tbuckley/cabot-search huggingface dataset:
Identification of <i>PCDH1</i> as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness
Authors: Gerard H. Koppelman, Deborah A. Meyers, Timothy D. Howard, S. Lilly Zheng, Greg A. Hawkins, Elizabeth J. Ampleford, Jianfeng Xu, Henk Koning, Marcel Bruinenberg, Ilja M. Nolte, Cleo C. van Diemen, H. Marike Boezen, Wim Timens, Paul A. Whittaker, O. Colin Stine, Sheila J. Barton, John W. Holloway, Stephen T. Holgate, Penelope E. Graves, Fernando D. Martinez, Antoon J. van Oosterhout, Eugene R. Bleecker, Dirkje S. Postma
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33.To identify a gene for BHR on chromosome 5q31-q33.In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry.In seven out of eight populations (n = 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages.PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.
Cortisone in the Treatment of Degenerative Joint Disease of the Hip
Authors: W. F. Dowdell, W. M. Solomon, R. M. Stecher, R. Wolpaw
Journal: Annals of the Rheumatic Diseases (1952)

Degenerative joint disease of the hip, often called osteo-arthritis, or malum coxae senilis, a clinical condition known for the pain and deformity it causes, is the most disabling form of degenerative joint disease.The cause of the condition is unknown; trauma, an old dislocation of the hip, a slipped epiphysis, Legg-Perthes disease, and senescent degenerative changes have all been suggested (Steindler, 1951) as the most likely factors in its formation.The pathology comprises fibrillation, erosion, and eburnation of the articulating cartilage and the production of exostoses of bone.The femoral head may show * This investigation
Mouse Homologue of a Novel Human Oncofetal Antigen, Glypican-3, Evokes T-Cell–Mediated Tumor Rejection without Autoimmune Reactions in Mice
Authors: Tetsuya Nakatsura, Hiroyuki Komori, Tatsuko Kubo, Yoshihiro Yoshitake, Satoru Senju, Toyomasa Katagiri, Yoichi Furukawa, Michio Ogawa, Yusuke Nakamura, Yasuharu Nishimura
Journal: Clinical Cancer Research (2004)

Abstract Purpose and Experimental Design: We recently identified glypican-3 (GPC3) overexpressed specifically in human hepatocellular carcinoma, as based on cDNA microarray analysis of 23,040 genes, and we reported that GPC3 is a novel tumor marker for human hepatocellular carcinoma and melanoma. GPC3, expressed in almost all hepatocellular carcinomas and melanomas, but not in normal tissues except for placenta or fetal liver, is a candidate of ideal tumor antigen for immunotherapy. In this study, we attempted to identify a mouse GPC3 epitope for CTLs in BALB/c mice, and for this, we set up a preclinical study to investigate the usefulness of GPC3 as a target for cancer immunotherapy in vivo. Results: We identified a mouse GPC3-derived and Kd- restricted CTL epitope peptide in BALB/c mice. Inoculation of this GPC3 peptide-specific CTL into s.c. Colon26 cancer cells transfected with mouse GPC3 gene (C26/GPC3) led to rejection of the tumor in vivo, and i.v. inoculation of these CTLs into sublethally irradiated mice markedly inhibited growth of an established s.c. tumor. Inoculation of bone marrow-derived dendritic cells pulsed with this peptide prevented the growth of s.c. and splenic C26/GPC3 accompanied with massive infiltration of CD8+ T cells into tumors. Evidence of autoimmune reactions was never observed in surviving mice that had rejected tumor cell challenges. Conclusions: We found the novel oncofetal protein GPC3 to be highly immunogenic in mice and elicited effective antitumor immunity with no evidence of autoimmunity. GPC3 is useful not only for diagnosis of hepatocellular carcinoma and melanoma but also for possible immunotherapy or prevention of these tumors.
CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes.
Authors: M Azuma, M Cayabyab, D Buck, J H Phillips, L L Lanier
Journal: The Journal of Experimental Medicine (1992)

Engagement of the CD3/T cell antigen receptor complex on small, resting T cells is insufficient to trigger cell-mediated cytotoxicity or to induce a proliferative response. In the present study, we have used genetic transfection to demonstrate that interaction of the B7-BB1 B cell activation antigen with the CD28 T cell differentiation antigen costimulates cell-mediated cytotoxicity and proliferation initiated by either anti-CD2 or anti-CD3 monoclonal antibody (mAb). Moreover, a B7-negative Burkitt's lymphoma cell line that fails to stimulate an allogeneic mixed lymphocyte response is rendered a potent stimulator after transfection with B7. The mixed leukocyte reaction proliferative response against the B7 transfectant is inhibited by either anti-CD28 or B7 mAb. We also demonstrate that freshly isolated small, resting human T cells can mediate anti-CD3 or anti-CD2 mAb-redirected cytotoxicity against a murine Fc receptor-bearing mastocytoma transfected with human B7. These preexisting cytotoxic T lymphocytes in peripheral blood are present in both the CD4 and CD8 subsets, but are preferentially within the CD45RO+ "memory" population. While small, resting T cells apparently require costimulation by CD28/B7 interactions, this requirement is lost after T cell activation. Anti-CD3 initiates a cytotoxic response mediated by in vitro cultured T cell clones in the absence of B7 ligand. The existence of functional cytolytic T cells in the small, resting T cell population may be advantageous in facilitating rapid responses to immune challenge.
The Genetic Privacy of Presidential Candidates
Authors: Robert C Green, George J Annas
Journal: New England Journal of Medicine (2008)

In the wake of the often bitter presidential election, with its emphasis on negative campaigning and intermittent controversies over the release of candidates' health information, it is not too soon to begin planning for the next presidential campaign. By then, advances in genomics will make it more likely that DNA will be collected and analyzed to assess genetic risk information that could be used for or, more likely, against presidential candidates.Since 1972, when George McGovern was forced to replace his vice-presidential running mate, Thomas Eagleton, after it was revealed that he had been hospitalized for depression, the health status . . .
The Synergistic Combination of the Farnesyl Transferase Inhibitor Lonafarnib and Paclitaxel Enhances Tubulin Acetylation and Requires a Functional Tubulin Deacetylase
Authors: Adam I. Marcus, Jun Zhou, Aurora O'Brate, Ernest Hamel, Jason Wong, Michael Nivens, Adel El-Naggar, Tso-Pang Yao, Fadlo R. Khuri, Paraskevi Giannakakou
Journal: Cancer Research (2005)

Abstract Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the lonafarnib/taxane synergistic antiproliferative combination.
Practice Guidelines and Reminders to Reduce Duration of Hospital Stay for Patients with Chest Pain: An Interventional Trial
Authors: Scott R. Weingarten
Journal: Annals of Internal Medicine (1994)

Objective: The acceptability, safety, and efficacy of practice guidelines have rarely been evaluated. Moreover, despite the recent development of guidelines and decision aids for patients admitted to coronary care and intermediate care units, few have been tested in clinical practice. Design: A prospective, controlled clinical trial with an alternate-month design. Setting: A large teaching community hospital. Patients: Patients admitted to coronary care and intermediate care units with chest pain who were considered at low risk for complications according to a practice guideline (n = 375). Intervention: Physicians caring for patients with chest pain who were at low risk for complications received concurrent, personalized written and verbal reminders regarding a guideline that recommended a 2-day hospital stay. Results: Use of the practice guideline recommendation with concurrent reminders was associated with a 50% to 69% increase in guideline compliance (P < 0.001) and a decrease in length of stay from 3.54 ±4.1 to 2.63 ±3.0 days (0.91-day reduction, 95% CI, 0.18 to 1.63; P = 0.02) for all patients with chest pain considered at low risk for complications. The intervention was associated with a total (direct and indirect) cost reduction of $1397 per patient (CI, $176 to $2618; P = 0.03). No significant difference was found in the hospital complication rate between patients admitted to the hospital during control and intervention periods, and no significant difference was noted in complications, patient health status, or patient satisfaction when measured 1 month after hospital discharge. Conclusion: These results suggest that implementation of this practice guideline through concurrent reminders reduced hospital costs for patients with chest pain considered at low risk for complications. Further study of the guideline is warranted.
Regulation of Airway Hyperresponsiveness by Calcitonin Gene-related Peptide in Allergen Sensitized and Challenged Mice
Authors: Azzeddine Dakhama, Arihiko Kanehiro, Mika J. Mäkelä, Joan E. Loader, Gary L. Larsen, Erwin W. Gelfand
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Sensory neuropeptides are localized to airway nerves and endocrine cells in both human and animal species and may participate in the development of airway inflammation and hyperresponsiveness (AHR). We used a mouse model to identify the changes that occur in calcitonin gene-related peptide (CGRP) expression in the airways during development of allergic inflammation and to investigate the potential role of this neuropeptide in modulating AHR. In sensitized mice, allergen challenge induced eosinophilic airway inflammation and AHR and resulted in considerable depletion of CGRP in neuroepithelial bodies and submucosal nerve plexuses without altering the overall density of airway nerve fibers. This depletion was subsequent to the development of airway inflammation and was prevented by anti-very late antigen-4 and anti-interleukin-5 treatments, which blocked airway eosinophilia and abolished AHR. Administration of CGRP to sensitized and challenged mice resulted in the normalization of airway responsiveness to inhaled methacholine, an effect that was neutralized by the receptor antagonist CGRP(8–37). These data demonstrate that replacement of CGRP following its depletion in allergic mice can reverse the changes in airway responsiveness and suggest that CGRP may have potential for the treatment of allergic AHR.
Defensins: Antimicrobial and Cytotoxic Peptides of Mammalian Cells
Authors: R I Lehrer, A K Lichtenstein, T Ganz
Journal: Annual Review of Immunology (1993)

Defensins are antimicrobial and cytotoxic peptides that contain 29-35 amino acid residues, including six invariant cysteines whose intramolecular disulfide bonds cyclize and stabilize them in a complexly folded, triple-stranded beta-sheet configuration. Generated by the proteolytic processing of 93-95 amino acid precursor peptides, the constitute > 5% of the total cellular protein in human and rabbit neutrophils (polymorphonucleated neutrophils--PMN) and are also produced by rabbit lung macrophages and by mouse and rabbit small intestinal Paneth cells. Despite their prominence in rat PMN, defensins are not found in murine PMN. The antimicrobial spectrum of defensins includes gram positive and gram negative bacteria, mycobacteria, T. pallidum, many fungi, and some enveloped viruses. Defensins exert nonspecific cytotoxic activity against a wide range of normal and malignant targets, including cells resistant to TNF-alpha and NK-cytolytic factor. They appear to kill mammalian target cells and microorganisms by a common mechanism, which involves initial electrostatic interactions with negatively charged target cell surface molecules (likely the head groups of polar membrane lipids), followed by insertion into the cell membranes which they permeabilize, forming voltage-regulated channels. In addition to their antimicrobial and cytotoxic properties, some defensins act as opsonins, while others inhibit protein kinase C, bind specifically to the ACTH receptor and block steroidogenesis or act as selective chemoattractants for monocytes. Defensins are a newly delineated family of effector molecules whose contribution to host defense, inflammation, and cytotoxicity may be considerable for humans, even though it is unlikely to be revealed by experimentation with mice.
Takayasu's arteritis associated with idiopathic ulcerative colitis.
Authors: V Sakhuja, K L Gupta, D K Bhasin, N Malik, K S Chugh
Journal: Gut (1990)

Two patients with ulcerative colitis associated with Takayasu9s arteritis are described. Gangrene of a limb was the presenting feature in one patient and renovascular disease in the other. Angiography showed vascular occlusions affecting several medium or large sized vessels in both patients.
Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial
Authors: David W Andrews, Charles B Scott, Paul W Sperduto, Adam E Flanders, Laurie E Gaspar, Michael C Schell, Maria Werner-Wasik, William Demas, Janice Ryu, Jean-Paul Bahary, Luis Souhami, Marvin Rotman, Minesh P Mehta, Walter J Curran
Journal: The Lancet (2004)
Nine lives: plasticity among T helper cell subsets
Authors: Richard M. Locksley
Journal: The Journal of Experimental Medicine (2009)

The division of labor among two types of T helper (Th) subsets, first described over 20 yr ago, has been buffeted by the discovery of new subsets and new cytokines that can be coaxed out of T cells with increasing disregard for the subset of origin. Although Th17 cells and regulatory T (T reg) cells are widely accepted subsets, and others are being proposed, their plasticity is difficult to reconcile with the definitions of Th subsets as put forth in the initial description of Th1 and Th2 cells. A deeper molecular context will be required to reconcile the ever-increasing complexity of effector T cells.
Suppressor T-cell mechanisms in contact sensitivity. III. Apparent non-major histocompatibility complex restriction is a result of multiple sets of major histocompatibility complex-specific suppressor T cells induced by syngeneic 2,4-dinitrophenyl-modified lymphoid cells.
Authors: S D Miller
Journal: The Journal of Experimental Medicine (1979)

This report has examined the mechanisms by which major histocompatibility complex (MHC) non-restricted suppressor T cells (Ts), induced by the i.v. injection of 2,4-dinitropheny (DNP)-modified, syngeneic lymphoid cells (DNP-LC), suppress the passive transfer of contact sensitivity mediated by syngeneic and allogeneic immune delayed hypersensitivity T cells (TDH). In terms of suppression of syngeneic TDH, it was found that the suppressive action of the Ts was only blocked by pretreatment with soluble syngeneic DNP-LC membrane preparations. Monomeric DNP-lysine, polymeric DNP-protein conjugates, and syngeneic TNP-LC membranes did not inhibit Ts function. Further experiments showed that inhibition of syngeneic suppression could be achieved by DNP-modified-membrane preparations that were only H-2D-region compatible with the Ts donor. Thus, Ts antigen receptors in this system specifically recognize DNP-modified H-2D-region determinants. In contrast, it was found that pretreatment os syninduced Ts with syngeneic DNP-LC membranes did not inhibit the ability to suppress allogeneic TDH. However, pretreatment of Ts with DNP-allogeneic membranes which were H-2D-end compatible to the allogeneic target TDH eliminated their ability to suppress the specific allogeneic TDH, leaving intact suppression of syngeneic or third party TDH. It is proposed that perturbation of the immune system by i.v. injection of syngeneic NDP-LC leads to the induction of a polyclonal wave of DNP-specific Ts activity. Some members of this set of Ts recognize DNP-self MHC determinants with moderate affinity and are thus specifically inhibited after pretreatment with those DNP-self determinants. Other members of this set display receptors which cross-react with high affinity with DNP-allogeneic determinants and thus suppress allogeneic TDH cells. These allosuppressive clones can thus be specifically inhibited only by pretreatment with DNP-LC membranes, MHC-compatible with the target TDH. The data are discussed in terms of current models of T-cell cross-reactivity and T-cell-receptor recognition.
The Temporal Course of Fluid Intake and Response to Fluid Loads in Perinephritic Hypertension in Rats
Authors: D. M. GREEN, F. M. STURTEVANT, C. G. VAN ARMAN
Journal: Circulation Research (1954)

The spontaneous intake of water and saline and their output under load were measured in the early and late stages of perinephritic hypertension in rats. The conclusion was drawn that sodium exchange is increased in the prehypertensive phase, but reverts toward or drops below normal with the development of chronic sustained hypertension.
Coordinated Membrane Ballooning and Procoagulant Spreading in Human Platelets
Authors: Ejaife O. Agbani, Marion T.J. van den Bosch, Ed Brown, Christopher M. Williams, Nadine J.A. Mattheij, Judith M.E.M Cosemans, Peter W. Collins, Johan W.M. Heemskerk, Ingeborg Hers, Alastair W. Poole
Journal: Circulation (2015)

Platelets are central to the process of hemostasis, rapidly aggregating at sites of blood vessel injury and acting as coagulation nidus sites. On interaction with the subendothelial matrix, platelets are transformed into balloonlike structures as part of the hemostatic response. It remains unclear, however, how and why platelets generate these structures. We set out to determine the physiological relevance and cellular and molecular mechanisms underlying platelet membrane ballooning.Using 4-dimensional live-cell imaging and electron microscopy, we show that human platelets adherent to collagen are transformed into phosphatidylserine-exposing balloonlike structures with expansive macro/microvesiculate contact surfaces, by a process that we termed procoagulant spreading. We reveal that ballooning is mechanistically and structurally distinct from membrane blebbing and involves disruption to the platelet microtubule cytoskeleton and inflation through fluid entry. Unlike blebbing, procoagulant ballooning is irreversible and a consequence of Na(+), Cl(-), and water entry. Furthermore, membrane ballooning correlated with microparticle generation. Inhibition of Na(+), Cl(-), or water entry impaired ballooning, procoagulant spreading, and microparticle generation, and it also diminished local thrombin generation. Human Scott syndrome platelets, which lack expression of Ano-6, also showed a marked reduction in membrane ballooning, consistent with a role for chloride entry in the process. Finally, the blockade of water entry by acetazolamide attenuated ballooning in vitro and markedly suppressed thrombus formation in vivo in a mouse model of thrombosis.Ballooning and procoagulant spreading of platelets are driven by fluid entry into the cells, and are important for the amplification of localized coagulation in thrombosis.
Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
Authors: Melissa C. Mizesko, Pinaki P. Banerjee, Linda Monaco-Shawver, Emily M. Mace, William E. Bernal, Julie Sawalle-Belohradsky, Bernd H. Belohradsky, Valerie Heinz, Alexandra F. Freeman, Kathleen E. Sullivan, Steven M. Holland, Troy R. Torgerson, Waleed Al-Herz, Janet Chou, Imelda C. Hanson, Michael H. Albert, Raif S. Geha, Ellen D. Renner, Jordan S. Orange
Journal: Journal of Allergy and Clinical Immunology (2013)