tbuckley/cabot-search huggingface dataset:
Coupling Tumor Necrosis Factor-α with αV Integrin Ligands Improves Its Antineoplastic Activity
Authors: Flavio Curnis, Anna Gasparri, Angelina Sacchi, Renato Longhi, Angelo Corti
Journal: Cancer Research (2004)

Despite the impressive results obtained in animal models, the clinical use of tumor necrosis factor-alpha (TNF) as an anticancer drug is limited by severe toxicity. We have shown previously that targeted delivery of TNF to aminopeptidase N (CD13), a marker of angiogenic vessels, improved the therapeutic index of this cytokine in tumor-bearing mice. To assess whether the vascular-targeting approach could be extended to other markers of tumor blood vessels, in this work, we have fused TNF with the ACDCRGDCFCG peptide, a ligand of alpha(V) integrins by recombinant DNA technology. We have found that subnanogram doses of this conjugate are sufficient to induce antitumor effects in tumor-bearing mice when combined with melphalan, a chemotherapeutic drug. Cell adhesion assays and competitive binding experiments with anti-integrin antibodies showed that the Arg-Gly-Asp moiety interacts with cell adhesion receptors, including alpha(V)beta(3) integrin, as originally postulated. In addition, ACGDRGDCFCG-mouse TNF conjugate induced cytotoxic effects in standard cytolytic assays, implying that ACGDRGDCFCG-mouse TNF conjugate can also bind TNF receptors and trigger death signals. These results indicate that coupling TNF with alpha(V) integrin ligands improves its antineoplastic activity and supports the concept that vascular targeting is a strategy potentially applicable to different endothelial markers, not limited to CD13.
Diagnosis and management of haemophilia
Authors: K. Fijnvandraat, M. H. Cnossen, F. W. G. Leebeek, M. Peters
Journal: BMJ (2012)

In patients with major (head) trauma or major spontaneous bleeding, always give coagulation factor concentrates without delay, before diagnostic imaging or other interventions Prophylactic administration of factor VIII or factor IX concentrate is the standard of care for patients with severe haemophilia in countries where this is economically feasible Avoid drugs that affect haemostasis, such as platelet inhibitors and anticoagulants because they aggravate bleeding symptoms A safety amulet that makes patients with haemophilia easily recognisable may be life saving and is recommended for all patients Advise female relatives of patients with haemophilia to seek genetic counselling because they may be carriers Female carriers may have reduced plasma concentrations of factor VIII or factor IX, similar to those seen in patients with mild haemophilia and may also have bleeding symptoms Sources and selection criteriaWe searched Medline and the Cochrane Database of Systematic Reviews for "haemophilia" and "hemophilia", and we consulted the TRIP database for national guidelines on the management of haemophilia.Finally, we also used our personal reference libraries, giving preference to the highest level of evidence available.32 High KA.Gene therapy for haemophilia: a long and winding road.
Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study
Authors: Jae-Gahb Park, Duck-Woo Kim, Chang Won Hong, Byung-Ho Nam, Young-Kyoung Shin, Sung-Hye Hong, Il-Jin Kim, Seok-Byung Lim, Melyssa Aronson, Marie Luise Bisgaard, Gregor J. Brown, John Burn, Elizabeth Chow, Peggy Conrad, Fiona Douglas, Malcolm Dunlop, James Ford, Marc S. Greenblatt, Jarvinen Heikki, Karl Heinimann, Elly L. Lynch, Finlay Macrae, Wendy C. McKinnon, Gabriela Möeslein, Benedito Mauro Rossi, Paul Rozen, Lyn Schofield, Carlos Vaccaro, Hans Vasen, Mary Velthuizen, Alessandra Viel, Juul Wijnen
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P &amp;lt; 0.001). Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P &amp;lt; 0.001).
COMPARATIVE STUDIES BETWEEN PATHOGENESIS OF STREET AND FIXED RABIES INFECTION
Authors: Kaneatsu Miyamoto, Seiichi Matsumoto
Journal: The Journal of Experimental Medicine (1967)

Comparative neuropathology of Ammon's horn caused by both the street and fixed rabies infection was studied by combined light and electron microscopy. Neurons containing Negri bodies appeared comparatively little damaged. In striking contrast, in the case of fixed virus infection, neurons showed the following variety of degeneration. Lightly damaged neurons showed an increase in the number of small vesicles throughout the cytoplasm. A considerable number of lysosomes were also encountered within these nerve cells. Severe necrotic alteration involving the nucleus as well as the cytoplasm was found in the nerve cell band. The characteristic homogeneous foci (matrices) were discernible within these neurons. It appears that the matrix is morphologically identical with the ground substance of the Negri body, though its size is smaller than that of the Negri body. This evidence suggests a possibility that fixed virus injures neurons so extensively that they cannot bring about the full development of the characteristic matrix of the Negri body recognizable by the light microscope. Selective vulnerability was demonstrated among different groups of neurons in respect of cytopathogenesis of both street and fixed virus infection.
From Pulsus to Pulseless
Authors: James N. Weiss, Alain Karma, Yohannes Shiferaw, Peng-Sheng Chen, Alan Garfinkel, Zhilin Qu
Journal: Circulation Research (2006)

Computer simulations and nonlinear dynamics have provided invaluable tools for illuminating the underlying mechanisms of cardiac arrhythmias. Here, we review how this approach has led to major insights into the mechanisms of spatially discordant alternans, a key arrhythmogenic factor predisposing the heart to re-entry and lethal arrhythmias. During spatially discordant alternans, the action potential duration (APD) alternates out of phase in different regions of the heart, markedly enhancing dispersion of refractoriness so that ectopic beats have a high probability of inducing reentry. We show how, at the cellular level, instabilities in membrane voltage (ie, steep APD restitution slope) and intracellular Ca (Cai) cycling dynamics cause APD and the Cai transient to alternate and how the characteristics of alternans are affected by different "modes" of the bidirectional coupling between voltage and Cai. We illustrate how, at the tissue level, additional factors, such as conduction velocity restitution and ectopic beats, promote spatially discordant alternans. These insights have illuminated the mechanistic basis underlying the clinical association of cardiac alternans (eg, T wave alternans) with arrhythmia risk, which may lead to novel therapeutic approaches to avert sudden cardiac death.
Polymyositis, invasion of non-necrotic muscle fibres, and the art of repetition
Authors: Gerald J D Hengstman, Baziel G M van Engelen
Journal: BMJ (2004)

<i>The presence of cellular inflammatory infiltrates with invasion of non-necrotic muscle fibres has become a prerequisite for the diagnosis of polymyositis, but a structured literature search shows that the research evidence is insufficiently strong for this histological feature to be used as a diagnostic criterion</i>
Clonotypic analysis of T cells in patients with autoimmune and viral hepatitis
Authors: A Tanaka, S Iwabuchi, M Takatori, A Ohno, H Yamada, N Hashimoto, Y Ikeda, T Kato, K Nishioka, S Iino, K Yamamoto
Journal: Hepatology (1997)

The immunopathogenesis of autoimmune hepatitis (AIH), and the role of T cells in the onset and maintenance of this disease, are still unclear. Since T cells expand clonally after stimulation by an antigen, it is important to analyze the behavior of T cells at a clonal level. We have established recently a novel system, using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP) that allows the identification of clonal accumulation of T cells in a lymphocyte population. Using this system, we demonstrated that oligoclonal T cells were accumulated in the liver of patients with AIH, and that identical T-cell clonotypes were detected in two different regions of the liver, although these features were also observed in cases with viral hepatitis. Only in cases with AIH, however, nearly all identical T cells were found to belong to CD8+ subset and there were very few CD4+ T cells in this population. Our results suggest that common antigens presented to CD8+ T cells in the context of HLA class I molecule are distributed diffusely in the liver of AIH. These findings also suggest that antigens recognized by CD4+ T cells may be relatively heterogeneous in the liver with AIH.
Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial
Authors: Richard B Pollard, Jürgen K Rockstroh, Giuseppe Pantaleo, David M Asmuth, Barry Peters, Adriano Lazzarin, Felipe Garcia, Kim Ellefsen, Daniel Podzamczer, Jan van Lunzen, Keikawus Arastéh, Dirk Schürmann, Bonaventura Clotet, W David Hardy, Ronald Mitsuyasu, Graeme Moyle, Andreas Plettenberg, Martin Fisher, Gerd Fätkenheuer, Margaret Fischl, Babafemi Taiwo, Ingebjørg Baksaas, Darren Jolliffe, Stefan Persson, Øyvind Jelmert, Arnt-Ove Hovden, Maja A Sommerfelt, Vidar Wendel-Hansen, Birger Sørensen
Journal: The Lancet Infectious Diseases (2014)
Biodistribution and tissue expression kinetics of plasmid DNA complexed with polyethylenimines of different molecular weight and structure
Authors: Gil-Jae Jeong, Hyang-Min Byun, Jung Mogg Kim, Ho Yoon, Han-Gon Choi, Won-Ki Kim, Sun-Jae Kim, Yu-Kyoung Oh
Journal: Journal of Controlled Release (2006)
Host-Derived Angiopoietin-2 Affects Early Stages of Tumor Development and Vessel Maturation but Is Dispensable for Later Stages of Tumor Growth
Authors: Patrick Nasarre, Markus Thomas, Karoline Kruse, Iris Helfrich, Vivien Wolter, Carleen Deppermann, Dirk Schadendorf, Gavin Thurston, Ulrike Fiedler, Hellmut G. Augustin
Journal: Cancer Research (2009)

The angiopoietin/Tie2 system has been identified as the second vascular-specific receptor tyrosine kinase system controlling vessel assembly, maturation, and quiescence. Angiopoietin-2 (Ang-2) is prominently up-regulated in the host-derived vasculature of most tumors, making it an attractive candidate for antiangiogenic intervention. Yet, the net outcome of Ang-2 functions on tumor angiogenesis is believed to be contextual depending on the local cytokine milieu. Correspondingly, Ang-2 manipulatory therapies have been shown to exert protumorigenic as well as antitumorigenic effects. To clarify the role of Ang-2 for angiogenesis and tumor growth in a definite genetic experimental setting, the present study was aimed at comparatively studying the growth of different tumors in wild-type and Ang-2-deficient mice. Lewis lung carcinomas, MT-ret melanomas, and B16F10 melanomas all grew slower in Ang-2-deficient mice. Yet, tumor growth in wild-type and Ang-2-deficient mice dissociated during early stages of tumor development, whereas tumor growth rates during later stages of primary tumor progression were similar. Analysis of the intratumoral vascular architecture revealed no major differences in microvessel density and perfusion characteristics. However, diameters of intratumoral microvessels were smaller in tumors grown in Ang-2-deficient mice, and the vasculature had an altered pattern of pericyte recruitment and maturation. Ang-2-deficient tumor vessels had higher pericyte coverage indices. Recruited pericytes were desmin and NG2 positive and predominately alpha-smooth muscle actin negative, indicative of a more mature pericyte phenotype. Collectively, the experiments define the role of Ang-2 during tumor angiogenesis and establish a better rationale for combination therapies involving Ang-2 manipulatory therapies.
Sinonasal inflammation in COPD: a systematic review: Table 1–
Authors: Kåre Håkansson, Lars Konge, Simon F. Thomsen, Vibeke Backer, Christian von Buchwald
Journal: European Respiratory Journal (2012)

In this review, we demonstrate that patients with chronic obstructive pulmonary disease (COPD) frequently report sinonasal symptoms. Furthermore, we present evidence that smoking on its own can cause nasal disease and that, in COPD patients, nasal inflammation mimics that of the bronchi. All this evidence suggests that COPD-related sinonasal disease does exist and that smoking on its own rather than systemic inflammation triggers the condition. However, COPD-related sinonasal disease remains to be characterised in terms of symptoms and endoscopic findings. In addition, more studies are needed to quantify the negative impact of sinonasal symptoms on the quality of life in COPD patients.
Prostate Cancer Quality of Life: Beyond Initial Treatment—and the Patient
Authors: James A. Talcott
Journal: Journal of Clinical Oncology (2007)

The clinical course of cancer produces the illusion of discontinuity, and the distortion can harm treatment decision making. Most cancers grow for years to achieve a size sufficient for symptoms, screening, or serendipitous test results to draw attention to it. However long in coming, a cancer diagnosis arrives as a thunderbolt, kicking off a disorienting frenzy of testing, consultation, and treatment. The aftermath depends on the cancer’s response. Progressive cancer is a batterer, provoking treatment counterpunches on behalf of the patient, with the family’s support. 1,2 But they must come to an accommodation with it, their eventual acquiescence variably admixed with grace and peace, but at great emotional cost, 3 and too often disastrously late to benefit from hospice and other palliative care. 4 For the fortunate patient with a complete remission, usually with surgery as part of treatment, the reverberations of treatment eventually die down. Fear of cancer gives way to thanks for its departure, and hope that it will not return seeps in, with cure becoming conviction in time. Biologically, recurrent cancer simply extends the primary tumor’s relentless, occult growth, albeit displaced. Too often, it clinically reprises the initial surprise attack, triggering a new, urgent round of tests and consultations that echoes the first. It needn’t be
Risk factors for bronchial hyperresponsiveness in workers exposed to acid anhydrides
Authors: R.D. Barker, M.J.A. van Tongeren, J.M. Harris, K. Gardiner, K.M. Venables, A.J. Newman Taylor
Journal: European Respiratory Journal (2000)

Risk factors for bronchial hyperresponsiveness have previously been established in the general community. In settings where occupational asthma is a risk, it has not been established whether occupational sensitization or measures of exposure are important. Bronchial responsiveness to histamine was measured in a cohort of 506 workers exposed to acid anhydrides. Skin-prick tests were performed with conjugates of phthalic, maleic and trimellitic anhydride with human serum albumin and with common inhalant allergens. Employment and smoking histories were recorded. Occupational exposure was measured using personal air samplers and estimates of past exposure made by retrospective exposure assessment. Three hundred and seventy workers (73%) had bronchial responsiveness measured (median age 39 yrs, range 18-77) and 46 (12%) of these were hyperresponsive (provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1; PD20) &lt; or = 8 micromol). Twelve (3%) of these responsive workers had a skin-prick test reaction to an acid anhydride conjugate, 124 (34%) to a common inhalant allergen, and 148 (40%) were current smokers. Multivariate analysis showed that occupational sensitization, sensitization to a common inhalant allergen, age, and pack-years of smoking were independent risk factors for bronchial hyperresponsiveness. Of these only occupational sensitization was completely independent of baseline FEV1. It is concluded that sensitization to acid anhydrides is a significant risk factor for bronchial hyperresponsiveness. However, measures of personal acid anhydride exposure were not associated with bronchial hyperresponsiveness.
Prostate Cancer Cells Promote Osteoblastic Bone Metastases through Wnts
Authors: Christopher L. Hall, Anna Bafico, Jinlu Dai, Stuart A. Aaronson, Evan T. Keller
Journal: Cancer Research (2005)

Abstract Prostate cancer produces painful osteoblastic bone metastases. Although prostate cancer cells produce numerous osteogenic factors, to date, none have been shown to mediate osteoblastic bone metastases in an in vivo model of prostate cancer. Wnts are a large family of proteins that promote bone growth. Wnt activity is antagonized by endogenous proteins including dickkopf-1 (DKK-1). We explored if prostate cancer cells mediate osteoblastic activity through Wnts using DKK-1 as a tool to modify Wnt activity. A variety of Wnt mRNAs were found to be expressed in prostate cancer cell lines and Wnt mRNA expression was increased in primary prostate cancer compared with nonneoplastic prostate tissue. In addition to expressing Wnts, PC-3 prostate cancer cells expressed the Wnt inhibitor DKK-1. To determine if DKK-1 masked Wnt-mediated osteoblastic activity in osteolytic PC-3 cells, the cells were stably transfected with DKK-1 short hairpin RNA. Decreasing DKK-1 enabled PC-3 cells to induce osteoblastic activity, including alkaline phosphatase production and mineralization, in murine bone marrow stromal cells indicating that DKK-1 blocked Wnt-mediated osteoblastic activity in PC-3 cells. Another prostate cancer cell line, C4-2B, induces mixed osteoblastic/osteolytic lesions. To determine if Wnts contribute to C4-2B's ability to induce mixed osteoblastic/osteolytic lesions, C4-2B cells were stably transfected with either empty vector or DKK-1 expression vector to block Wnt activity. The cells were then injected in the tibiae of mice and allowed to grow for 12 weeks. Blocking Wnt activity converted the C4-2B cells to a highly osteolytic tumor. Taken together, these data show that Wnts contribute to the mechanism through which prostate cancer induces osteoblastic activity.
Small bowel transplantation in children: an immunohistochemical study of intestinal grafts.
Authors: G Fromont, N Cerf-Bensussan, N Patey, D Canioni, C Rambaud, O Goulet, D Jan, Y Revillon, C Ricour, N Brousse
Journal: Gut (1995)

Seven children with short bowel syndrome underwent small bowel allografting. Episodes of early rejection were observed in five patients who received a graft from paediatric or adult donors but not in two patients who received a neonatal graft. This study aimed, firstly, to define immunohistochemical parameters accompanying rejection and, secondly, to compare immunohistochemical parameters in neonatal grafts with those in grafts from older donors. An immunohistochemical analysis was performed on 85 intestinal biopsy specimens taken for monitoring the transplant. Acute histological rejection was associated with pericryptic infiltrates of CD3+TcR alpha beta + T cells containing clusters of CD8+ cells, numerous CD25+ cells, and increased numbers of CD68+ macrophages. These changes were associated with the appearance of major histocompatibility (MHC) class II antigens on crypt enterocytes and with an appreciable increase in the expression of E-selectin on mucosal endothelial cells. Immunohistochemistry was useful in predicting rejection by showing the appearance of pericryptic CD25+ T cells 48 hours before the first histological lesions of crypt necrosis. Comparison of neonatal grafts with grafts from older donors did not show any significant difference in the density of CD68+ macrophages or in the endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or E-selectin. In contrast to grafts from older donors, however, neonatal grafts did not express MHC class II antigens on epithelial cells and contained very low numbers of intraepithelial lymphocytes. These data indicate, firstly, that immunohistochemistry is useful for monitoring intestinal transplants and, secondly, that the better clinical tolerance of neonatal allografts may be related to the lower immunogenicity of the neonatal epithelium.
A mutation associated with clofazimine and bedaquiline cross-resistance in MDR-TB following bedaquiline treatment
Authors: Akos Somoskovi, Vera Bruderer, Rico Hömke, Guido V. Bloemberg, Erik C. Böttger
Journal: European Respiratory Journal (2014)

The world-wide increase in the incidence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) poses a major clinical challenge. The treatment outcome of MDR-TB and XDR-TB patients is often poor and unsuccessful in the absence of an optimal number of active drugs [1]. Novel antituberculous compounds are urgently required and only very few, such as bedaquiline, have recently been approved for tuberculosis treatment [2]. In a recent phase 2b clinical trial that was based on a 160 newly diagnosed MDR-TB patients, the addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversion at 120 weeks compared with the control group. However, there were more deaths in the bedaquiline than in the placebo group and half of these patients died due to tuberculosis. So far, it is unclear whether the death of any of these patients may have been associated with diminished susceptibility to bedaquiline [3]. Acquired clofazimine and bedaquiline cross-resistance in a patient due to mutation in the M. tuberculosis Rv0678 gene <http://ow.ly/Cnkk7>