RESUMEN

During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat AT1 epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if ß1-containing integrins are required during repair following acute injury, we administered E. coli lipopolysaccharide (LPS) by intratracheal injection to mice with a postdevelopmental deletion of ß1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, ß1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells coexpressing AT2 epithelial, AT1 epithelial, and mixed intermediate cell state markers, with few mature type 1 cells. AT2 cells deficient in ß1 showed persistently increased proliferation after injury, which was blocked by inhibiting NF-κB activation in these cells. Lineage tracing experiments revealed that ß1-deficient AT2 cells failed to differentiate into mature AT1 epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires ß1-containing integrins.

Asunto(s)

Enfisema , Lipopolisacáridos , Ratones , Animales , Lipopolisacáridos/toxicidad , Escherichia coli , Pulmón , Integrinas

RESUMEN

BACKGROUND: Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC. METHODS: This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. RESULTS: The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached. CONCLUSIONS: Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.

Asunto(s)

Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Diferenciación Celular , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anilidas/administración & dosificación , Anilidas/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma/enzimología , Carcinoma/mortalidad , Carcinoma/secundario , Supervivencia sin Enfermedad , Esquema de Medicación , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Estados Unidos

RESUMEN

OBJECTIVES: Therapeutic HIV vaccinations may alter the size of the resting memory CD4 T-cell latent HIV reservoir as HIV establishes latency when memory responses are formed, including those toward HIV. Alternatively, latently infected CD4 T cells maybe killed, while exiting the reservoir upon activation. METHODS: The effect of therapeutic immunization with modified vaccinia Ankara and Fowlpox-based HIV vaccines on the latent reservoir was examined in 19 young adults who were receiving effective antiretroviral therapy. Correlations between size of the reservoir [measured in infectious units per million (IUPM)] resting CD4 T cells and HIV-specific immune responses, including immune activation were examined. Decay of the reservoir was assessed using random-effects model. RESULTS: A modest transient decrease in the size of the reservoir was observed at week 40 [mean -0.31 log(10) IUPM (95% confidence interval: -0.60 to -0.03; P = 0.03] following HIV vaccinations. The estimated half-life (T1/2) of the reservoir during the 40 weeks following vaccination was 9.8 months and statistically different from zero (P = 0.02), but 35.3 months and not different from zero (P = 0.21) over 72 weeks of study. Latent reservoir size at baseline was not correlated with HIV-specific CD4, CD8 responses or immune activation, but became correlated with CD4 IFNγ (r = 0.54, P = 0.02) and IL-2 responses at 6 weeks after immunization (r = 0.48, P = 0.04). CONCLUSION: Therapeutic HIV vaccinations led to a transient increase in decay of latently infected CD4 T cells. Further studies of therapeutic HIV vaccines may provide important insights into facilitating decay of the latent reservoir.

Asunto(s)

Vacunas contra el SIDA/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Vacunas contra el SIDA/inmunología , Infecciones por VIH/virología , Humanos , Resultado del Tratamiento , Vacunación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Adulto Joven

RESUMEN

We previously reported high deltamethrin resistance in bed bugs, Cimex lectularius, collected from multiple areas of the United States (Romero et al., 2007). Recently, two mutations, the Valine to Leucine mutation (V419L) and the Leucine to Isoleucine mutation (L925I) in voltage-gated sodium channel alpha-subunit gene, had been identified to be responsible for knockdown resistance (kdr) to deltamethrin in bed bugs collected from New York (Yoon et al., 2008). The current study was undertaken to investigate the distribution of these two kdr mutations in 110 bed bug populations collected in the United States. Out of the 17 bed bug populations that were assayed for deltamethrin susceptibility, two resistant populations collected in the Cincinnati area and three deltamethrin-susceptible lab colonies showed neither of the two reported mutations (haplotype A). The remaining 12 populations contained L925I or both V419L and L925I mutations in voltage-gated sodium channel alpha-subunit gene (haplotypes B&C). In 93 populations that were not assayed for deltamethrin susceptibility, 12 contained neither of the two mutations (haplotype A) and 81 contained L925I or V419L or both mutations (haplotypes B-D). Thus, 88% of the bed bug populations collected showed target-site mutations. These data suggest that deltamethrin resistance conferred by target-site insensitivity of sodium channel is widely spread in bed bug populations across the United States.

Asunto(s)

Chinches/genética , Resistencia a los Insecticidas/genética , Insecticidas , Nitrilos , Mutación Puntual , Piretrinas , Canales de Sodio/genética , Alelos , Animales , Chinches/crecimiento & desarrollo , ADN/química , ADN/genética , Reacción en Cadena de la Polimerasa , Estados Unidos

RESUMEN

Treatment failure and drug resistance create obstacles to long-term management of HIV-1 infection. Nearly 60% of infected persons fail their first highly active antiretroviral therapy (HAART) regimen, partially because of nonadherence, requiring a switch to a second regimen to prevent drug resistance. Among HIV-infected youth, a group with rising infection rates, treatment switch is often delayed; virologic and immunologic consequences of this delay are unknown. We conducted a retrospective, longitudinal study of drug resistance outcomes of initial HAART in U.S. youth enrolled between 1999-2001 in a multicenter, observational study and experiencing delayed switch in their first nonsuppressive treatment regimen for up to 3 years. HIV-1 genotyping was performed on plasma samples collected longitudinally, and changes in drug resistance mutations, CD4+ T cell numbers and viral replication capacity were assessed. Forty-four percent (n = 18) of youth in the parent study experiencing virologic nonsuppression were maintained on their initial HAART regimen for a median of 144 weeks. Drug resistance was detected in 61% (11/18) of subjects during the study. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (8/10) drug resistance mutations than those on protease-inhibitor (PI) regimens (2/7) (p = 0.058). Subjects developing NNRTI-resistance (NNRTI-R), showed a trend toward lower CD4+ T cell gains (median: -6 cells/mm(3) per year) than those without detectable NNRTI-R (median: +149 cells/mm(3) per year) (p = 0.16). HIV-1-infected youth maintained on initial nonsuppressive NNRTI-based HAART regimens are more likely to develop drug-resistant viremia than with PI-based HAART. This finding may have implications for initial treatment regimens and transmission risk in HIV-infected youth, a group with rising infection rates.

Asunto(s)

Fármacos Anti-VIH/farmacología , Terapia Antirretroviral Altamente Activa , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Esquema de Medicación , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , Masculino , Datos de Secuencia Molecular , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Análisis de Secuencia de ADN , Insuficiencia del Tratamiento , Carga Viral , Replicación Viral

RESUMEN

A longitudinal study of viral reservoirs in children initiating highly active antiretroviral therapy (HAART) in early infancy was undertaken to test the hypothesis that early effective treatment affects the persistence of replication-competent viral latency and the evolution of HIV-1 in resting CD4(+) T cells. An end point dilution culture assay was used to measure the frequencies of latently-infected resting CD4(+) T cells harboring replication-competent virus in early and late treated children. Gag, pol, and env also were sequenced and compared to pretreatment sequences. HIV-1-specific humoral and cellular immune responses were also assessed. Blood samples were obtained from 12 HIV-1-infected children who started HAART at a median of 1.9 months of age and who maintained suppression of HIV-1 replication for up to 5.5 years. Replication-competent HIV-1 was recovered from 10/12 (84%) subjects. Evolution in gag, pol, and env was restricted for years in early-treated children. HAART initiated from early infancy does not prevent the establishment of a reservoir of latent provirus, but does significantly limit the evolution of HIV-1 in viral reservoirs. The effect of early therapy on HIV-1 evolution may have implications for long-term pharmacologic control of HIV-1.

Asunto(s)

Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/virología , Evolución Molecular , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Latencia del Virus/fisiología , Replicación Viral/fisiología , Preescolar , Esquema de Medicación , Genes env/genética , Genes pol/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Filogenia , ARN Viral/sangre , Carga Viral , Latencia del Virus/genética