering of Tfh cell development requires ICOS–ICOSL–dependent signaling. LAPCs appear to play a pivotal role in driving Tfh differentiation of Ag-primed CD4+ T cells and antiviral antibody responses.
Cytokine Receptors and Signal Transduction
Authors: Atsushi Miyajima, Toshio Kitamura, Nobuyuki Harada, Takashi Yokota, Ken-ichi Arai
Journal: Annual Review of Immunology (1992)

Cytokines play a vital role in coordinating immune and inflammatory responses. Unlike growth factor receptors with a tyrosine kinase, cytokine receptors have no intrinsic tyrosine kinase activity. Based on their structure, cytokine receptors are classified into several groups. High affinity receptors for IL-2, IL-3, IL-5, IL-6, and GM-CSF are composed of at least two distinct subunits, alpha and beta. The alpha subunits are primary cytokine binding proteins, and the beta subunits are required for formation of high affinity binding sites as well as for signal transduction. The GM-CSF, IL-3, and IL-5 receptors appear to share the same beta subunit in human, and therefore cross-talk among these cytokines may occur at the receptor level. High affinity receptors presumably are linked to various signal transduction pathways that lead to different cytokine functions. Differential expression of the cytokine receptors as well as reorganization of intracellular signalling pathways are critical for development of hemopoietic cells.
Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2
Authors: Susan E. Hiby, Richard Apps, Andrew M. Sharkey, Lydia E. Farrell, Lucy Gardner, Arend Mulder, Frans H. Claas, James J. Walker, Christopher C. Redman, Linda Morgan, Clare Tower, Lesley Regan, Gudrun E. Moore, Mary Carrington, Ashley Moffett
Journal: Journal of Clinical Investigation (2010)

Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells--influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.
IL15 Can Reverse the Unresponsiveness of Wilms' Tumor Antigen-Specific CTL in Patients with Prostate Cancer
Authors: Judy W. King, Sharyn Thomas, Fabrizio Corsi, Liquan Gao, Roberto Dina, Roopinder Gillmore, Katharine Pigott, Amir Kaisary, Hans J. Stauss, Jonathan Waxman
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients. Experimental Design: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro. Results: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2–positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNγ production of WT1-specific T cells in a subgroup of prostate cancer patients. Conclusion: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.
Role of Integrins in Endothelial Mechanosensing of Shear Stress
Authors: John Y.-J. Shyy, Shu Chien
Journal: Circulation Research (2002)

The focal pattern of atherosclerotic lesions in arterial vessels suggests that local blood flow patterns are important factors in atherosclerosis. Although disturbed flows in the branches and curved regions are proatherogenic, laminar flows in the straight parts are atheroprotective. Results from in vitro studies on cultured vascular endothelial cells with the use of flow channels suggest that integrins and the associated RhoA small GTPase play important roles in the mechanotransduction mechanism by which shear stress is converted to cascades of molecular signaling to modulate gene expression. By interacting dynamically with extracellular matrix proteins, the mechanosensitive integrins activate RhoA and many signaling molecules in the focal adhesions and cytoplasm. Through such mechanotransduction mechanisms, laminar shear stress upregulates genes involved in antiapoptosis, cell cycle arrest, morphological remodeling, and NO production, thus contributing to the atheroprotective effects. This review summarizes some of the recent findings relevant to these mechanotransduction mechanisms. These studies show that integrins play an important role in mechanosensing in addition to their involvement in cell attachment and migration.
Airway Nitric Oxide Levels in Cystic Fibrosis Patients Are Related to a Polymorphism in the Neuronal Nitric Oxide Synthase Gene
Authors: HARTMUT GRASEMANN, NICOLA KNAUER, RAINER BÜSCHER, KARIN HÜBNER, JEFFREY M. DRAZEN, FELIX RATJEN
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Patients with cystic fibrosis (CF) have decreased concentrations of expired nitric oxide (FENO) as compared with healthy individuals. A number of factors, including viscous mucus as a diffusion barrier for airway NO, consumption of NO by bacterial enzymes, and decreased NO production have been hypothesized to account for these low levels of FENO. We examined the relationship between the size of an AAT repeat polymorphism in intron 20 of the NOS1 gene and FENO in 75 patients with CF. Mean FENO was significantly (p = 0.027) lower in CF patients who harbored two alleles with a high number of repeats (>/= 12) than in those who harbored alleles with fewer repeats at this locus (4.0 +/- 0.8 [mean +/- SEM] ppb versus 6.4 +/- 0.9 ppb). Colonization of the airways with Pseudomonas aeruginosa was significantly (p = 0.0358) more common in CF patients with high numbers of AAT repeats in the NOS1 gene. Significant differences between NOS1 genotypes were also observed among patients homozygous for the cystic fibrosis transmembrane regulator delta F508 mutation for FENO (2.3 +/- 0.4 ppb versus 5.3 +/- 0.7 ppb, p = 0.0006), and this was also true for colonization of the airways with P. aeruginosa (p = 0.0147) and Aspergillus fumigatus (p = 0.0221). These data provide evidence that the NOS1 gene is not only associated with the variability of FENO, but also with P. aeruginosa colonization of airways in CF patients.
Relationship between asthma severity and progression of Alzheimer's disease
Authors: T Ohrui
Journal: Thorax (2002)

Mean (SE) 67.0 (0.7) 22.3 (0.3) 17.0 (0.7)* 8.4 (0.5) 1.8 (0.4)† 2.2 (0.3) 0.4 (0.2)‡ 2.4 (0.2) 0.1 (0.1)§
Diagnostic Strategies for Invasive Fungal Infections in Patients With Hematologic Malignancies and Hematopoietic Stem Cell Transplant Recipients
Authors: Maxim Norkin, John R. Wingard
Journal: Journal of the National Comprehensive Cancer Network (2013)

Invasive fungal infections (IFIs) frequently occur and are associated with high morbidity and mortality in patients with hematologic malignancies (HMs) and hematopoietic stem cell transplant (HSCT) recipients. Early diagnosis of IFI in these patients facilitates prompt institution of therapy and leads to improved clinical outcomes. This article reviews widely used methodologies for diagnosing IFIs in patients with HM and HSCT recipients. Advantages and limitations of radiologic studies; microbiologic and histopathologic techniques; fungal biomarker assays, including those for galactomannan antigen and β-(1-3)-D-glucan; and molecular assays that are available to establish an early diagnosis of clinically relevant invasive fungal infections are discussed. Recommendations are provided regarding effective use of these methodologies in clinical practice.
Selection on Amino Acid Substitutions in Arabidopsis
Authors: J. P. Foxe, V.-u.-N. Dar, H. Zheng, M. Nordborg, B. S. Gaut, S. I. Wright
Journal: Molecular Biology and Evolution (2008)

Studies of nucleotide diversity have found an excess of low-frequency amino acid polymorphisms segregating in Arabidopsis thaliana, suggesting a predominance of weak purifying selection acting on amino acid polymorphism in this inbreeding species. Here, we investigate levels of diversity and divergence at synonymous and nonsynonymous sites in 6 circumpolar populations of the outbreeding Arabidopsis lyrata and compare these results with A. thaliana, to test for differences in mutation and selection parameters across genes, populations, and species. We find that A. lyrata shows an excess of low-frequency nonsynonymous polymorphisms both within populations and species wide, consistent with weak purifying selection similar to the patterns observed in A. thaliana. Furthermore, nonsynonymous polymorphisms tend to be more restricted in their population distribution in A. lyrata, consistent with purifying selection preventing their geographic spread. Highly expressed genes show a reduced ratio of amino acid to synonymous change for both polymorphism and fixed differences, suggesting a general pattern of stronger purifying selection on high-expression proteins.
Plague The mysterious past and terrifying future of the world’s most deadly disease
Authors: Brendan Wren
Journal: Journal of Clinical Investigation (2005)

Original citation: J. Clin. Invest. 115:4(2005).

Citation for this erratum: J. Clin. Invest. 115:476 (2005).

The title of the book reviewed was incorrectly given. The correct book title is Plague: the mysterious past and terrifying future of the world's most dangerous disease.
A Dramatic Story of Hope and Reality
Authors: Edward A. Stadtmauer
Journal: Journal of Clinical Oncology (2007)

In the late 1980s and early 1990s, high-dose chemotherapy and autologous stem-cell transplantation seemed to be so promising for patients with metastatic breast cancer. Advanced breast cancer was a devastating disease with limited treatment options. Though responses were frequent, long-term remissions were generally uncommon, and median survival was perceived to be short. Conventional-dose chemotherapy and radiation therapy were inadequate and surgery of limited practicality. Attemptstoimproveoutcomefocusedonthegrowingbodyof evidence at that time that increased dose intensity could overcome inherent tumor resistance, particularly with alkylating agents. A strong relationship of dose to response was demonstrated both in vitro and in early clinical trials in various solid tumors, but, ultimately, dose escalation was limited by bone marrow destruction and the resultant increased likelihood of infection and bleeding. The 1980s saw the development and accessibility of the necessary technology of hematopoietic stem-cell collection, cryopreservation, and storage. Advances in supportive care for patients with prolonged cytopenia and transient organ dysfunction also allowed for the widespread use of high-dose alkylating agent regimens and autologous stem-cell transplantation. This approach was applied to various chemotherapyresponsive malignancies, particularly leukemia, lymphoma, germ cell cancer, ovarian cancer, and breast cancer. Preliminary results showed high response rates, even in patients with relapsed and chemotherapy-resistant breast cancer, with relatively low rates of morbidity and mortality when the dismal prognosis of this group of patients was taken into consideration. A number of prominent cancer centers began to focus on this approach for breast cancer, and a number of moderately sized phase II trials were reported suggesting long-term survival that appeared superior to reported historical data. The degree of evidence for benefit was at least as extensiveasmanypriorestablishedtherapies,andhigh-dosechem
Omalizumab for Asthma
Authors: Robert C. Strunk, Gordon R. Bloomberg
Journal: New England Journal of Medicine (2006)

A 16-year-old boy with a history of severe persistent asthma despite treatment with inhaled corticosteroids presents for evaluation. Treatment with omalizumab, a monoclonal anti-IgE antibody, is recommended. This agent has been found to reduce the frequency of exacerbations of asthma in clinical trials. It is not known how the efficacy of omalizumab compares with that of other available therapies. The drug is more expensive than other agents.
Osteosarcoma: Current Treatment and a Collaborative Pathway to Success
Authors: Michael S. Isakoff, Stefan S. Bielack, Paul Meltzer, Richard Gorlick
Journal: Journal of Clinical Oncology (2015)

Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.
Globo-H Ceramide Shed from Cancer Cells Triggers Translin-Associated Factor X-Dependent Angiogenesis
Authors: Jing-Yan Cheng, Sheng-Hung Wang, Juway Lin, Yi-Chien Tsai, John Yu, Jen-Chine Wu, Jung-Tung Hung, Jin-Jin Lin, Yih-Yiing Wu, Kun-Tu Yeh, Alice L. Yu
Journal: Cancer Research (2014)

Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca(2+) mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer(+) breast cancer specimens contained higher vessel density than GHCer(-) breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca(2+) mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis.