RESUMO
Homocystinuria due to cystathionine beta synthase (CBS) deficiency results in elevated plasma homocysteine and methionine levels, which are associated with multiple organ pathologies, including vascular, respiratory, musculoskeletal, nervous, and ocular tissues. This autosomal recessive disorder is caused by homozygous or compound heterozygous mutations in the CBS gene encoding for the CBS. Although homocystinuria is observed in Arab and North African patients, their clinical presentations have not been described and molecular causes remained largely uninvestigated. In this study, we describe the clinical presentations of 22 homocystinuria patients from 13 Saudi Arabian families and 1 North African Sudanese family. Cardinal biochemical features of homocystinuria manifested in all patients, but heterogeneity of expression was observed for other associated phenotypes. One patient developed Legg-Calvé-Perthes disease that has not been previously described in homocystinuria. In the Saudi families, a novel nonsense mutation, p.Trp323X, and recurrent p.Arg336Cys and p.Gly153Arg mutations were identified in the CBS gene. The p.Trp323X mutation was found in 10 of the 13 unrelated Saudi families. In the Sudanese family, the p.Thr257Met mutation in the CBS gene, previously described in Italian and Spanish patients, was found. This study shows that the spectrum of CBS gene mutations in Saudi homocystinuria patients is quite different than the Arab patients from Qatar and Israel. This study is the only detailed phenotypic and genetic depiction of homocystinuria patients from Saudi Arabia and Sudan. The data are useful for diagnosis and management of Saudi patients.
Assuntos
Homocistinúria/etnologia , Homocistinúria/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Feminino , Humanos , Israel , Masculino , Mutação , Linhagem , Fenótipo , Catar , Arábia Saudita , SudãoRESUMO
Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Sarcoma/genética , Sarcoma/terapia , Linfócitos T Reguladores , Microambiente TumoralRESUMO
In viral myocarditis, inflammation and destruction of cardiac myocytes leads to fibrosis, causing progressive impairment in cardiac function. Here we show the etiologic importance of serine elastase activity in the pathophysiology of acute viral myocarditis and the therapeutic efficacy of an elastase inhibitor. In DBA/2 mice inoculated with the encephalomyocarditis virus, a more than 150% increase in myocardial serine elastase activity is observed. This is suppressed by a selective serine elastase inhibitor, ZD0892, which is biologically effective after oral administration. Mice treated with this compound had little evidence of microvascular constriction and obstruction associated with myocarditis-induced ischemia reperfusion injury, much less inflammation and necrosis, only mild fibrosis and myocardial collagen deposition, and normal ventricular function, compared with the infected nontreated group.
Assuntos
Infecções por Cardiovirus/tratamento farmacológico , Coração/fisiologia , Inflamação/tratamento farmacológico , Miocardite/tratamento farmacológico , Pirróis/uso terapêutico , Inibidores de Serina Proteinase/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Animais , Infecções por Cardiovirus/fisiopatologia , Infecções por Cardiovirus/virologia , Modelos Animais de Doenças , Vírus da Encefalomiocardite , Fibrose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Microcirculação/efeitos dos fármacos , Miocardite/fisiopatologia , Miocardite/virologia , Miocárdio/patologia , Perfusão , Peroxidase/metabolismo , Pirróis/administração & dosagem , Inibidores de Serina Proteinase/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
INTRODUCTION: A phase II study was conducted in patients, unsuited for surgery, with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) and without distant metastasis. The objectives were to evaluate overall response (OR) rate and safety of subjects treated with induction regimen docetaxel and cisplatin, followed by definitive chemoradiotherapy (CRT) in this setting. METHODS AND MATERIALS: Induction regimen consisted of docetaxel 75mg/m2 and cisplatin 75mg/m2 on day 1; cycles repeated every 21 days for three cycles with supportive G-CSF treatment beginning at first cycle. Definitive CRT consisted of weekly cisplatin 30mg/m2 for four weeks starting concomitantly with 60 Gy/30 fractions of conventional radiotherapy for six weeks. Primary and secondary efficacy criteria were OR rate at three weeks after cycle three and eight weeks after last cycle of CRT respectively. RESULTS: Three centers enrolled 35 patients. Primary efficacy endpoint: OR rate of evaluable patients after induction (n=27) was 88.9% (95% CI:71.9-96.2). Complete response (CR) was not achieved by any patient; partial response (PR) was achieved by 88.9% (24/27). From intent to treat (ITT) analysis OR rate was 68.6% (24/35). Secondary efficacy endpoint: OR rate of evaluable patients after definitive CRT (n=19) was 78.9%(95%CI:56.7-91.5) with CR and PR achieved by 2(10.5%) and 13(68.4%) patients respectively. From ITT analysis CR rate was 5.7% (2/35) and OR rate was 42.9% (15/35). During induction most common hematological toxicity was leukopenia in eight patients, with =Grade 3 leukopenia reported in three patients. During CRT most common adverse events were alopecia, stomatitis and nausea. CONCLUSION: We observed an ITT response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile. Hence, further investigation in this setting is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Docetaxel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Autoimmune polyendocrinopathy syndrome type 1 (APS1) is characterized by the presence of at least two out of three clinical features, which include Addison's disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. This disorder is caused by mutations in the AIRE (autoimmune regulator) gene. While several AIRE mutations have been described in APS1 patients of various ethnic origins, the genetic cause of APS1 in Arab patients requires further investigation. This study describes seven Arab families, in which 18 patients had APS1. In addition to the cardinal features of APS1, some patients exhibited alopecia, diabetes mellitus, nephrocalcinosis and other phenotypes associated with APS1. DNA sequencing of the AIRE gene of patients from this study identified four novel and one recurrent mutation. These mutations likely result in loss of AIRE function in the patients. In addition, it was noted that the non-pathogenic c.834C> G mutation (rs1800520, encoding for p.Ser278Arg) occurs with high incidence in the AIRE gene of Arab individuals. Furthermore, this investigation demonstrates inflammation of the hair follicles in APS1 patients with alopecia universalis. We conclude that Arab APS1 patients carry novel and recurrent mutations in the AIRE gene.
Assuntos
Mutação , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Alopecia/genética , Criança , Humanos , Masculino , Linhagem , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
Elastases degrade the extracellular matrix, releasing growth factors and chemotactic peptides, inducing glycoproteins such as tenascin, and thereby promoting vascular cell proliferation and migration. Administration of serine elastase inhibitors reduces experimentally induced vascular disease. The ability to mount an intrinsic anti-elastase response may, therefore, protect against intimal/medial thickening after vascular injury. To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system. Ten days after injury, nontransgenic littermates show vessel enlargement, intimal thickening, increased medial area and cellularity, and 2-fold increase in tenascin. Injured vessels in transgenic mice become enlarged but are otherwise similar to sham-operated controls. Injury-induced vessel wall thickening, which is observed only in nontransgenic mice, is related to foci of neutrophils and macrophages, in addition to smooth muscle cells that fail to stain for alpha-actin and are likely dedifferentiated. Our study therefore suggests that a major determinant of the vascular response to injury is the early transient induction of serine elastase activity, which leads to cellular proliferation and inflammatory cell migration.
Assuntos
Lesões das Artérias Carótidas/fisiopatologia , Artéria Carótida Externa/fisiologia , Músculo Liso Vascular/lesões , Proteínas/fisiologia , Animais , Lesões das Artérias Carótidas/patologia , Artéria Carótida Externa/patologia , Divisão Celular , Indução Enzimática , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiologia , Elastase Pancreática/biossíntese , Proteínas Secretadas Inibidoras de Proteinases , Proteínas/genéticaRESUMO
Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.
Assuntos
Infecções por Cardiovirus/prevenção & controle , Vírus da Encefalomiocardite , Miocardite/prevenção & controle , Proteínas/fisiologia , Inibidores de Serina Proteinase/fisiologia , Animais , Infecções por Cardiovirus/mortalidade , Infecções por Cardiovirus/patologia , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Elastina/metabolismo , Endotelina-1 , Endotelinas/genética , Endotélio Vascular/citologia , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Miocardite/mortalidade , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Elastase Pancreática/antagonistas & inibidores , Precursores de Proteínas/genética , Proteínas Secretadas Inibidoras de Proteinases , Proteínas/genética , Artéria Pulmonar/citologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Inibidores de Serina Proteinase/genética , Ovinos , Distribuição TecidualRESUMO
OBJECTIVE: Provide an overview of the demographics and pathology of breast cancer in the female population of Karachi South during a 3 year period, 1995-1997. METHODS: Epidemiological data for 709 incident breast cancer cases, ICD-10 category C50 registered at Karachi Cancer Registry during 1st January 1995 to 31st December 1997 were reviewed. RESULTS: Breast cancer accounted for approximately one-third of the cancers in females. The age standardized incidence rate (ASR) world per 100,000 was 53.8, the crude incidence rate was 30.9. In KS 60% of the newly diagnosed breast cancers were observed in women below 50 years. The age-specific curves showed a gradual increase in risk from the third up till the seventh decade, followed by an actual/apparent decrease in risk. The socio-economic distribution was 24.9% in category I the financially deprived class, 38.9% in category II the middle class and 35.9% in category III, the affluent class. Microscopic confirmation of malignancies was 99%. Invasive breast cancers predominated with 99.4%, with in-situ cancers contributing to 0.6% of the malignancies. The morphology of cancers was tilted towards duct cell carcinoma (DCC), pure DCC (92%), combinations of DCC /Paget's disease (0.6%) and lobular carcinoma (0.4%). Approximately 45% of duct cell carcinoma were seen in the premenopausal age group (<45 years). All bilateral breast cancers were duct cell carcinoma with a family history of first degree relative with breast cancer. The majority of the cases presented as moderately differentiated or grade 2 lesions (59.0%). Approximately 56% cancers had spread to the regional lymph nodes and 8.3% to a distant site at the time of diagnosis. A family history of first degree relative with breast cancer was present in 3% and second degree relatives in 7% of the cases. Odds ratio (OR) for 680 breast cancer cases with complete demographic information was calculated with 675 gender matched controls. A slightly higher risk was observed in non-Muslims and migrant ethnicities: two to three fold elevation in the Indian migrants (Gujrati speaking Mohajirs OR 3.86 (95% CI 2.51; 5.92) Urdu speaking Mohajirs OR 2.85 (95% CI 2.05; 3.96), Memon Mohajirs OR 2.21 (95% CI 1.48; 3.29) and Afghan migrants [OR 2.99 (95% CI 11.20; 7.44)]. The risk was also high in the females of Punjabi ethnicity settled in KS [OR 2.73 (95% CI 1.87; 3.99)]. The risk seems much less for the ethnicities belonging to North Western Pakistan i.e. Pathans [OR 1.684 (95% CI 0.89; 3.17)] and Baluchs [OR 0.90 (95% CI 0.58; 1.39)]. A marginally higher risk was observed in the higher socio-economic categories. The risk of developing breast cancer increased gradually for each age category from illiterate [OR 1.2 (95% CI 0.94; 1.55)] to college graduates [OR 13.12 (95% CI 7.31; 23.73)]. CONCLUSIONS: The incidence of breast cancer in Karachi South (KS) for the period 1995-1997 was the third highest in Asia. The hallmarks were a high reproductive age malignancy involving a higher socio-economic class, an invasive duct cell carcinoma diagnosed at an advanced stage, in younger more educated females and a low in-situ malignancy. More studies are required to obtain a deeper insight into this breast cancer epidemic in Karachi. Implementation of breast cancer screening with stress on public health education is today a major responsibility of the government.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Demografia , Escolaridade , Etnicidade , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Paquistão/epidemiologia , Sistema de Registros , Religião , Fatores SocioeconômicosRESUMO
AIMS: To establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. MATERIALS AND METHODS: A dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events - NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical - LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0-1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. RESULTS: Seventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29-0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6-30.5), k = 2.7 (0.9-4.5) (CLPS-IMRT) and 28.9 Gy (26.1-31.9), k = 2.4 (1.4-3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3-27.6), k = 1.9 (0.5-3.8); CLPS-IMRT 24.0 Gy (17.7-30.1), k = 2.1 (0.1-4.1). CONCLUSION: BSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Glândula Parótida/efeitos da radiação , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Xerostomia/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Xerostomia/etiologiaRESUMO
AIMS: To determine the toxicity and tumour control rates after chemo-intensity-modulated radiotherapy (chemo-IMRT) for locally advanced nasopharyngeal cancers (LA-NPC). MATERIALS AND METHODS: Patients with LA-NPC were enrolled in a trial to receive induction chemotherapy followed by parotid-sparing chemo-IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions and at risk nodal levels received 54 Gy in 30 fractions. Incidence of ≥grade 2 subjective xerostomia was the primary end point. Secondary end points included incidences of acute and late toxicities and survival outcomes. RESULTS: Forty-two patients with American Joint Committee on Cancer stages II (12%), III (26%) and IV (62%) (World Health Organization subtype: I [5%]; II [40%]; III [55%]) completed treatment between January 2006 and April 2010 with a median follow-up of 32 months. Incidences of ≥grade 2 acute toxicities were: dysphagia 83%; xerostomia 76%; mucositis 97%; pain 76%; fatigue 99% and ototoxicity 12%. At 12 months, ≥grade 2 subjective xerostomia was observed in 31%, ototoxicitiy in 13% and dysphagia in 4%. Two year locoregional control was 86.2% (95% confidence interval: 70.0-94.0) with 2 year progression-free survival at 78.4% (61.4-88.6) and 2 year overall survival at 85.9% (69.3-93.9). CONCLUSIONS: Chemo-IMRT for LA-NPC is feasible with good survival outcomes. At 1 year, 31% experience ≥grade 2 subjective xerostomia.
Assuntos
Quimiorradioterapia/métodos , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Idoso , Quimiorradioterapia/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/mortalidade , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodosRESUMO
Regulation of p53 gene expression at the post-transcriptional level was investigated during growth induction of human peripheral blood mononuclear cells (PBMCs). Freshly isolated PBMCs, which are in the Go phase of the cell cycle, were shown to express low levels of p53 mRNA that was rapidly degraded with a half life of 1 h. The rapid decay of p53 mRNA in quiescent PBMCs was dependent on global protein synthesis as treatment with cycloheximide resulted in stabilization of the p53 message. PBMCs were stimulated to enter the cell cycle by treatment with a combination of the mitogenic lectin phytohemagglutinin (PHA) and phorbol ester (TPA). Progressive stabilization of the p53 message occurred in PBMCs during growth induction. By 24 h of incubation in the presence of PHA and TPA, the half life of p53 mRNA was 6 h and p53 mRNA steady state levels were increased 4.5 to 5.0-fold. p53 protein was not detected in quiescent PBMCs, but was readily detected in PBMCs stimulated for 24 h with PHA and TPA. Stabilization of p53 mRNA was observed in PBMCs treated with either PHA or TPA, but to a lesser degree than when PHA and TPA were used as co-stimulants. These results indicate that differential degradation of p53 messenger RNA occurs in quiescent vs mitogen stimulated PBMCs and suggest that post-transcriptional regulation importantly contributes to increased p53 mRNA steady state levels as PBMCs enter the cell cycle.
Assuntos
Genes p53/genética , Leucócitos Mononucleares/citologia , Processamento Pós-Transcricional do RNA , Divisão Celular/genética , Cicloeximida/farmacologia , Humanos , Leucócitos Mononucleares/metabolismo , Mitógenos/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , RNA Mensageiro/sangue , Proteína Supressora de Tumor p53/sangueRESUMO
BACKGROUND: Leukocyte infiltration and serine elastase activity lead to smooth muscle cell proliferation in association with posttransplant coronary arteriopathy and may also be involved in vein graft neointimal formation. A number of therapies have targeted cellular proliferation, but the inhibition of serine elastase-mediated extracellular matrix remodeling has not been investigated as a potential strategy to prevent neointimal formation and subsequent atherosclerotic degeneration in vein grafts. METHODS AND RESULTS: We studied jugular vein grafts 48 hours after interposition into the carotid arteries of rabbits and demonstrated inflammatory cell infiltration and elevated serine elastase activity, a stimulus for matrix remodeling and deposition of elastin. Therefore, elastolytic activity in vein grafts was targeted through transient expression of the selective serine elastase inhibitor elafin with hemagglutinating virus of Japan liposome-mediated gene transfer. Elafin transfection reduced inflammation by 60% at 48 hours and neointimal formation by approximately 50% at 4 weeks after implantation. At 3 months, a 74% decrease in neointimal elastin deposition correlated with protection against cholesterol-induced macrophage infiltration and lipid accumulation, which were both reduced by approximately 50% in elafin-transfected grafts relative to controls. CONCLUSIONS: Gene transfer of the selective serine elastase inhibitor elafin in vein grafts is effective in reducing the early inflammatory response. Although transient expression of elafin delays neointimal formation, it is also sufficient to cause an alteration in elastin content of the extracellular matrix, making it relatively resistant to atherosclerotic degeneration.
Assuntos
Oclusão de Enxerto Vascular/prevenção & controle , Veias Jugulares/transplante , Proteínas/administração & dosagem , Proteínas/genética , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/genética , Animais , Arteriosclerose/enzimologia , Arteriosclerose/patologia , Arteriosclerose/prevenção & controle , Artérias Carótidas/cirurgia , Modelos Animais de Doenças , Elastina/metabolismo , Matriz Extracelular/enzimologia , Técnicas de Transferência de Genes , Oclusão de Enxerto Vascular/enzimologia , Oclusão de Enxerto Vascular/patologia , Imuno-Histoquímica , Veias Jugulares/efeitos dos fármacos , Veias Jugulares/enzimologia , Lipossomos , Proteínas Secretadas Inibidoras de Proteinases , Proteínas/metabolismo , Coelhos , Respirovirus/genética , Inibidores de Serina Proteinase/metabolismo , Transfecção , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologiaAssuntos
Artérias/anormalidades , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Hérnias Diafragmáticas Congênitas , Mutação , Doenças Cardiovasculares/congênito , Hérnia Diafragmática/complicações , Humanos , SíndromeAssuntos
Mutação de Sentido Incorreto/genética , Neutropenia/congênito , Neutropenia/genética , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Sequência de Bases , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Proteínas/químicaRESUMO
The biochemical response of pulmonary tissue to MnO2 dust burden of 30 days duration was studied in rats. The activities of enzymes from isolated fractions of rat lungs were not significantly altered, even though manganese content was increased significantly in tissues remote from lungs, indicating translocation of the dust from its intrapulmonary location.
Assuntos
Manganês , Pneumoconiose , Animais , Modelos Animais de Doenças , Poeira , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Manganês/metabolismo , Pneumoconiose/enzimologia , Pneumoconiose/patologia , Proteínas/metabolismo , Ratos , Distribuição TecidualRESUMO
The pulmonary angiothrombotic lesions in narcotic addicts attributed to the talc present in drug tablets were studied experimentally in guinea pigs following repeated intravenous administration of a suspension of talc dust (75 mg per animal). In early periods there was a moderate localization of talc particles in the alveolar capillaries of lung, liver and abdominal lymph nodes. The vascular injury in the pulmonary tissue was in the form of mild proliferation of the endothelial cells. In addition, many nodular collections comprising macrophages and lymphocytes developed around such vascular structures. At later periods (150 days) the only significant reaction obtained was moderate thickening of interalveolar septa and the lesions were in no way comparable to the human reports. The significance of these findings has been discussed.
Assuntos
Pulmão/efeitos dos fármacos , Talco/toxicidade , Animais , Cobaias , Injeções Intravenosas , Fígado/efeitos dos fármacos , Masculino , Talco/administração & dosagemRESUMO
Histopathological changes in the tracheo-bronchial lymph nodes were studied up to 365 days in guinea pigs following intratracheal injection of a suspension of mica dust. In general, the cytotoxic effect provoked by dust was not pronounced as the majority of the swollen dust-laden macrophages retained their normal structure at the termination of the experiment and fibrotic lesions were limited to the formation of thick reticulin fibers. The poor fibrogenic response of mica dust has been attributed to its low cytotoxicity.
Assuntos
Silicatos de Alumínio/farmacologia , Poeira , Linfonodos/efeitos dos fármacos , Silicatos de Alumínio/administração & dosagem , Animais , Feminino , Cobaias , Intubação Intratraqueal , Linfonodos/anatomia & histologia , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Fatores de TempoRESUMO
We evaluated the efficacy and toxicity of gemcitabine with or without cisplatin in 11 chemonaive patients with histologically confirmed advanced gallbladder cancer. All were symptomatic and had stage IV disease. Eight patients received gemcitabine 1 g/m2 on days 1 and 8 along with cisplatin 70 mg/m2 on day 1. Three received gemcitabine alone. Treatment cycles were repeated every 21 days. One patient (9%) had complete remission of disease and 6 (55%) achieved a partial response to chemotherapy with an overall response rate of 64%. Median time to progression was 28 weeks and median overall survival was 42 weeks. Toxicity was easily manageable, and no treatment-related deaths occurred. We conclude that gemcitabine in combination with cisplatin may be one of the most effective therapies for patients with advanced gallbladder cancer. If confirmed by others, it may provide an important therapeutic option in managing these patients who otherwise have a dismal prognosis.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Neoplasias da Vesícula Biliar/tratamento farmacológico , Adenocarcinoma/secundário , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , GencitabinaRESUMO
The contents of collagen, hexosamine, phospholipids, and cholesterol and the activities of acid and alkaline phosphatases, glutamic oxalo-acetate transaminase, glutamic pyruvate transminase, aldolase, hexokinase, and lactic dehydrogenase were determined in the lungs of rats 150 days after the intratracheal injection of amosite, anthophyllite, and chyrsotile. Anthophyllite did not cause any significant change, while amosite and chrysotile caused significant increases in the contents of collagen and mucopolysaccharides. Lactic dehydrogenase and acid phosphatase activities were increased by all the dusts, while the othe enzymes were not seriously affected. The biochemical significance of the findings in relation to abestosis was discussed.