59 research outputs found
Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire
Idiosyncratic adverse drug reactions are unpredictable, dose independent and
potentially life threatening; this makes them a major factor contributing to
the cost and uncertainty of drug development. Clinical data suggest that many
such reactions involve immune mechanisms, and genetic association studies have
identified strong linkage between drug hypersensitivity reactions to several
drugs and specific HLA alleles. One of the strongest such genetic associations
found has been for the antiviral drug abacavir, which causes severe adverse
reactions exclusively in patients expressing the HLA molecular variant B*57:01.
Abacavir adverse reactions were recently shown to be driven by drug-specific
activation of cytokine-producing, cytotoxic CD8+ T cells that required
HLA-B*57:01 molecules for their function. However, the mechanism by which
abacavir induces this pathologic T cell response remains unclear. Here we show
that abacavir can bind within the F-pocket of the peptide-binding groove of
HLA-B*57:01 thereby altering its specificity. This supports a novel explanation
for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can
alter the repertoire of self-peptides presented to T cells thus causing the
equivalent of an alloreactive T cell response. Indeed, we identified specific
self-peptides that are presented only in the presence of abacavir, and that
were recognized by T cells of hypersensitive patients. The assays we have
established can be applied to test additional compounds with suspected HLA
linked hypersensitivities in vitro. Where successful, these assays could speed
up the discovery and mechanistic understanding of HLA linked hypersensitivities
as well as guide the development of safer drugs
Non-Agonistic Bivalent Antibodies That Promote c-MET Degradation and Inhibit Tumor Growth and Others Specific for Tumor Related c-MET
The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519–561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies
Measuring the predictability of life outcomes with a scientific mass collaboration.
How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences
Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism
From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços cientÃficos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clÃnica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosÃdeos de transcriptase reversa (INTR), inibidores nucleotÃdeos de transcriptase reversa (INtTR), inibidores não-nucleosÃdeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade quÃmica devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponÃveis na terapêutica
Bio-analytical Assay Methods used in Therapeutic Drug Monitoring of Antiretroviral Drugs-A Review
Hepatocyte growth factor in cerebrospinal fluid differentiates community-acquired or nosocomial septic meningitis from other causes of pleocytosis
La stimolazione dei nervi sacrali \ue8 un trattamento efficace nel dolore anale cronico?
Is sacral nerve stimulation an effective treatment for chronic idiopathic anal pain?
BACKGROUND: Chronic idiopathic anal pain is a common, benign symptom, the etiology of which remains unclear. Traditional treatments are often ineffective. This study investigated the efficacy of sacral nerve stimulation in treating chronic idiopathic anal pain. METHODS: Twelve patients (10 women and 2 men; mean age, 61.0 +/- 10.3 years; range, 48-82 years) implanted with a permanent device for sacral nerve stimulation were followed in the Italian Group for Sacral Neuromodulation (GINS) Registry. All patients had frequent chronic anal or perianal pain; 75 percent had previously undergone pelvic surgery. Pharmacologic and rehabilitative therapy had yielded poor results. Changes from baseline to last follow-up examination were evaluated for scores on a visual analog pain scale (0-10) and the Short-Form 36 (SF-36) health status questionnaire. Manometric measurements recorded at last follow-up were compared with preimplantation values. RESULTS: In one patient, the permanent device was removed because of technical failure. After a mean follow-up of 15 (range, 3-80) months, visual analog pain scores had significantly improved (from 8.2 +/- 1.7 to 2.2 +/- 1.3, P < 0.001). SF-36 physical component scores increased from 26.27 +/- 5.65 to 38.95 +/- 9.08, P < 0.02). Scores on the mental component showed improvement, although not significant. Postimplantation changes in manometric functional data were not significant, but sensitivity thresholds showed a considerable decrease. CONCLUSIONS: Long-term follow-up data showing improvements in scores on the visual analog pain scale and quality of life questionnaire indicate that, before adopting more aggressive surgical procedures, SNS should be considered for patients with chronic idiopathic anal pain in whom pharmacologic and biofeedback treatments have failed to produce effective results
La neuromodulazione sacrale nel trattamento del dolore anale idiopatico. Risultati preliminari su 10 pazienti
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