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1.
Immunity ; 50(6): 1513-1529.e9, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31126879

RESUMO

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

2.
Infection ; 47(2): 257, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805900

RESUMO

In this article the cooperating partners of the ClinSurv HIV cohort were not listed in the acknowledgements. The correct paragraph appears below.

3.
Infection ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30414065

RESUMO

PURPOSE: The aim of the study was to assess guideline adherence to combined antiretroviral therapy (ART) in the German ClinSurv HIV Cohort and the real-life impact of the Strategic Timing of Antiretroviral Therapy (START) study, to identify patients not treated as recommended by new guidelines. METHODS: We used data from the multicenter ClinSurv cohort of the Robert-Koch-Institute (RKI) between 1999 and 2016. Inclusion criteria were people living with HIV/AIDS, ≥ 18 years of age and cART naïve at the first visit (FV). Adherence was defined as starting cART within 6 months of crossing the CD4+ T cell threshold as suggested by the German-Austrian treatment guidelines. Logistic regression was used to identify factors associated with non-adherence. RESULTS: 11,817 patients met the inclusion criteria. We observed an overall adherence rate of 60%, in patients with treatment indication who started cART timely between 2002 and 2015. Adherence rate increased constantly, demonstrating a potential increase in patients, with treatment indication, starting cART within 6 months of presentation from 55% in 2008 to 94% in 2015. Patients reporting injection drug use (OR 2.18, 95% CI 1.70-2.95) and patients between 18 years and 39 years of age at the time of their first visit (OR 2.89, 95% CI 1.35-6.18) were identified as risk groups associated with non-adherence. CONCLUSION: The majority of patients below the CD4+ T cell count threshold of applicable guidelines initiated treatment within 6 months. We observed a slowly diminishing proportion of patients not starting cART timely. Delayed treatment was more frequent in patients reporting injection drug use.

4.
AIDS ; 32(10): 1361-1367, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29851663

RESUMO

OBJECTIVE: Model trajectories of CD4 and CD8 cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4 : CD8 ratio. DESIGN: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. METHODS: We jointly estimated CD4 and CD8 cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4 : CD8 ratio trend from this model. We assessed whether CD4 and CD8 cell count trends and the CD4 : CD8 ratio trend varied according to CD4 cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS: A total of 39 979 patients were included (median follow-up was 53 months). Among patients with baseline CD4 cell count at least 50 cells/µl, predicted mean CD8 cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4 : CD8 ratio. During 15 years of follow-up, normalization of the predicted mean CD4 : CD8 ratio (to >1) was only observed among patients with baseline CD4 cell count at least 200 cells/µl. A higher baseline CD4 cell count predicted a shorter time to normalization. CONCLUSION: Declines in CD8 cell count and increases in CD4 : CD8 ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4 : CD8 ratio is strongly related to baseline CD4 cell count.

5.
AIDS ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29734221

RESUMO

OBJECTIVE: Model trajectories of CD4 and CD8 cell counts after starting combination antiretroviral therapy (ART), and use the model to predict trends in these counts and the CD4:CD8 ratio. DESIGN: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with >6 months of follow-up data. METHODS: We jointly estimated CD4 and CD8 count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4:CD8 ratio trend from this model. We assessed whether CD4 and CD8 count trends and the CD4:CD8 ratio trend varied according to CD4 count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS: A total of 39,979 patients were included (median follow-up was 53 months). Among patients with baseline CD4 count ≥50 cells/mm, predicted mean CD8 counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4:CD8 ratio. During 15 years of follow-up, normalisation of the predicted mean CD4:CD8 ratio (to >1) was only observed among patients with baseline CD4 count ≥200 cells/mm. A higher baseline CD4 count predicted a shorter time to normalisation. CONCLUSIONS: Declines in CD8 count and increases in CD4:CD8 ratio occurred up to 15 years after starting ART. The likelihood of normalisation of the CD4:CD8 ratio is strongly related to baseline CD4 count.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

6.
Haematologica ; 103(5): 857-864, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29439188

RESUMO

Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate.

7.
Clin Infect Dis ; 65(6): 959-966, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903507

RESUMO

Background: We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count. Methods: We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy (ART)-naive adults who started ART during 1996-2010, who were followed from the date they had CD4 count ≥350 cells/µL and were virologically suppressed (baseline). We used stratified Cox models to estimate unadjusted and adjusted (for sex, people who inject drugs, ART initiation year, and baseline age, CD4 count, AIDS, duration of ART) all-cause and cause-specific mortality hazard ratios for tertiles of CD4:CD8 ratio (0-0.40, 0.41-0.64 [reference], >0.64) and CD8 count (0-760, 761-1138 [reference], >1138 cells/µL) and examined the shape of associations using cubic splines. Results: During 276526 person-years, 1834 of 49865 patients died (249 AIDS-related; 1076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11 (95% confidence interval [CI], 1.00-1.25). The association of CD8 count with all-cause mortality was U-shaped: aHR for higher vs middle tertile was 1.13 (95% CI, 1.01-1.26). AIDS-related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. There was little evidence that CD4:CD8 ratio or CD8 count was prognostic for non-AIDS mortality. Conclusions: In this large cohort collaboration, the magnitude of adjusted associations of CD4:CD8 ratio or CD8 count with mortality was too small for them to be useful as independent prognostic markers in virally suppressed patients on ART.


Assuntos
Relação CD4-CD8 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Causas de Morte , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Carga Viral , Adulto Jovem
8.
Cell Host Microbe ; 22(1): 111-119.e4, 2017 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-28704647

RESUMO

It was widely accepted that HIV-1 downregulates HLA-A/B to avoid CTL recognition while leaving HLA-C unaltered in order to prevent NK cell activation by engaging inhibitory NK cell receptors, but it was recently observed that most primary isolates of HIV-1 can mediate HLA-C downmodulation. Now we report that HIV-1-mediated downmodulation of HLA-C was associated with reduced binding to its respective inhibitory receptors. Despite this, HLA-C-licensed NK cells displayed reduced antiviral activity compared to their unlicensed counterparts, potentially due to residual binding to the respective inhibitory receptors. Nevertheless, NK cells were able to sense alterations of HLA-C expression demonstrated by increased antiviral activity when exposed to viral strains with differential abilities to downmodulate HLA-C. These results suggest that the capability of HLA-C-licensed NK cells to control HIV-1 replication is determined by the strength of KIR/HLA-C interactions and is thus dependent on both host genetics and the extent of virus-mediated HLA-C downregulation.


Assuntos
Antivirais/metabolismo , Infecções por HIV/metabolismo , HIV-1/fisiologia , Antígenos HLA-C/metabolismo , Células Matadoras Naturais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Células HEK293 , HIV-1/genética , Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Humanos , Ativação Linfocitária , Receptores KIR2DL1/metabolismo , Receptores KIR2DL3/metabolismo , Replicação Viral/fisiologia
9.
Mol Metab ; 6(7): 737-747, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28702329

RESUMO

OBJECTIVE: Metformin, the first line drug for treatment of type 2 diabetes, suppresses hepatic gluconeogenesis and reduces body weight in patients, the latter by an unknown mechanism. METHODS: Mice on a high fat diet were continuously fed metformin in a therapeutically relevant dose, mimicking a retarded formulation. RESULTS: Feeding metformin in pharmacologically relevant doses to mice on a high fat diet normalized HbA1c levels and ameliorated glucose tolerance, as expected, but also considerably slowed down weight gain. This was due to increased energy expenditure, since food intake was unchanged and locomotor activity was even decreased. Metformin caused lactate accumulation in the intestinal wall and in portal venous blood but not in peripheral blood or the liver. Increased conversion of glucose-1-13C to glucose-1,6-13C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver. CONCLUSIONS: The reported glucose-lactate-glucose cycle is a highly energy consuming process, explaining the beneficial effects of metformin given continuously on the development of a type 2 diabetic-like state in our mice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético , Hipoglicemiantes/farmacologia , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Metformina/farmacologia , Animais , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Mucosa Intestinal/metabolismo , Ácido Láctico/sangue , Fígado/metabolismo , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL
10.
Ann Intern Med ; 166(1): 9-17, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27750294

RESUMO

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. Objective: To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIV-infected patients. Design: Cohort study. Setting: 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Patients: HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Measurements: Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. Results: A total of 52 479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40 219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100 000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Limitation: Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. Conclusion: In HIV-infected patients receiving ART, chronic co-infection with HBV and HCV is associated with an increased risk for NHL. Primary Funding Source: European Union Seventh Framework Programme.


Assuntos
Infecções por HIV/complicações , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Linfoma não Hodgkin/complicações , Adulto , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Anticorpos Anti-Hepatite/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite C/imunologia , Hepatite C Crônica/diagnóstico , Humanos , Imunoglobulina G/sangue , Linfoma não Hodgkin/mortalidade , Masculino , RNA Viral/sangue , Fatores de Risco
11.
Diabetes ; 65(9): 2540-52, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27284107

RESUMO

Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.


Assuntos
Bezafibrato/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina/fisiologia , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Consumo de Oxigênio/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores
12.
AIDS ; 30(5): 753-60, 2016 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-26605513

RESUMO

OBJECTIVE: The risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is increased in HIV-infected individuals. We studied the kinetics of lymphocyte subsets in patients who subsequently developed HL or NHL while on virologically suppressive antiretroviral therapy (ART). DESIGN: Using a nested case-control design, cases of HIV+ HL or NHL were selected from two prospective clinical studies. Aviremia was defined as less than 200 HIV-RNA copies/ml for at least 6 months prior to lymphoma diagnosis. Each case was matched to three aviremic HIV+ controls without lymphoma. RESULTS: In the 81 cases (50 HL and 31 NHL), prediagnostic CD4 T cells and CD8 T cells displayed discordant kinetics compared with controls. Within the last and within the next-to-last year preceding HL diagnosis, mean CD4 T cells decreased by -168 and by -2 cells/µl, compared with an increase of +44 and +73 cells/µl in the controls, respectively. Mean CD8 T cells decreased by -352 and -115 cells/µl, compared with nonsignificant changes of -29 and ±0 cells/µl in the controls, respectively. T-cell kinetics demonstrated a marked inter-individual variability. Kinetics of CD4 and CD8 T cells were also discordant between NHL cases and controls. CONCLUSION: This study on a large number of aviremic patients developing HL and NHL who were carefully matched with controls, gives insights to prediagnostic kinetics of immune parameters. The discordant kinetics of both CD4 and CD8 T cells are already seen 1-2 years prior to lymphoma diagnosis, are more pronounced during the last year and in patients developing HL but are also seen in NHL.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/complicações , Doença de Hodgkin/patologia , Linfoma não Hodgkin/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
13.
Br J Haematol ; 168(6): 806-10, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25403997

RESUMO

Overall survival (OS) of patients with acquired immunodeficiency syndrome (AIDS)-related Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) was analysed in the German AIDS-related-Lymphoma-Cohort-Study. Of 291 patients prospectively included between January 2005 and December 2012, 154 had DLBCL, 103 BL and 34 PBL. Two-year OS rates were similar between BL (69%) and DLBCL patients (63%) but lower for PBL patients (43%). Intermediate (Hazard ratio [HR] 4·1 95% confidence interval [CI] 1·98-8·49) or high (HR 4·92 95% CI 2·1-11·61) International Prognostic Index, bone marrow involvement (HR 1·69 95% CI 1·00-2·84) and PBL histology (HR 2·24 95% CI 1·24-4·03) were independent predictors of mortality.


Assuntos
Linfoma de Burkitt/mortalidade , HIV-1 , Linfoma Relacionado a AIDS/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Adulto , Idoso , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/imunologia , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Linfoma Relacionado a AIDS/diagnóstico , Linfoma Relacionado a AIDS/imunologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
14.
Leuk Lymphoma ; 55(10): 2341-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24397614

RESUMO

The results of intensive immunochemotherapy were analyzed in human immunodeficiency virus (HIV)-related Burkitt lymphoma/leukemia (BLL) in two cohorts (Spain and Germany). Alternating cycles of chemotherapy were administered, with dose reductions for patients over 55 years. Eighty percent of patients achieved remission, 11% died during induction, 9% failed and 7% died in remission. Four-year overall survival (OS) and progression-free survival (PFS) probabilities were 72% (95% confidence interval [CI]: 62-82%) and 71% (95% CI: 61-81%). CD4 T-cell count < 200/µL and bone marrow involvement were associated with poor OS (hazard ratio [HR] 3.2 [1.2-8.3] and HR 2.7 [1.1-6.6]) and PFS (HR 3.5 [1.3-9.1] and HR 2.4 [1-5.7]), bone marrow involvement with poor disease-free survival (DFS) (HR 14.4 [1.7-119.7] and Eastern Cooperative Oncology Group (ECOG) score > 2 (odds ratio [OR] 11.9 [1.4-99.9]) with induction death. In HIV-related BLL, intensive immunochemotherapy was feasible and effective, but toxic. Prognostic factors were performance status, CD4 T-cell count and bone marrow involvement.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/etiologia , Infecções por HIV/complicações , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Linfoma de Burkitt/mortalidade , Linfoma de Burkitt/patologia , Estudos de Coortes , Feminino , Alemanha , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Rituximab , Espanha , Resultado do Tratamento , Adulto Jovem
15.
J Hepatol ; 60(4): 816-23, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24291365

RESUMO

BACKGROUND & AIMS: To determine if diabetic and insulin-resistant states cause mitochondrial dysfunction in liver or if there is long term adaptation of mitochondrial function to these states, mice were (i) fed with a high-fat diet to induce obesity and T2D (HFD), (ii) had a genetic defect in insulin signaling causing whole body insulin resistance, but not full blown T2D (IR/IRS-1(+/-) mice), or (iii) were analyzed after treatment with streptozocin (STZ) to induce a T1D-like state. METHODS: Hepatic lipid levels were measured by thin layer chromatography. Mitochondrial respiratory chain (RC) levels and function were determined by Western blot, spectrophotometric, oxygen consumption and proton motive force analysis. Gene expression was analyzed by real-time PCR and microarray. RESULTS: HFD caused insulin resistance and hepatic lipid accumulation, but RC was largely unchanged. Livers from insulin resistant IR/IRS-1(+/-) mice had normal lipid contents and a normal RC, but mitochondria were less well coupled. Livers from severely hyperglycemic and hypoinsulinemic STZ mice had massively depleted lipid levels, but RC abundance was unchanged. However, liver mitochondria isolated from these animals showed increased abundance and activity of the RC, which was better coupled. CONCLUSIONS: Insulin resistance, induced either by obesity or genetic manipulation and steatosis do not cause mitochondrial dysfunction in mouse liver. Also, mitochondrial dysfunction is not a prerequisite for liver steatosis. However, severe insulin deficiency and high blood glucose levels lead to an enhanced performance and better coupling of the RC. This may represent an adaptation to fuel overload and the high energy-requirement of an unsuppressed gluconeogenesis.


Assuntos
Adaptação Fisiológica , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina/fisiologia , Mitocôndrias Hepáticas/fisiologia , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/fisiopatologia , Expressão Gênica , Proteínas Substratos do Receptor de Insulina/deficiência , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Canais Iônicos/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade/etiologia , Obesidade/fisiopatologia , Fosforilação Oxidativa , Força Próton-Motriz , Receptor de Insulina/deficiência , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais , Proteína Desacopladora 2
16.
Haematologica ; 98(11): 1762-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23975176

RESUMO

High-dose chemotherapy with autologous peripheral blood stem cell rescue has been reported as feasible and effective in HIV-associated lymphoma. Although a sufficient number of stem cells seems achievable in most patients, there are cases of stem cell harvest failure. The aim of this study was to describe the mobilization policies used in HIV-associated lymphoma, evaluate the failure rate and identify factors influencing mobilization results. We analyzed 155 patients who underwent attempted stem cell mobilization at 10 European centers from 2000-2012. One hundred and twenty patients had non-Hodgkin lymphoma and 35 Hodgkin lymphoma; 31% had complete remission, 57% chemosensitive disease, 10% refractory disease, 2% untested relapse. Patients were mobilized with chemotherapy + G-CSF (86%) or G-CSF alone (14%); 73% of patients collected >2 and 48% >5 × 10(6) CD34(+) cells/kg. Low CD4+ count and refractory disease were associated with mobilization failure. Low CD4(+) count, low platelet count and mobilization with G-CSF correlated with lower probability to achieve >5 × 10(6) CD34(+) cells/kg, whereas cyclophosphamide ≥ 3 g/m(2) + G-CSF predicted higher collections. Circulating CD34(+) cells and CD34/WBC ratio were strongly associated with collection result. HIV infection alone should not preclude an attempt to obtain stem cells in candidates for autologous transplant as the results are comparable to the HIV-negative population.


Assuntos
Soropositividade para HIV/terapia , Mobilização de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Linfoma não Hodgkin/terapia , Adulto , Idoso , Feminino , Soropositividade para HIV/diagnóstico , Soropositividade para HIV/epidemiologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/epidemiologia , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
17.
AIDS ; 27(5): 842-5, 2013 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23574794

RESUMO

Out of 302 AIDS-related lymphoma (ARL) patients enrolled in the German ARL cohort study, 18 patients had plasmablastic lymphoma (PBL). Twelve out of 18 patients (67%) have died with a median survival of 4 months (range 0-11 months). In univariate analysis, an intermediate or high international prognostic index score was associated with a significantly lower overall survival and progression-free survival. The predominant cause of death was progressive lymphoma (67%). Our data indicate that the outcome of AIDS-related PBL is still very poor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/mortalidade , Linfoma Relacionado a AIDS/mortalidade , Linfoma não Hodgkin/mortalidade , Adulto , Idoso , Análise de Variância , Estudos de Coortes , Alemanha , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/etiologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
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