tbuckley/cabot-search huggingface dataset:
Differential Desensitization of Thromboxane A <sub>2</sub> Receptor Subtypes
Authors: Masao Yukawa, Ryoji Yokota, Robert T. Eberhardt, Laila von Andrian, J. Anthony Ware
Journal: Circulation Research (1997)

Abstract Two subtypes of the thromboxane A 2 (TxA 2 ) receptor (TxA 2 R-E and TxA 2 R-P), which differ in their alternatively spliced cytoplasmic tails, have been identified. The initial concentration of the TxA 2 mimetic IBOP required to reduce peak intracellular Ca 2+ concentration ([Ca 2+ ] i ) induced by a second addition of IBOP (100 nmol/L) was similar (IC 50 for TxA 2 R-E and TxA 2 R-P, 0.46±0.16 and 0.40±0.07 nmol/L) in fibroblasts overexpressing either the TxA 2 R-E or -P subtype. Although the number of TxA 2 binding sites decreased in TxA 2 R-P cells after prolonged stimulation with a TxA 2 mimetic, those in the TxA 2 R-E cells increased markedly. To determine whether the mechanism for desensitization differs between subtypes, the effect of activation of protein kinase C (PKC) or cAMP-dependent kinase on TxA 2 -induced [Ca 2+ ] i mobilization was measured. Forskolin reduced the IBOP-induced peak [Ca 2+ ] i in neither TxA 2 R-E nor TxA 2 R-P cells; however, treatment with phorbol esters (IC 50 , 0.57±0.70 nmol/L) strongly prevented IBOP-mediated [Ca 2+ ] i rise in TxA 2 R-E but not in TxA 2 R-P cells. Desensitization of TxA 2 R-E by phorbol esters was prevented by the PKC inhibitor calphostin C or by downregulation of PKC-α. Thus, the response of TxA 2 R-E to prolonged stimulation differs from that of TxA 2 R-P in both the regulation of the number of binding sites and the mechanism for desensitization; agonists that activate PKC-α might interfere with TxA 2 R-E–mediated signaling.
Contemporary Research on the Pathology of Rheumatic Disease reviewed in the Light of 100 years of Cellular Pathology
Authors: D. H. Collins
Journal: Annals of the Rheumatic Diseases (1957)

The immunohistological features of rheumatoid nodules and rheumatoid synovium were examined using monoclonal and polyclonal antibodies raised against macrophages, HLA-DR, leucocyte common antigen, and immunoglobulin components. The palisading cells surrounding the necrotic centre of the rheumatoid nodule were shown to be HLA-DR positive leucocytes, mostly histiocytes. The inflammatory infiltrate associated with rheumatoid nodules showed many immunohistochemical similarities to that of rheumatoid synovium, including a preponderance of IgG positive plasma cells, and a similar number and microanatomical pattern of distribution of HLA-DR positive cells. The significance of these findings for the cellular immunopathology and aetiology of the rheumatoid lesion is discussed.
Doses of Insulin and Its Analogues and Cancer Occurrence in Insulin-Treated Type 2 Diabetic Patients
Authors: Edoardo Mannucci, Matteo Monami, Daniela Balzi, Barbara Cresci, Laura Pala, Cecilia Melani, Caterina Lamanna, Ilaria Bracali, Michela Bigiarini, Alessandro Barchielli, Niccol̀o Marchionni, Carlo Maria Rotella
Journal: Diabetes Care (2010)

OBJECTIVE Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer. The present study is aimed at assessing the long-term association of different insulin analogues with cancer incidence. RESEARCH DESIGN AND METHODS A nested case-control study dataset was generated from the cohort study dataset (n = 1,340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who are at risk for the same follow-up time of the case subject. Five-year age classes, sex, and BMI classes (&amp;lt;18.5, 18.5–24.9, 25–29.9, and ≥30 kg/m2) were considered as additional categorical matching variables. RESULTS During a median follow-up of 75.9 months (interquartile range 27.4–133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10–0.39] versus 0.16 IU/kg/day [0.12–0.24], P = 0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18–13.53], P &amp;lt; 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues. CONCLUSIONS The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer.
Enhanced Immune Recognition of Cryptic Glycan Markers in Human Tumors
Authors: Thomas E. Newsom-Davis, Denong Wang, Lawrence Steinman, Paul F-T. Chen, Lai-Xi Wang, A. Katharina Simon, Gavin R. Screaton
Journal: Cancer Research (2009)

Abnormal glycosylation is one of the hallmarks of the cancer cell and is associated with tumor invasion and metastasis. The development of tumor-associated carbohydrate antigen (TACA) vaccines has been problematic due to poor immunogenicity. However, when appropriate targets can be identified, passive immunization with monoclonal antibodies (mAbs) directed against TACAs has been shown to have antitumor activity. Fas ligand (FasL) is a transmembrane protein that induces apoptosis in cells expressing its receptor, Fas. When grafted into mice, FasL-expressing tumor cells break immunologic tolerance to self-antigens and induce antibody-mediated tumor immunity. Here, five IgM mAbs were produced from mice vaccinated with FasL-expressing B16F10 mouse melanoma cells. They recognize various syngeneic and allogeneic murine tumor cell lines. One mAb, TM10, recognizes a range of human tumor cell lines, including melanoma, prostate, and ovarian cancer. It does not bind to untransformed cells. The epitopes recognized by all the mAbs were carbohydrates expressed on proteins. Using carbohydrate microarrays, the antigenic targets of TM10 were found to be high-mannose core structures of N-linked glycans. In normal cells, high-mannose clusters are hidden by extensive saccharide branching but they become exposed in cancer cells as a result of abnormal glycosylation pathways. Vaccination with FasL-expressing tumors therefore enables the immune system to break tolerance to self-antigens, allowing identification of novel TACAs that can form the basis of future humoral anticancer therapy.
S36 Check novel in vivo real time imaging of the bronchial mucosa using an endo-cytoscopy
Authors: K. Shibuya, N. Okada, H. Kohno, N. Iwai, M. Noro, B. Akikusa, H. Hoshino, I. Yoshino
Journal: Thorax (2010)

<h3>Objectives</h3> We investigated the capabilities of an Endo-Cytoscopy system (ECS) that enables microscopic imaging of the tracheobronchial tree during bronchoscopy, including normal bronchial epithelium, dysplastic mucosa and hilar lung cancer. <h3>Methods</h3> The newly developed integrated-type ECS for the bronchoscope has a built-in two imaging system with a conventional mode and a high-power endocytoscopic mode. ECS has a high magnification of 570×. Thirty-seven patients including 9 hilar lung cancer, 6 abnormal sputum cytology, 19 squamous dysplasia, and 3 after photodynamic therapy were entered into the study and underwent white light, narrow band imaging and autofluorescence imaging bronchoscopy. Both the abnormal area of interest and surrounding normal bronchial mucosa were stained with 0.5% methylene blue and examined with ECS. Histological examinations with haematoxylin and eosin stain were performed using the biopsied specimens. The ECS imaging was analysed and correlated with the corresponding histological examination. <h3>Results</h3> ECS imaging could distinguish between different types of bronchial epithelium including normal bronchial mucosa, squamous dysplasia, and hilar lung cancer. Squamous dysplasia and hilar lung cancer were predictive with sensitivity of 85.7% (12/14) and 90.9% (10/11) and specificity of 100% (12/12), respectively. These ECS images corresponded well conventional histology. <h3>Conclusion</h3> ECS was useful for the discrimination between normal bronchial epithelial cells and dysplastic cells or malignant cells during bronchoscopy in real time. This novel technology has an excellent potential to provide <i>in vivo</i> diagnosis during bronchoscopic examinations.
Mechanism of secondary bacterial infection following viral pulmonary infection (the viral-bacterial synergy)
Authors: Bhagi Jayaraman
Journal: Thorax (2008)

This paper examines the mechanism causing secondary bacterial infection which often occurs after pulmonary viral infection. C57BL/6 mice were infected intranasally with influenza virus strain A/PR8/34(H1N1). By day 12 there was immune-mediated viral clearance; however, the mice showed a high susceptibility to pneumococcal infection during this recovery stage.

Normal initial bacterial clearance requires innate …
The future of child protection
Authors: D M B Hall
Journal: Journal of the Royal Society of Medicine (2005)

The abuse of children is as old as mankind, but delineation of child abuse as a recognizable clinical entity dates back only to 1962 when a classic paper by Kempe et al. described the key features of physical abuse.1 Since that time, the spectrum of child abuse has grown to include sexual abuse, emotional abuse and neglect. Gradually, various more subtle manifestations of abuse were identified, including the puzzling and often bizarre clinical syndromes known originally as Munchausen syndrome by proxy (MSBP) and now categorized as fabricated and induced illness (FII). Taking a more global perspective, child trafficking and prostitution, forced child labour, and the abduction of children to be trained as soldiers can all be regarded as forms of child abuse, but these are beyond the scope of this review.

In the last few years, a series of high profile controversial child protection cases has shaken the confidence of paediatricians. A recent survey showed that most specialist registrars would seek a consultant job in which they would not have to be involved in this work. This is most unfortunate: first, because it puts an excessive burden on the few doctors willing to take on such cases; and secondly, because doctors who are reluctant to consider the possibility that a child's symptoms could be related to ill treatment may make clinical errors and miss opportunities for effective intervention.
ABC of mental health: Mental health assessment
Authors: T. Davies
Journal: BMJ (1997)

<h3>Background</h3> Iodine-containing disinfectants are widely used for skin preparation before caesarean section. Current evidence suggests that maternal exposure to these disinfectants results in thyroid dysfunction in the newborns, but its extent is not known. <h3>Objectives</h3> The purpose of this study was to explain the quality of the effect of these disinfectants on the thyroid function of newborns. <h3>Methods</h3> This cohort study was performed on all the healthy mothers with a term pregnancy who underwent caesarean section in the obstetrics emergency department of an educational hospital affiliated with Tehran University of Medical Sciences from December 2013 to December 2014. We divided this 12-month period into two consecutive 6 months. Povidone–iodine 10% (PVP-I) and chlorhexidine gluconate 4% (CHX) were used in the first and second 6 months, respectively, for skin preparation before caesarean section and also for umbilical cord disinfection. Cord blood thyroid stimulating hormone (TSH) and thyroxine (T4) were assayed by the ELISA method. <h3>Results</h3> We included 326 cases in this study, 153 in the PVP-I group and 173 in the CHX group. The incidence of cord blood TSH ≥10 mIU/L and T4 ≤7.3 µg/dL was significantly higher in the PVP-I than the CHX group. Cord blood TSH concentration showed a significant positive correlation with cord blood T4 concentration in the CHX group. Through selection of cases with cord blood T4 &lt;13 µg/dL, we found a negative correlation between cord blood TSH and T4 concentration in the PVP-I group. <h3>Conclusions</h3> It seems that PVP-I has the potential to cause false-positive screening-test results and increase recall rates, which should be evaluated in further studies. <h3>Trial registration number</h3> Iranian Registry of Clinical Trials (IRCT) number IRCT201204289568N1.
Phase II Study of Thalidomide Plus Dexamethasone Induction Followed by Tandem Melphalan-Based Autotransplantation and Thalidomide-Plus-Prednisone Maintenance for Untreated Multiple Myeloma: A Southwest Oncology Group Trial (S0204)
Authors: Mohamad A. Hussein, Vanessa Bolejack, Jeffrey A. Zonder, Brian G.M. Durie, Andrzej J. Jakubowiak, John J. Crowley, Bart Barlogie
Journal: Journal of Clinical Oncology (2009)

Purpose Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. Patients and Methods Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. Conclusion Both overall survival (P = .0002) and event-free survival (P &lt; .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.
Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice
Authors: Kenichi Asano, Miyu Miwa, Keiko Miwa, Rikinari Hanayama, Hiroko Nagase, Shigekazu Nagata, Masato Tanaka
Journal: The Journal of Experimental Medicine (2004)

Apoptotic cells are rapidly phagocytosed by professional phagocytes, such as macrophages and dendritic cells. This process prevents the release of potentially noxious or immunogenic intracellular materials from dying cells, and is thought to play a critical role for the maintenance of normal functions in surrounding tissues. Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. Here, we report that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited not only the phagocytosis of apoptotic cells by a wide variety of phagocytes, but also inhibited the enhanced production of IL-10 by thioglycollate-elicited peritoneal macrophages phagocytosing apoptotic cells. When intravenously injected into mice, the D89E protein induced the production of autoantibodies including antiphospholipids antibodies and antinuclear antibodies. The production of autoantibodies was enhanced by the coinjection of syngeneic apoptotic thymocytes. After the induction of autoantibody production by D89E, the treated mice showed a long-term elevation of the titer for autoantibodies, and developed IgG deposition in the glomeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to autoantibody production.
Evaluation of Monodansylcadaverine for Effects on Tumor Growth
Authors: Sidney T. Yancey, Koloman Laki
Journal: JNCI Journal of the National Cancer Institute (1974)

Certain sulfonamide compounds particularly N-(5-aminopentyl)-p-toluenesulfonamide (tosylcadaverine), and N-(5-aminopentyl)-5-dimethylamino-l-naphthalene sulfonamide (monodansylcadaverine) reportedly possess high inhibitory activity in the enzymatic crosslinking of fibrin. Our experiments showed that monodansylcadaverine prevented establishment of the plasma-cell tumor YPC-l in mice when mixed with the tumor in concentrations of 1.5-4.0 mg/ml and injected subcutaneously (sc) or intraperitoneally. Monodansylcadaverine also prevented establishment of lymphoid leukemia L1210 in mice when mixed with the tumor in concentrations of 1.5-4.0 mg/ml and given sc, Two injections of monodansylcadaverine (15.0 and 30.0 mg/kg) given on days 8 and 1 before YPC-l tumor inoculation reduced tumor size, but had little or no effect on survival time of the treated mice over the vehicular or untreated controls. These experiments indi cate that monodansylcadaverine inhibits the stabilization reaction when mixed with tumor. Since the YPC-l tumor possesses both clot-forming and clot-stabilizing enzymes, inhibition of the clot-stabilizing enzyme in the tumor may have provided a means of preventing stabilization of the clot. Thus, the tumor appears to have been controlled by denying it the fibrin network. Our studies in vitro indicate that a direct cytotoxic effect of monodansylcadaverineis unlikely.
Aetiology, outcome and prognostic factors in community-acquired pneumonia requiring hospitalization
Authors: A Ortqvist, J Hedlund, L Grillner, E Jalonen, I Kallings, M Leinonen, M Kalin
Journal: European Respiratory Journal (1990)

Outcome and prognostic factors were prospectively studied in 277 adult patients (average age 62 yrs) with community-acquired pneumonia requiring hospitalization. The aetiology was established in 68%, with S. pneumoniae as the predominating agent. Mortality was 4% (12 of 277), and all but one who died were greater than or equal to 60 yrs of age. Features associated with high mortality included greater age, absence of chills and chest pain, high respiratory rate (greater than 30 breaths.min-1) and low serum albumin on admission, and the occurrence of airway colonization and secondary infection during hospital stay. Multivariate analysis showed that low serum albumin and the occurrence of secondary infection, but also absence of chills and airway colonization, were correlated to a higher mortality. In patients who survived, the median length of hospital stay was seven days, and at follow-up, about eight weeks after admission, 81% had recovered and chest X-ray was normal in 84%. In conclusion, we believe that the outcome of community-acquired pneumonia can be influenced by prophylactic measures against pneumococcal infection, and an increased surveillance of risk patients.
THE MECHANISM OF ANAPHYLATOXIN FORMATION
Authors: James W. Jobling, William Petersen
Journal: The Journal of Experimental Medicine (1914)

1. The unsaturated lipoids (serum antitrypsin) can be adsorbed from guinea pig serum, rabbit serum, and horse serum by kaolin, starch, agar, and bacteria. 2. Diphtheria toxin and cobra venom also reduce the serum antitrypsin, possibly because of their affinity for lipoids. 3. Anaphylatoxins represent sera rendered toxic by partial removal of serum antitrypsin. 4. The matrix of the protein split products lies in the serum proteins so exposed. 5. The amount of removal of serum antitrypsin depends on definite quantitative relations; very large amounts and very small amounts of adsorbing substances are least effective (kaolin, starch, and bacteria). 6. Bacteria previously treated with serum or with oils do not adsorb serum antitrypsin. 7. Bacteria treated with serum become more resistant to the action of trypsin.
Homoharringtonine and omacetaxine for myeloid hematological malignancies
Authors: Shuqing Lü, Jianmin Wang
Journal: Journal of Hematology & Oncology (2014)

Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies.
Histone Chaperone CHAF1A Inhibits Differentiation and Promotes Aggressive Neuroblastoma
Authors: Eveline Barbieri, Katleen De Preter, Mario Capasso, Zaowen Chen, Danielle M. Hsu, Gian Paolo Tonini, Steve Lefever, John Hicks, Rogier Versteeg, Andrea Pession, Frank Speleman, Eugene S. Kim, Jason M. Shohet
Journal: Cancer Research (2013)

Neuroblastoma arises from the embryonal neural crest secondary to a block in differentiation. Long-term patient survival correlates inversely with the extent of differentiation, and treatment with retinoic acid or other prodifferentiation agents improves survival modestly. In this study, we show the histone chaperone and epigenetic regulator CHAF1A functions in maintaining the highly dedifferentiated state of this aggressive malignancy. CHAF1A is a subunit of the chromatin modifier chromatin assembly factor 1 and it regulates H3K9 trimethylation of key target genes regulating proliferation, survival, and differentiation. Elevated CHAF1A expression strongly correlated with poor prognosis. Conversely, CHAF1A loss-of-function was sufficient to drive neuronal differentiation in vitro and in vivo. Transcriptome analysis of cells lacking CHAF1A revealed repression of oncogenic signaling pathways and a normalization of glycolytic metabolism. Our findings demonstrate that CHAF1A restricts neural crest differentiation and contributes to the pathogenesis of high-risk neuroblastoma.
GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement
Authors: Kfir Lapid, Tomer Itkin, Gabriele D’Uva, Yossi Ovadya, Aya Ludin, Giulia Caglio, Alexander Kalinkovich, Karin Golan, Ziv Porat, Massimo Zollo, Tsvee Lapidot
Journal: Journal of Clinical Investigation (2013)

Regulation of hematopoietic stem and progenitor cell (HSPC) steady-state egress from the bone marrow (BM) to the circulation is poorly understood. While glycogen synthase kinase-3β (GSK3β) is known to participate in HSPC proliferation, we revealed an unexpected role in the preferential regulation of CXCL12-induced migration and steady-state egress of murine HSPCs, including long-term repopulating HSCs, over mature leukocytes. HSPC egress, regulated by circadian rhythms of CXCL12 and CXCR4 levels, correlated with dynamic expression of GSK3β in the BM. Nevertheless, GSK3β signaling was CXCL12/CXCR4 independent, suggesting that synchronization of both pathways is required for HSPC motility. Chemotaxis of HSPCs expressing higher levels of GSK3β compared with mature cells was selectively enhanced by stem cell factor–induced activation of GSK3β. Moreover, HSPC motility was regulated by norepinephrine and insulin-like growth factor-1 (IGF-1), which increased or reduced, respectively, GSK3β expression in BM HSPCs and their subsequent egress. Mechanistically, GSK3β signaling promoted preferential HSPC migration by regulating actin rearrangement and microtubuli turnover, including CXCL12-induced actin polarization and polymerization. Our study identifies a previously unknown role for GSK3β in physiological HSPC motility, dictating an active, rather than a passive, nature for homeostatic egress from the BM reservoir to the blood circulation.