RESUMEN
This research investigated the effectiveness of a brief Restorative Justice Intervention. Probationers who attended a Restorative Justice Intervention ( n = 383) were compared with probationers receiving treatment as usual ( n = 130) over a 2- to 6-year follow-up period. The proportion of individuals who recidivated in the control condition ( n = 89, 68.46%) were higher compared with those who recidivated in the intervention condition ( n = 127, 33.16%; z = 7.04, p < .001). In addition, among those who recidivated, those in the intervention condition did so less frequently. Qualitative analyses from a postintervention course evaluation given only to the intervention condition showed that 50% of probationers acknowledged an empathic understanding associated with participation. This brief intervention has a positive multilevel impact on restorative justice. Implications of these effects are discussed.
Asunto(s)
Víctimas de Crimen , Criminales , Evaluación de Programas y Proyectos de Salud , Reincidencia/prevención & control , Adulto , Estudios de Casos y Controles , Empatía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Reincidencia/estadística & datos numéricos , Estados UnidosRESUMEN
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia-telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.
Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias Inducidas por Radiación/genética , Neoplasias Cutáneas/genética , Quinasas p21 Activadas/genética , Animales , Apoptosis/efectos de la radiación , Proteínas de la Ataxia Telangiectasia Mutada/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Daño del ADN/efectos de la radiación , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Ratones , Neoplasias Inducidas por Radiación/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/patología , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversosRESUMEN
Human immunodeficiency virus type 1 (HIV-1) is the result of cross-species transmission of simian immunodeficiency virus from chimpanzees (SIVcpz). SIVcpz is a chimeric virus which shares common ancestors with viruses infecting red-capped mangabeys and a subset of guenon species. The epidemiology of SIV infection in hominoids is characterized by low prevalences and an uneven geographic distribution. Surveys in Cameroon indicated that two closely related members of the guenon species subset, mustached guenons and greater spot-nosed guenons, infected with SIVmus and SIVgsn, respectively, also have low rates of SIV infections in their populations. Compared to that for other monkeys, including red-capped mangabeys and closely related guenon species, such an epidemiology is unusual. By intensifying sampling of geographically distinct populations of mustached and greater spot-nosed guenons in Gabon and including large sample sets of mona guenons from Cameroon, we add strong support to the hypothesis that the paucity of SIV infections in wild populations is a general feature of this monophyletic group of viruses. Furthermore, comparative phylogenetic analysis reveals that this phenotype is a feature of this group of viruses infecting phylogenetically disparate hosts, suggesting that this epidemiological phenotype results from infection with these HIV-1-related viruses rather than from a common host factor. Thus, these HIV-1-related viruses, i.e., SIVcpz and the guenon viruses which share an ancestor with part of the SIVcpz genome, have an epidemiology distinct from that found for SIVs in other African primate species.IMPORTANCE Stable virus-host relationships are established over multiple generations. The prevalence of viral infections in any given host is determined by various factors. Stable virus-host relationships of viruses that are able to cause persistent infections and exist with high incidences of infection are generally characterized by a lack of morbidity prior to host reproduction. Such is the case for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections of humans. SIV infections of most African primate species also satisfy these criteria, with these infections found at a high prevalence and with rare cases of clinical disease. In contrast, SIVcpz, the ancestor of HIV-1, has a different epidemiology, and it has been reported that infected animals suffer from an AIDS-like disease in the wild. Here we conclusively demonstrate that viruses which are closely related to SIVcpz and infect a subset of guenon monkeys show an epidemiology resembling that of SIVcpz.
Asunto(s)
Variación Genética , Filogeografía , Síndrome de Inmunodeficiencia Adquirida del Simio/epidemiología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/clasificación , Virus de la Inmunodeficiencia de los Simios/genética , Topografía Médica , Animales , Camerún , Gabón , Haplorrinos , Prevalencia , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificaciónRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is the eighth largest cause of cancer-related mortality across the world, with a median 5-year survival rate of less than 3.5%. This is partly because the molecules and the molecular mechanisms that contribute to PDAC are not well understood. Our goal is to understand the role of p21-activated kinase 1 (Pak1) signaling axis in the progression of PDAC. Pak1, a serine/threonine kinase, is a well-known regulator of cytoskeletal remodeling, cell motility, cell proliferation and cell survival. Recent reports suggest that Pak1 by itself can have an oncogenic role in a wide variety of cancers. In this study, we analyzed the expression of Pak1 in human pancreatic cancer tissues and found that Pak1 levels are significantly upregulated in PDAC samples as compared with adjacent normals. Further, to study the functional role of Pak1 in pancreatic cancer model systems, we developed stable overexpression and lentiviral short hairpin RNA-mediated knockdown (KD) clones of Pak1 and studied the changes in transforming properties of the cells. We also observed that Pak1 KD clones failed to form tumors in nude mice. By adopting a quantitative PCR array-based approach, we identified fibronectin, a component of the extracellular matrix and a mesenchymal marker, as a transcriptional target of Pak1 signaling. The underlying molecular mechanism of Pak1-mediated transformation includes its nuclear import and recruitment to the fibronectin promoter via interaction with nuclear factor-κB (NF-κB)-p65 complex. To our knowledge, this is the first study illustrating Pak1-NF-κB-p65-mediated fibronectin regulation as a potent tumor-promoting mechanism in KRAS intact model.
Asunto(s)
Carcinoma Ductal Pancreático/etiología , Transformación Celular Neoplásica , Fibronectinas/genética , Neoplasias Pancreáticas/etiología , Transcripción Genética , Quinasas p21 Activadas/fisiología , Animales , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Neoplasias Pancreáticas/metabolismo , Regiones Promotoras Genéticas , Factor de Transcripción ReIA/fisiologíaRESUMEN
BACKGROUND: The recent discoveries of novel human T-lymphotropic virus type 3 (HTLV-3) and highly divergent simian T-lymphotropic virus type 3 (STLV-3) subtype D viruses from two different monkey species in southern Cameroon suggest that the diversity and cross-species transmission of these retroviruses are much greater than currently appreciated. RESULTS: We describe here the first full-length sequence of a highly divergent STLV-3d(Cmo8699AB) virus obtained by PCR-based genome walking using DNA from two dried blood spots (DBS) collected from a wild-caught Cercopithecus mona monkey. The genome of STLV-3d(Cmo8699AB) is 8913-bp long and shares only 77% identity to other PTLV-3s. Phylogenetic analyses using Bayesian and maximum likelihood inference clearly show that this highly divergent virus forms an independent lineage with high posterior probability and bootstrap support within the diversity of PTLV-3. Molecular dating of concatenated gag-pol-env-tax sequences inferred a divergence date of about 115,117 years ago for STLV-3d(Cmo8699AB) indicating an ancient origin for this newly identified lineage. Major structural, enzymatic, and regulatory gene regions of STLV-3d(Cmo8699AB) are intact and suggest viral replication and a predicted pathogenic potential comparable to other PTLV-3s. CONCLUSION: When taken together, the inferred ancient origin of STLV-3d(Cmo8699AB), the presence of this highly divergent virus in two primate species from the same geographical region, and the ease with which STLVs can be transmitted across species boundaries all suggest that STLV-3d may be more prevalent and widespread. Given the high human exposure to nonhuman primates in this region and the unknown pathogenicity of this divergent PTLV-3, increased surveillance and expanded prevention activities are necessary. Our ability to obtain the complete viral genome from DBS also highlights further the utility of this method for molecular-based epidemiologic studies.
Asunto(s)
Cercopithecus/virología , ADN Viral/genética , Infecciones por Deltaretrovirus/veterinaria , Genoma Viral , Análisis de Secuencia de ADN , Virus Linfotrópico T Tipo 3 de los Simios/genética , Infecciones Tumorales por Virus/veterinaria , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Paseo de Cromosoma , Análisis por Conglomerados , ADN Viral/química , Modelos Moleculares , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Filogenia , Reacción en Cadena de la Polimerasa/métodos , Homología de Secuencia , Virus Linfotrópico T Tipo 3 de los Simios/aislamiento & purificaciónRESUMEN
Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases. The closest known relative of P. falciparum is a chimpanzee parasite, Plasmodium reichenowi, of which one single isolate was previously known. The co-speciation hypothesis suggests that both parasites evolved separately from a common ancestor over the last 5-7 million years, in parallel with the divergence of their hosts, the hominin and chimpanzee lineages. Genetic analysis of eight new isolates of P. reichenowi, from wild and wild-born captive chimpanzees in Cameroon and Côte d'Ivoire, shows that P. reichenowi is a geographically widespread and genetically diverse chimpanzee parasite. The genetic lineage comprising the totality of global P. falciparum is fully included within the much broader genetic diversity of P. reichenowi. This finding is inconsistent with the co-speciation hypothesis. Phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, which may have occurred as early as 2-3 million years ago, or as recently as 10,000 years ago. The evolutionary history of this relationship may be explained by two critical genetic mutations. First, inactivation of the CMAH gene in the human lineage rendered human ancestors unable to generate the sialic acid Neu5Gc from its precursor Neu5Ac, and likely made humans resistant to P. reichenowi. More recently, mutations in the dominant invasion receptor EBA 175 in the P. falciparum lineage provided the parasite with preference for the overabundant Neu5Ac precursor, accounting for its extreme human pathogenicity.
Asunto(s)
Malaria/parasitología , Filogenia , Plasmodium falciparum/genética , Plasmodium/genética , Secuencia de Aminoácidos , Animales , Glicoproteínas/genética , Humanos , Malaria/metabolismo , Malaria/veterinaria , Datos de Secuencia Molecular , Mutación , Ácido N-Acetilneuramínico/metabolismo , Pan troglodytes/parasitología , Plasmodium/química , Plasmodium/metabolismo , Plasmodium falciparum/química , Plasmodium falciparum/metabolismo , Infecciones Protozoarias en Animales/metabolismo , Infecciones Protozoarias en Animales/parasitología , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Alineación de SecuenciaRESUMEN
Pulmonary extension of recurrent invasive papillomatosis often poses a diagnostic challenge to the examining bronchoscopist, pathologist, radiologist and surgeon, in distinguishing it as a benign lesion that is confined to the mucosa and extending along the branches of the tracheobronchial tree from true invasion of a malignant tumor. We document here a case of recurrent invasive respiratory papillomatosis which initially presented as a laryngeal papilloma. After multiple recurrences, the patient presented with bronchopulmonary involvement, complicated by invasive aspergillosis in a non-immunocompromised setting.
Asunto(s)
Aspergilosis/virología , Enfermedades Pulmonares Fúngicas/virología , Neoplasias Pulmonares/secundario , Papiloma/diagnóstico por imagen , Adolescente , Aspergilosis/complicaciones , Aspergilosis/diagnóstico , Diagnóstico Diferencial , Humanos , Itraconazol/administración & dosificación , Itraconazol/uso terapéutico , Enfermedades Pulmonares Fúngicas/diagnóstico , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Masculino , Papiloma/complicaciones , Papiloma/terapia , Recurrencia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Methyl isobutyl ketone was found to potentiate intrahepatic cholestasis induced by taurolithocholate and the combination of manganese-bilirubin. The aim of this study was to elucidate the mechanism of this potentiation using the lithocholate-induced cholestasis model. Male rats were given methyl isobutyl ketone 7.5 mumol/kg body wt. daily for 3 days. The effect of this treatment on lithocholate-induced cholestasis, bile formation and taurocholic acid transport was examined. The data showed that methyl isobutyl ketone treatment potentiated lithocholate-induced cholestasis and reduced significantly bile salt, phospholipid and cholesterol secretion rates as well as the transport maximum of taurocholic acid. It is suggested that methyl isobutyl ketone potentiates lithocholate-induced cholestasis by reducing the bile salt pool and interfering with the haptic secretion rate of bile salts.