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1.
Cancer Sci ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34716979

RESUMO

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.

2.
Breed Sci ; 71(2): 208-216, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34377069

RESUMO

Epicotyl length (ECL) of adzuki bean (Vigna angularis) affects the efficiency of mechanized weeding and harvest. The present study investigated the genetic factors controlling ECL. An F2 population derived from a cross between the breeding line 'Tokei1121' (T1121, long epicotyls) and the cultivar 'Erimo167' (common epicotyls) was phenotyped for ECL and genotyped using simple sequence repeats (SSRs) and single-nucleotide polymorphism (SNP) markers. A molecular linkage map was generated and fifty-two segregating markers, including 27 SSRs and 25 SNPs, were located on seven linkage groups (LGs) at a LOD threshold value of 3.0. Four quantitative trait loci (QTLs) for ECL, with LOD scores of 4.0, 3.4, 4.8 and 6.4, were identified on LGs 2, 4, 7 and 10, respectively; together, these four QTLs accounted for 49.3% of the phenotypic variance. The segregation patterns observed in F5 residual heterozygous lines at qECL10 revealed that a single recessive gene derived from T1121 contributed to the longer ECL phenotype. Using five insertion and deletion markers, this gene was fine mapped to a ~255 kb region near the end of LG10. These findings will facilitate marker-assisted selection for breeding in the adzuki bean and contribute to an understanding of the mechanisms associated with epicotyl elongation.

3.
Sci Rep ; 11(1): 14146, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238999

RESUMO

Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.


Assuntos
Indóis/sangue , Serotonina/metabolismo , Choque Séptico/sangue , Quinases Associadas a rho/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Permeabilidade Capilar/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Choque Séptico/metabolismo , Choque Séptico/patologia
4.
Virchows Arch ; 478(6): 1161-1171, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33423127

RESUMO

Uterine carcinosarcoma (UCS) is an uncommon and highly aggressive tumor. There is no HER2 testing protocol for UCS despite the development of HER2 antibody conjugates. We aimed to elucidate histopathological HER2 expression details in UCS, to compare HER2 scores between ASCO/CAP criteria for gastric and breast cancer, and to propose requirements for HER2 testing for UCS. Eighty-nine specimens from 84 patients with metastatic/recurrent UCS were prospectively collected from May 2018 to July 2020. We performed HER2 immunohistochemistry (IHC) for 89 specimens and FISH for 44 specimens. HER2 expression details and HER2 score were evaluated according to the latest ASCO/CAP criteria for gastric (2016) and breast cancer (2018). HER2 IHC scores according to the gastric cancer criteria were 0 in 31 cases (35%), 1+ in 26 (29%), 2+ in 22 (25%), and 3+ in 10 cases (11%) of the 89 specimens. A lateral/basolateral membranous staining pattern was observed in 28/32 (88%) specimens with HER2 scores of 2+/3+. HER2 intratumoral heterogeneity was identified in 28/32 (88%) of the specimens with HER2 scores of 2+/3+. The overall concordance rate of HER2 score was 70% between the gastric and breast criteria. FISH revealed HER2 gene amplification in 10/44 (23%) specimens containing only lateral/basolateral membranous staining pattern. Based on the histopathological features of HER2 expression in UCS, a scoring system that accepts lateral/basolateral staining patterns should be applied. Furthermore, we proposed specific requirements for UCS testing, including specimen selection, scoring system, and calculating the proportion of HER2-positive cells.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Amplificação de Genes/genética , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/terapia , Carcinossarcoma/genética , Carcinossarcoma/metabolismo , Carcinossarcoma/terapia , Feminino , Amplificação de Genes/fisiologia , Humanos , Hibridização in Situ Fluorescente/métodos , Pessoa de Meia-Idade , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Neoplasias Uterinas/patologia
5.
Oral Dis ; 27(6): 1339-1342, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33140899
6.
Opt Express ; 28(25): 37188-37198, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33379557

RESUMO

We investigated the switching dynamics of optical modulators consisting of a Si waveguide with a VO2 cladding layer by utilizing the photothermal effect, which induces a metal-insulator transition in VO2. The devices exhibited stable optical switching with a high extinction ratio exceeding 16 dB. The switching time of the insulator-to-metal transition (heating process) ranged from tens of nanoseconds to microseconds depending on the incident light power, and that of the metal-to-insulator transition (cooling process) was several microseconds regardless of the incident light power. The heat transfer in the devices was numerically simulated to reproduce the switching characteristics and revealed that the temperature change in the first few micrometers of the VO2/Si waveguide governed the switching time. The thermal structural design of the device is thus of key importance to improve the switching speed of the device.

7.
Pharmaceut Med ; 34(5): 315-326, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33030675

RESUMO

Medical science liaisons (MSLs) are field-based professionals sited in medical affairs (MA) departments who contribute to the generation of medical evidence and exchange advanced medical and scientific information with healthcare professionals to standardize treatments and maximize the value of medical products for patient outcomes. As such, it is essential for companies to have MSL training programs that cover areas such as advanced scientific expertise, pharmaceutical regulations, and medical communication proficiency and to certify the knowledge and skills that enable MSLs to perform their tasks effectively. The lack of a standardized training curriculum, assessment of MSL capabilities, and key performance indicators (KPIs) in Japan has made it difficult for MSLs to carry out these tasks. It is important to clarify the status of MSLs in MA divisions within the Japanese pharmaceutical industry. The mission of the Japanese Association of Pharmaceutical Medicine (JAPhMed) is to promote pharmaceutical medicine by enhancing the knowledge, expertise, and skills of pharmaceutical professionals. JAPhMed established an accreditation system for the MSL certification programs of individual companies in early 2015 and then embarked on defining the individual MSL qualifications from late 2015 to mid-2017. Here, we describe the MSL recommendation that covers (1) MA in Japan, (2) definition of MSL, (3) roles and activities of MSLs, (4) regulation and compliance for MSLs, (5) qualification requirements for MSLs, (6) KPIs for MSLs, and (7) a training curriculum for MSLs. In the training curriculum, JAPhMed considered the relevance of each part of the training curriculum in terms of the fixed roles and activities of MSLs.


Assuntos
Certificação/normas , Indústria Farmacêutica/normas , Pessoal de Saúde/normas , Papel Profissional , Currículo , Pessoal de Saúde/educação , Humanos , Japão , Descrição de Cargo
8.
Nihon Yakurigaku Zasshi ; 155(5): 332-339, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879176

RESUMO

Tedizolid, a novel oxazolidinone antibacterial agent, is a protein synthesis inhibitor that acts on bacterial ribosomes to inhibit initiation of translation. Tedizolid phosphate, a prodrug of tedizolid, is rapidly converted to the active form of tedizolid by phosphatase after administration. Tedizolid has antimicrobial activity mainly against gram-positive pathogens, and generally shows 4-8 times stronger in vitro activity than linezolid, an oxazolidinone antibacterial agent. Tedizolid has antimicrobial activity against Staphylococcus aureus (S. aureus) regardless of being methicillin-resistant or susceptible, with 90% minimum inhibitory concentrations (MIC90) ranging from 0.25-0.5 µg/mL. Although antimicrobial activity of tedizolid against linezolid-resistant S. aureus (LRSA) is generally reduced, tedizolid is still active to LRSA whose linezolid resistance is caused by cfr gene. Structure-activity relationship analysis suggests that the C-5 hydroxymethyl group, the C-ring pyridine, and the D-ring tetrazole group of tedizolid are associated with enhanced antimicrobial activity of tedizolid and its antimicrobial activity against linezolid-resistant bacteria by the cfr gene. Frequency of spontaneous resistance mutation to tedizolid is low, and about 16-fold lower than that to linezolid. Pharmacokinetic/pharmacodynamic (PK/PD) parameter most related to the efficacy of tedizolid is the area under free drug concentration-time curve/minimum inhibitory concentration (fAUC/MIC), and fAUC/MIC value required for bacteriostasis under immunocompetent conditions was calculated to be three. Phase III studies of tedizolid phosphate were conducted in Japan and overseas countries and demonstrated its efficacy and safety in patients with skin and soft tissue infections caused by gram positive organisms including methicillin-resistant S. aureus (MRSA).


Assuntos
Staphylococcus aureus Resistente à Meticilina , Oxazolidinonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Japão , Organofosfatos , Oxazóis , Oxazolidinonas/farmacologia , Staphylococcus aureus , Comprimidos
9.
Plant Biotechnol (Tokyo) ; 37(2): 177-184, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32821225

RESUMO

Biolistic transformation systems are widely used to introduce foreign genes into common wheat (Triticum aestivum L.); however, these techniques often generate high transgene copy numbers and complex transgene integration patterns that hinder the stable expression of the transgenes. To improve the efficiency of stable transgene expression, we examined the effect of low-temperature pretreatment of wheat flower spikes and of high maltose concentration (HMC) in the medium during the subsequent callus culture. Tillers of the spring wheat cultivar Bobwhite were stored at 5°C without water for one week before the isolation of their immature scutellar tissues, and the resulting particle-bombarded explants were cultured on 15% maltose for a month. Together, these treatments significantly increased the number of recovered transgenic lines expressing the reporter gene. The low-temperature pretreatment eliminated the negative effects of HMC, and HMC improved the efficiency of stable transgene expression. Southern blot analysis revealed that transgenic lines recovered after HMC treatment integrated a lower copy number of transgenes than those cultured at normal (4%) maltose concentration. These findings suggest that the HMC-mediated reduction of the transgene copy number results from the suppression of plasmid DNA rearrangement before or during transgene integration into the wheat genome.

10.
AIDS ; 34(9): 1325-1330, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32590431

RESUMO

OBJECTIVES: Certain human leucocyte antigen (HLA)-B alleles (protective alleles) associate with durable immune control of HIV-1, but with substantial heterogeneity in the level of control. It remains elusive whether viral factors including Nef-mediated immune evasion function diminish protective allele effect on viral control. DESIGN: The naturally occurring non-Ser variant at position 9 of HIV-1 subtype C Nef has recently exhibited an association with enhanced HLA-B downregulation function and decreased susceptibility to recognition by CD8 T cells. We therefore hypothesized this Nef genotype leads to diminished immune control mediated by protective HLA alleles. METHODS: Nef sequences were isolated from HIV-1 subtype C-infected patients harboring protective alleles and several Nef functions including downregulation of HLA-A, HLA-B, CD4, and SERINC5 were examined. Association between Nef non-Ser9 and plasma viral load was examined in two independent South African and Botswanan treatment-naïve cohorts. RESULTS: Nef clones isolated from protective allele individuals encoding Nef non-Ser9 variant exhibited greater ability to downregulate HLA-B when compared with the Ser9 variant, while other Nef functions including HLA-A, CD4, and SERINC5 downregulation activity were unaltered. By analyzing a cohort of South African participants chronically infected with subtype C HIV-1, Nef non-Ser9 associated with higher plasma viral load in patients harboring protective alleles. Corroboratively, the Nef non-Ser9 correlated with higher plasma viral load in an independent cohort in Botswana. CONCLUSION: Taken together, our study identifies the Nef genotype, non-Ser9 that subverts host immune control in HIV-1 subtype C infection.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Proteínas de Membrana/metabolismo , Alelos , Botsuana , Regulação para Baixo , Genótipo , Infecções por HIV/genética , HIV-1/isolamento & purificação , HIV-1/metabolismo , Humanos , Proteínas de Membrana/genética , Carga Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
11.
Reprod Sci ; 27(7): 1400-1410, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32329031

RESUMO

Endometriosis has several distinguishing features in the ectopic endometrium, including chronic inflammation and fibrosis. According to the retrograde menstruation theory, endometriotic cells are derived from eutopic endometrial cells, and adhesion of endometrial cells to the extracellular matrix can be the initial step in the development of endometriosis. Therefore, we hypothesized that cell adhesion, which mediates a sequence of events in the development of endometriosis triggering inflammatory responses and tissue fibrosis could be a possible therapeutic target for endometriosis. We found co-upregulation of focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 (MCP-1) in the endometriotic tissues compared with that in the normal endometrium. MCP-1 secretion was significantly higher in the endometriotic stromal cells than in the eutopic endometrial stromal cells. Furthermore, co-culture of U937 cells and endometriotic stromal cells upregulated secretion of transforming growth factor-ß1 (TGF-ß1). A FAK inhibitor significantly inhibited the secretion of MCP-1 in the endometriotic stromal cells and TGF-ß1 in the co-culture with macrophages. FAK inhibitor treatment in the murine endometriosis model demonstrated a decrease in the formation of endometriotic lesions as well as the expression of MCP-1 and TGF-ß1. Our results suggest that the FAK-mediated sequential development of endometriosis, including inflammatory response and tissue fibrosis, can be a new therapeutic target in endometriosis.


Assuntos
Adesão Celular/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Endometriose/metabolismo , Endometriose/patologia , Quinase 1 de Adesão Focal/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Técnicas de Cocultura , Endometriose/tratamento farmacológico , Feminino , Fibrose , Quinase 1 de Adesão Focal/antagonistas & inibidores , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Leiomioma/tratamento farmacológico , Leiomioma/metabolismo , Leiomioma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Quinolonas/administração & dosagem , Sulfonas/administração & dosagem , Células U937
12.
Opt Express ; 27(14): 19749-19757, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31503730

RESUMO

The broadband vertical optical inputs/outputs (I/Os) of silicon (Si) photonics pose significant challenges in terms of practical applications. Herein, we worked on a vertical optical I/O using a 45° curved micro-mirror. To verify the optical coupling characteristics, a simulation was conducted. As a result, efficient broadband optical coupling with various types of single-mode optical fibers was obtained owing to its lens function. An integration technology of the curved mirror was also developed based on the semiconductor manufacturing process. A curved micro-mirror with a spherical surface was obtained, and the vertical optical I/O with its lens function was demonstrated experimentally.

13.
Opt Express ; 27(4): 4147-4156, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30876035

RESUMO

We have fabricated compact optical modulators consisting of a Si waveguide with a VO2 cladding layer. These devices showed a sharp decrease in transmittance at around 60 °C, which is attributable to the metal-insulator transition of the VO2 cladding layer. By systematically varying the length of the device, we evaluated the transmission losses per unit length of the device to be 1.27 dB/µm, when the VO2 cladding layer was in the insulating (ON) state and 4.55 dB/µm when it was in the metallic (OFF) state. Furthermore, we found that the device showed an additional loss in the OFF state, which is attributable to a structural effect. As a result, an 8-µm-long device showed a large extinction ratio of more than 33 dB.

14.
J Clin Pharmacol ; 59(5): 688-701, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30575978

RESUMO

E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 µg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Administração Intravenosa , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Quimiocina CX3CL1/antagonistas & inibidores , Quimiocina CX3CL1/imunologia , Doença de Crohn/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Macaca fascicularis , Masculino , Modelos Biológicos , Placebos , Adulto Jovem
15.
Reprod Sci ; 26(7): 979-987, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30270745

RESUMO

Several features exist that distinguish endometriotic cells from eutopic endometrial cells. Progesterone resistance is one of the main distinguishing features, although how progesterone resistance affects the phenotype of endometriotic cells is not fully elucidated. Heart and neural crest derivatives expressed 2 (HAND2) is a transcriptional factor that plays an important role in maintaining endometrial function in a progesterone-dependent manner. Therefore, we explored whether progesterone-dependent HAND2 is implicated in the progression of endometriosis. HAND2 was less expressed by endometriotic tissues compared to endometrial tissues. Suppression of HAND2 expression induced fibroblast growth factor 1 (FGF1), FGF2, and FGF9 in endometriotic stromal cells and consequently enhanced migration and invasion capacity. AZD4547, a FGF receptor inhibitor, diminished the migration and invasion of endometriotic cells in vitro. In the murine model of endometriosis, AZD4547 showed suppressive effects on the development of endometriotic lesions at a relatively low concentration. In conclusion, we demonstrated that FGF1, FGF2, and FGF9 are downstream effectors of HAND2 in endometriotic cells. Since HAND2-dependent FGFs play roles in enhancing invasive capacity of endometriotic cells, our results suggest that FGF receptor inhibitors, such as AZD4547, can be promising therapeutic targets for endometriosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular , Endometriose/metabolismo , Endométrio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Benzamidas/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Endometriose/tratamento farmacológico , Endometriose/genética , Endometriose/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 9 de Crescimento de Fibroblastos/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Camundongos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Regulação para Cima
16.
J Infect Dis ; 219(9): 1456-1463, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30520960

RESUMO

BACKGROUND: HLA class I contributes to HIV immune control through antigen presentation to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In contrast to investigations of CTL, studies of NK cells in HIV control through HLA-killer immunoglobulin-like receptor (KIR) interactions remain sparse in African cohorts. METHODS: Treatment-naive, chronically HIV-infected adults (N = 312) were recruited from South Africa, and the effects of HLA-KIR pairs on clinical outcome were analyzed. RESULTS: There was no significant difference in viral load among all subjects with HLA alleles from the HLA-C1 group (P = .1). However, differences in HLA-C type significantly influenced viremia among 247 KIR2DL3 positives (P = .04), suggesting that specific HLA-KIR interactions contribute to immune control. Higher viral load (P = .02) and lower CD4+ T-cell counts (P = .008) were observed in subjects with HLA-C*16:01+KIR2DL3+. Longitudinal analysis showed more rapid progression to AIDS among HLA-C*16:01+KIR2DL3+ subjects (adjusted hazard ratio 1.9, P = .03) than those without this genotype, independent of CD4+ T-cell count and viral load. CONCLUSIONS: These results highlight the existence of unique anti-HIV innate immunity within distinct populations and the contribution of KIR on NK cells and some CTLs to the well-described HLA-mediated impact on HIV disease progression.


Assuntos
Infecções por HIV/genética , Infecções por HIV/imunologia , Antígenos HLA-C/genética , Receptores KIR2DL3/genética , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Doença Crônica , Progressão da Doença , Feminino , Frequência do Gene , Genes MHC Classe I/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade Inata , Desequilíbrio de Ligação , Masculino , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Receptores KIR2DL1/genética , África do Sul , Resultado do Tratamento , Carga Viral
17.
Int J Gynecol Cancer ; 28(8): 1576-1583, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30095702

RESUMO

OBJECTIVE: The aim of this study was to compare the outcomes and toxicities of radical hysterectomy (RH) and definitive chemoradiation (CRT) for International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer. MATERIALS AND METHODS: A retrospective analysis was performed on FIGO stage IIB patients who underwent RH with adjuvant radiotherapy (surgery group) or intended to receive CRT (CRT group). The distributions of disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Propensity score matching (PSM) was performed for the 2 groups based on age, tumor diameter, histological type, and pelvic node metastasis in pretreatment imaging tests. RESULTS: Median follow-up times were 58 months in the surgery group (n = 75) and 55 months in the CRT group (n = 65). Propensity score matching identified 37 patients with similar characteristics from each group. Significant differences were observed in the ratio of the chemotherapy combination between the surgery and CRT groups before (47% vs 98%) and after PSM (51% vs 100%). Five-year DFS rates were slightly higher in the surgery group than in the CRT group before PSM (69% vs 58%, P = 0.30) but were similar after PSM (76% vs 82%, P = 0.36). Five-year OS rates were similar between the surgery and CRT groups before (70% vs 75%, P = 0.59) and after PSM (78% vs 77%, P = 0.97). The results of multivariate analyses also showed that neither DFS nor OS was associated with the treatment modalities regardless of PSM. The incidence of late toxicities grade 2 or greater was similar between the surgery and CRT groups before (17% vs 23%, P = 0.31) and after PSM (19% vs 24%, P = 0.78). CONCLUSIONS: The results of this study suggest that RH with adjuvant radiotherapy and definitive CRT are equivalent treatment options for patients with FIGO stage IIB cancer. However, prospective larger studies are needed to confirm this.


Assuntos
Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Quimiorradioterapia/métodos , Quimiorradioterapia/estatística & dados numéricos , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia/métodos , Histerectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
18.
Int J Gynecol Cancer ; 28(6): 1211-1217, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29727352

RESUMO

OBJECTIVES: The objective of this study was to assess the effect of extensive lymphadenectomy on survival of early-stage cervical cancer patients with radical hysterectomy followed by adjuvant radiotherapy (RT). MATERIALS AND METHODS: A retrospective analysis was performed on early-stage patients with high-risk factors who received radical hysterectomy with lymphadenectomy followed by adjuvant RT. All patients were divided into the less than or equal to 40 dissected pelvic lymph nodes (DPLN ≤40) and greater than 40 dissected pelvic lymph nodes (DPLN >40) groups to assess the effect of extensive lymphadenectomy. Distributions of disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Significance of survival was assessed by the log-rank test. Cox proportional hazards models were applied to assess the effects of the factors on survival by univariate and multivariate analyses. RESULTS: After a median follow-up of 76 months for a total of 178 patients, 5-year DFS of the DPLN >40 group was significantly higher than that of the DPLN ≤40 group (86% vs 74%, P = 0.045). Five-year OS was comparable between the 2 groups (85% vs 78%, P = 0.49). The multivariate analysis showed that the DPLN ≤40 group was at a significantly higher risk of recurrence (hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.8; P = 0.020), whereas OS was not affected by the DPLN group (P = 0.26). Positive pelvic lymph node, parametrial invasion, histological type, and the absence of RT-combined chemotherapy remained significant prognostic factors for lower DFS and OS by the multivariate analysis. Adjusted hazard ratio of DPLN ≤40 for DFS was 1.2 (95% CI, 0.11-12; P = 0.91) in patients with negative pelvic lymph node (PLN) whereas it was 2.6 (95% CI, 1.1-5.8; P = 0.024) in patients with positive PLN. CONCLUSIONS: These results suggest that more extensive lymphadenectomy significantly improve the outcomes of patients with positive PLN even followed by adjuvant RT.


Assuntos
Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Histerectomia/métodos , Excisão de Linfonodo/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adulto Jovem
19.
J Acquir Immune Defic Syndr ; 78(3): 356-361, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528943

RESUMO

BACKGROUND: Class I human leukocyte antigen (HLA) molecules contribute to HIV control through antigen presentation to both cytotoxic T lymphocytes and natural killer cells. Contribution of cytotoxic T lymphocytes to HIV clinical outcome by HLA alleles has been well studied. However, reports about the role of natural killer cells in HIV clinical outcome, particularly, about the effect of HLA-killer immunoglobulin-like receptor (KIR) pairs, remain incomplete. METHODS: The effects of HLA allele-KIR pairs on HIV clinical outcome were statistically analyzed in a Thai cohort of treatment-naive chronically infected population (n = 209). RESULTS: Five HLA allele-KIR pairs scored significantly in viral load (VL) differences. Among them, opposing effects on VL were identified among subjects expressing KIR2DL2 ligands within the HLA-C1 group: higher VL in individuals expressing HLA-B*46:01+KIR2DL2+ compared with individuals without KIR (HLA-B*46:01+KIR2DL2-) (5.0 vs 4.6 log10 copies/mL, P = 0.02), in HLA-C*01:02+KIR2DL2+ (5.0 vs 4.6 log10 copies/mL; P = 0.02), and lower VL in HLA-C*12:03+KIR2DL2+ (4.3 vs 5.6 log10 copies/mL; P = 0.01). In the longitudinal analysis of a ten-year follow-up, HLA-B*46:01+KIR2DL2+ve subjects also had a higher mortality rate compared with the subjects without that pair, independent of variables including antiretroviral treatment, as well as CD4 T-cell count, sex, and age (adjusted hazard ratio 5.9, P = 0.02). CONCLUSION: We identified several HLA allele-KIR pairs associated with clinical outcome differences including opposing effects on VL within 1 HLA group with the same KIR. Among them, HLA-B*46:01 emerged in Southeast Asia about 50,000 years ago and is now the most prevalent HLA-B allele in that area. These findings highlight that each endemic area has unique features of anti-HIV innate immunity that impact clinical outcome.


Assuntos
Infecções por HIV/genética , Antígenos HLA/imunologia , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Tailândia , Carga Viral
20.
J Virol ; 92(4)2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29167337

RESUMO

The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05-restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLA-B*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLA-B*27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV.IMPORTANCE CD8+ T cells play a central role in successful control of HIV infection and have the potential also to mediate the eradication of viral reservoirs of infection. The principal means by which protective HLA class I molecules, such as HLA-B*27:05 and HLA-B*57:01, slow HIV disease progression is believed to be via the particular HIV-specific CD8+ T cell responses restricted by those alleles. We focus here on HLA-B*27:05, one of the best-characterized protective HLA molecules, and the closely related HLA-B*27:02, which differs by only 3 amino acids and which has not been well studied in relation to control of HIV infection. We show that HLA-B*27:02 is also protective against HIV disease progression, but the CD8+ T-cell immunodominance hierarchy of HLA-B*27:02 differs strikingly from that of HLA-B*27:05. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8+ T-cell activity in HLA-B*27:05-positive subjects.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Antígeno HLA-B27/genética , Epitopos Imunodominantes/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Genes MHC Classe I , Infecções por HIV/virologia , HIV-1 , Humanos , Carga Viral
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