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1.
Sci Transl Med ; 16(748): eadj4504, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38776389

RESUMO

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.


Assuntos
Antivirais , Pró-Fármacos , SARS-CoV-2 , Animais , SARS-CoV-2/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Camundongos , Administração Oral , Chlorocebus aethiops , Células Vero , Tratamento Farmacológico da COVID-19 , COVID-19/virologia , Replicação Viral/efeitos dos fármacos , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Nucleosídeos/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Modelos Animais de Doenças
2.
Sci Rep ; 14(1): 6422, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38494525

RESUMO

Persistent diarrhea is a severe gastroenteric disease with relatively high risk of pediatric mortality in developing countries. We conducted a randomized, double-blind, controlled clinical trial to evaluate the efficacy of liquid-form Bacillus clausii spore probiotics (LiveSpo CLAUSY; 2 billion CFU/5 mL ampoule) at high dosages of 4-6 ampoules a day in supporting treatment of children with persistent diarrhea. Our findings showed that B. clausii spores significantly improved treatment outcomes, resulting in a 2-day shorter recovery period (p < 0.05) and a 1.5-1.6 folds greater efficacy in reducing diarrhea symptoms, such as high frequency of bowel movement of ≥ 3 stools a day, presence of fecal mucus, and diapered infant stool scale types 4-5B. LiveSpo CLAUSY supportive treatment achieved 3 days (p < 0.0001) faster recovery from diarrhea disease, with 1.6-fold improved treatment efficacy. At day 5 of treatment, a significant decrease in blood levels of pro-inflammatory cytokines TNF-α, IL-17, and IL-23 by 3.24% (p = 0.0409), 29.76% (p = 0.0001), and 10.87% (p = 0.0036), respectively, was observed in the Clausy group. Simultaneously, there was a significant 37.97% decrease (p = 0.0326) in the excreted IgA in stool at day 5 in the Clausy group. Overall, the clinical study demonstrates the efficacy of B. clausii spores (LiveSpo CLAUSY) as an effective symptomatic treatment and immunomodulatory agent for persistent diarrhea in children.Trial registration: NCT05812820.


Assuntos
Bacillus clausii , Probióticos , Lactente , Humanos , Criança , Esporos Bacterianos , Diarreia/terapia , Citocinas , Probióticos/uso terapêutico
3.
JHEP Rep ; 6(2): 100975, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38274492

RESUMO

Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. Results: Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. Conclusions: Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. Impact and implications: Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. Clinical trial number: NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.

4.
Sci Rep ; 13(1): 14789, 2023 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-37684332

RESUMO

Influenza virus is a main cause of acute respiratory tract infections (ARTIs) in children. This is the first double-blind, randomized, and controlled clinical trial examining the efficacy of nasal-spraying probiotic LiveSpo Navax, which contains 5 billion of Bacillus subtilis and B. clausii spores in 5 mL, in supporting treatment of influenza viral infection in pediatric patients. We found that the nasal-spraying Bacillus spores significantly shortened the recovery period and overall treatment by 2 days and increased treatment effectiveness by 58% in resolving all ARTIs' symptoms. At day 2, the concentrations of influenza virus and co-infected bacteria were reduced by 417 and 1152 folds. Additionally, the levels of pro-inflammatory cytokines IL-8, TNF-α, and IL-6 in nasopharyngeal samples were reduced by 1.1, 3.7, and 53.9 folds, respectively. Compared to the standard control group, treatment regimen with LiveSpo Navax demonstrated significantly greater effectiveness, resulting in 26-fold reduction in viral load, 65-fold reduction in bacterial concentration, and 1.1-9.5-fold decrease in cytokine levels. Overall, nasal-spraying Bacillus spores can support the symptomatic treatment of influenza virus-induced ARTIs quickly, efficiently and could be used as a cost-effective supportive treatment for respiratory viral infection in general.Clinical trial registration no: NCT05378022 on 17/05/2022.


Assuntos
Bacillus , Doenças Transmissíveis , Influenza Humana , Infecções por Orthomyxoviridae , Orthomyxoviridae , Probióticos , Infecções Respiratórias , Humanos , Criança , Animais , Influenza Humana/terapia , Carga Viral , Esporos Bacterianos , Infecções Respiratórias/terapia , Citocinas , Sprays Nasais , Neópteros , Probióticos/uso terapêutico
5.
bioRxiv ; 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37425890

RESUMO

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

6.
J Hum Genet ; 68(5): 305-312, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36599957

RESUMO

BACKGROUND: Citrin deficiency (CD), a disorder caused by mutations in the SLC25A13 gene, may result in neonatal intrahepatic cholestasis. This study was purposely to explore the mutation spectrum of SLC25A13 gene in Vietnamese CD patients. METHODS: The 292 unrelated CD patients were first screened for four high-frequency mutations by PCR/PCR-RFLP. Then, Sanger sequencing was performed directly for heterozygous or undetected patients. Novel mutations identified would need to be confirmed by their parents. RESULTS: 12 pathogenic SLC25A13 mutations were identified in all probands, including three deletions c.851_854del (p.R284Rfs*3), c.70-63_133del (p.Y24_72Ifs*10), and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]), two splice-site mutations (IVS6+5G>A and IVS11+1G>A), one nonsense mutations c.1399C>T (p.R467*), one duplication mutation c.1638_1660dup (p.A554fs*570), one insertion IVSl6ins3kb (p.A584fs*585), and four missense mutation c.2T>C (p.M1T), c.1231G>A (p.V411M), c.1763G>A (p.R588Q), and c.135G>C (p.L45F). Among them, c.851_854del (mut I) was the most identified mutant allele (91.78%) with a total of 247 homozygous and 42 heterozygous genotypes of carriers. Interestingly, two novel mutations were identified: c.70-63_133del (p.Y24_72Ifs*10) and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]). CONCLUSION: The SLC25A13 mutation spectrum related to intrahepatic cholestasis infants in Vietnam revealed a quite similar pattern to Asian countries' reports. This finding supports the use of targeted SLC25A13 mutation for CD screening in Vietnam and contributed to the SLC25A13 mutation spectra worldwide. It also helps emphasize the role of DNA analysis in treatment, genetic counseling, and prenatal diagnosis.


Assuntos
Colestase Intra-Hepática , Citrulinemia , Proteínas de Transporte da Membrana Mitocondrial , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Colestase Intra-Hepática/genética , Citrulinemia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação , População do Sudeste Asiático , Vietnã
7.
Sci Rep ; 12(1): 12402, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35858943

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of Acute Respiratory Tract Infections (ARTIs) in young children. However, there is currently no vaccine or treatment available for children. Here, we demonstrated that nasal-spraying probiotics containing 5 billion of Bacillus spores (LiveSpo Navax) is an effective symptomatic treatment in a 6-day randomized controlled clinical study for RSV-infected children (n = 40-46/group). Navax treatment resulted in 1-day faster recovery-time and 10-50% better efficacy in relieving ARTI symptoms. At day 3, RSV load and level of pro-inflammatory cytokines in nasopharyngeal samples was reduced by 630 folds and 2.7-12.7 folds respectively. This showed 53-fold and 1.8-3.6-fold more effective than those in the control-standard of care-group. In summary, nasal-spraying Bacillus spores can rapidly and effectively relieve symptoms of RSV-induced ARTIs while exhibit strong impacts in reducing viral load and inflammation. Our nasal-spraying probiotics may provide a basis for simple-to-use, low-cost, and effective treatment against viral infection in general.


Assuntos
Bacillus , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Criança , Pré-Escolar , Humanos , Sprays Nasais , Infecções Respiratórias/terapia , Esporos Bacterianos
8.
J Pediatr Surg ; 56(7): 1169-1173, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33838902

RESUMO

BACKGROUND: A retrospective chart review of liver histologies in Kasai biliary atresia BA patients operated 1/2017- 7/2019 at our institution was conducted to identify histologic prognostic factors for biliary outcome. METHODS: Patients with wedge liver biopsies and portal plate biopsies (n = 85) were categorized into unfavorable and favorable outcome, based on a 3-month serum total bilirubin level of <34 µM or mortality. Hepatocellular histologies, presence of ductal plate malformation (DPM) and of large bile duct of ≥ 150 µm diameter size at the portal plate were evaluated. RESULTS: Total Bilirubin levels> 34 µM correlates with worse 1-year survival. Age at surgery, histologic fibrosis or inflammation does not predict outcome. Potential adverse predictors are severe hepatocellular swelling, severe cholestasis, presence of DPM (n = 24), and portal plate bile duct size < 150 µm (n = 28). In multivariate analyses adjusting for age at Kasai and postop cholangitis, bile duct size and severe hepatocellular swelling remain independent histologic prognosticators (OR 3.25, p = 0.039 and OR 3.26, p = 0.006 respectively), but not DPM. CONCLUSION: Advanced histologic findings of portal plate bile duct size of <150 µm and severe hepatocellular damage predict poor post-Kasai jaundice clearance and short-term survival outcome, irrespective of Kasai timing. LEVEL OF EVIDENCE: Level III.


Assuntos
Atresia Biliar , Colestase , Atresia Biliar/cirurgia , Humanos , Lactente , Fígado/cirurgia , Portoenterostomia Hepática , Estudos Retrospectivos , Resultado do Tratamento
9.
Hepatology ; 74(4): 1737-1749, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33704806

RESUMO

BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hexanóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptor 8 Toll-Like/agonistas , Adulto , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Cefaleia/induzido quimicamente , Hepatite B Crônica/sangue , Hexanóis/farmacologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Subunidade p40 da Interleucina-12/sangue , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pirimidinas/farmacologia , Resposta Viral Sustentada
10.
J Hepatol ; 71(5): 900-907, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31306680

RESUMO

BACKGROUND & AIMS: To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. METHODS: In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. RESULTS: There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log10 IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log10 by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24. CONCLUSIONS: In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. LAY SUMMARY: Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.


Assuntos
Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Vacinação , Adulto , Idoso , DNA Viral/sangue , Feminino , Seguimentos , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/virologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Nivolumabe/efeitos adversos , Nivolumabe/farmacologia , Projetos Piloto , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
11.
PLoS One ; 13(12): e0209341, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576365

RESUMO

Bacillus aquimaris SH6 spores produce carotenoids that are beneficial to white-leg shrimp (Litopenaeus vannamei) health. However, the optimal dose and mechanisms behind these effects are not well understood. We investigated the fate of SH6 spores in the gut of L. vannamei. Shrimp were divided into six groups administrated with either feed only (negative control) or SH6 spores at 5 × 106 CFU/g pellet (high dose, SH6 spore-H group), 1 × 106 CFU/g pellet (medium dose, SH6 spore-M group), 2 × 105 CFU/g pellet (low dose, SH6 spore-L group), astaxanthin at 0.5 mg/g pellet (Carophyll group), or carotenoids from SH6 vegetative cells at 5 µg/g pellet (SH6 carotenoid group). The growth rate was highest in SH6 spore-H (3.38%/day), followed by SH6 spore-M (2.84%/day) and SH6 spore-L (2.25%/day), which was significantly higher than the control (1.45%/day), Carophyll (1.53%/day) or SH6 carotenoid (1.57%/day) groups. The astaxanthin levels (1.9-2.0 µg/g shrimp) and red-colour scores (21-22) in SH6 spore-H/M were higher than the control (astaxanthin: 1.2 µg/g shrimp; red score: 20) or SH6 spore-L, but lower than the Carophyll and SH6 carotenoids. Feeding with medium and high doses of SH6 spores after 28 days resulted in respective 1.3-2-fold increases in phenol oxidase activity and 8-9 fold increases in Rho mRNA expression compared to the control and low dose group. The live-counts of SH6 in the gut gradually increased during the 28-day feeding period with SH6 spores at different concentrations, starting from 4.1, 8.2, and 5.4 × 104 CFU/g gut at day 1 and reaching 5.3, 5.1, and 4.4 × 105 CFU/g gut in the SH6-H/M/L groups, respectively, at day 28. Gut microbiota became more diversified, resulting in a 2-8-fold increase in total bacterial live-counts compared to the controls. SH6 spore germination was detected by measuring the mRNA expression of a specific sequence coding for SH6 amylase at 4 h, reaching saturation at 24 h. Our results confirm that SH6 spores colonize and germinate in the gut to improve the microbial diversity and boost the immune system of shrimp, exhibiting beneficial effects at >1 × 106 CFU/g pellet.


Assuntos
Carotenoides/administração & dosagem , Microbioma Gastrointestinal/fisiologia , Penaeidae/microbiologia , Probióticos/administração & dosagem , Esporos Bacterianos/metabolismo , Ração Animal/microbiologia , Animais , Aquicultura/métodos , Bacillus/fisiologia , Carotenoides/imunologia , Carotenoides/metabolismo , Cor , Epitélio/microbiologia , Epitélio/fisiologia , Penaeidae/fisiologia , Frutos do Mar , Esporos Bacterianos/imunologia , Vírus da Síndrome da Mancha Branca 1
12.
J Glob Oncol ; 4: 1-9, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30422746

RESUMO

PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States. METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared. RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET. CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Genômica/métodos , Neoplasias Pulmonares/genética , Oncogenes/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Taxa de Sobrevida , Estados Unidos , Vietnã
13.
J Hepatol ; 68(3): 431-440, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29104121

RESUMO

BACKGROUND & AIMS: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.


Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Pteridinas , Imunidade Adaptativa/efeitos dos fármacos , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Pteridinas/administração & dosagem , Pteridinas/efeitos adversos , Pteridinas/farmacocinética , Receptor 7 Toll-Like/agonistas , Resultado do Tratamento
14.
Antivir Ther ; 20(7): 699-708, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25105516

RESUMO

BACKGROUND: GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4 and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-α and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics and pharmacodynamics of GS-9620 in treatment-naive patients chronically infected with HCV genotype 1. METHODS: In this double-blind, placebo-controlled study, 51 patients were randomized 5:1 (active:placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2 and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-α and interferon-γ-inducible protein (IP)-10 levels and HCV RNA quantification. RESULTS: GS-9620 was well-tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 h. Transient, dose-dependent ISG15 induction was observed at 1, 2 and 4 mg, with peak mean fold change within 48 h followed by a decline to baseline levels within 7 days of dosing. Serum interferon-α induction post-baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed. CONCLUSIONS: GS-9620 was safe, well-tolerated and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-α or systemic AEs in most patients, supporting a pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.


Assuntos
Antivirais/uso terapêutico , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Pteridinas/uso terapêutico , Receptor 7 Toll-Like/agonistas , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacocinética , Biomarcadores , Citocinas/genética , Feminino , Expressão Gênica , Genótipo , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/metabolismo , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pteridinas/efeitos adversos , Pteridinas/farmacocinética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 7 Toll-Like/genética , Resultado do Tratamento , Ubiquitinas/genética , Carga Viral , Adulto Jovem
15.
J Clin Endocrinol Metab ; 96(8): 2464-74, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21677041

RESUMO

CONTEXT: Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. OBJECTIVE: The objective of the study was to examine, using longitudinal measurements, the relations of serum androgens, estrogens, gonadotropins, and SHBG to the prevalence and progression of frailty in older men. DESIGN: Concord Health and Ageing in Men Project is an observational cohort study of 1705 men (aged 70 yr or older) living in the suburb of Concord, Sydney, Australia. Measurements were obtained at baseline (2005-2007) and 2-yr follow-up (2007-2009). Testosterone (T), dihydrotestosterone, estradiol, and estrone were obtained by liquid chromatography-tandem mass spectrometry, whereas SHBG, LH, and FSH were measured by immunoassay. SETTING: Subjects from the general community were sampled. PARTICIPANTS: A total of 1645 subjects constituting a representative sample of community-dwelling men aged 70 yr old or older participated in the study. OUTCOME MEASURES: The frailty syndrome was measured according to the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fractures (SOF) indices. RESULTS: Androgens and estrogens showed significant age-adjusted associations with concurrent frailty. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting greater CHS frailty as compared with the highest T quintile (P < 0.001); results for dihydrotestosterone, estradiol, estrone, and calculated free T were similar, and were unchanged when the SOF frailty index was substituted for the CHS frailty index. A 1 sd, 2-yr decrease in T, calculated free T, or LH was associated with a 1.2- to 1.3-fold increase in the odds of progression (increase in severity) of frailty. The control for comorbid medical conditions did not affect results. CONCLUSIONS: Age-related changes in blood androgens and estrogens may contribute to the development or progression of frailty in men.


Assuntos
Envelhecimento/metabolismo , Idoso Fragilizado/estatística & dados numéricos , Hormônios Esteroides Gonadais/sangue , Idoso , Idoso de 80 Anos ou mais , Androgênios/sangue , Progressão da Doença , Estrogênios/sangue , Hormônio Foliculoestimulante/sangue , Avaliação Geriátrica , Nível de Saúde , Humanos , Estudos Longitudinais , Hormônio Luteinizante/sangue , Masculino , Valor Preditivo dos Testes , Prevalência , Análise de Regressão , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue
16.
Stroke ; 38(1): 16-21, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17138952

RESUMO

BACKGROUND AND PURPOSE: Emerging evidence raises the possibility of an association between depression and stroke risk. This study sought to examine whether depressive symptoms are associated with an increased risk of cerebrovascular events in a community-based sample. METHODS: A prospective study was conducted on 4120 Framingham Heart Study participants aged 29 to 100 years with up to 8 years of follow-up. The Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms. Incident stroke and transient ischemic attack (TIA) events were assessed by uniform diagnostic criteria. The association between depressive symptoms and risk of stroke/TIA was analyzed with Cox proportional-hazards models, after adjusting for traditional stroke risk factors. RESULTS: In participants <65 years, the risk of developing stroke/TIA was 4.21 times greater (P= <0.001) in those with symptoms of depression. After adjusting for components of the Framingham Stroke Risk Profile (hazard ratio=3.43, 95% CI=1.60 to 7.36, P=0.002) and education (hazard ratio=4.89, 95% CI=2.19 to 10.95), similar results were obtained. In subjects aged 65 and older, depressive symptoms were not associated with an increased risk of stroke/TIA. Taking antidepressant medications did not alter the risk associated with depressive symptoms. CONCLUSIONS: In this community-based study, depressive symptoms were an independent risk factor for incident stroke/TIA in individuals <65 years. These data suggest that identification of depressive symptoms at younger ages may have an impact on the primary prevention of stroke.


Assuntos
Transtorno Depressivo/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/psicologia , Adulto , Distribuição por Idade , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Antidepressivos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Comorbidade , Diagnóstico Precoce , Escolaridade , Feminino , Humanos , Ataque Isquêmico Transitório/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Comportamento de Redução do Risco , Fumar/tendências , Acidente Vascular Cerebral/fisiopatologia
17.
J Womens Health (Larchmt) ; 15(3): 281-94, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16620187

RESUMO

BACKGROUND: Microbicides for HIV/sexually transmitted infection (STI) prevention are still in development. Microbicide acceptability studies have thus focused on soliciting input from individuals about hypothetical products using traditional epidemiological and behavioral research methodologies. Here, we integrate a well-established market research method, conjoint analysis, with more traditional epidemiological and behavioral research to examine potential users' preferences for different microbicide formulations. METHODS: Focus group discussions (n = 67) were held with a diverse population of young men and women (aged 18-32 years) from Northern California. Then, young women participated in structured surveys (n = 321) that included a conjoint study, a methodology not yet used in microbicide acceptability. The main outcome measures were intentions for different microbicide formulations, inferred preferences for microbicide characteristics, and self-reported risk factors for HIV, other STIs, and pregnancy. RESULTS: Risk of STIs and unwanted pregnancies is a concern within this population. Participants' responses suggest that the ideal microbicide would (1) offer protection from pregnancy, HIV, STIs, and vaginal infections, (2) offer as much protection as condoms, (3) allow insertion up to 8 hours prior to sexual activity, (4) be available over the counter (OTC), (5) be inserted with an applicator, and (6) have only slight leakage not requiring a panty liner. The average predicted purchase probability for this ideal microbicide was 69%. CONCLUSIONS: Our findings help illustrate microbicide product preferences and demand among young women in California, and the methodological approach should lend itself to other populations as well as during clinical trials when understanding product use and nonuse is critical.


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Infecções Sexualmente Transmissíveis/prevenção & controle , Cremes, Espumas e Géis Vaginais/uso terapêutico , Saúde da Mulher , Administração Intravaginal , Adulto , California , Comportamento Contraceptivo , Feminino , Grupos Focais , Infecções por HIV/prevenção & controle , Humanos , Inquéritos e Questionários
18.
Biochemistry ; 45(8): 2570-6, 2006 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-16489750

RESUMO

Single-molecule imaging of the entrance of a protein into the hydrophobic environment of a cell membrane was investigated. The pre-stem of LukF, one of the two components of the pore-forming toxin staphylococcal gamma-hemolysin, was specifically labeled with 6-bromoacetyl-2-dimethylaminonaphthalene (Badan), an environment-sensitive fluorophore. Incubation of this derivative with erythrocyte ghost membranes resulted in a pronounced increase in fluorescence indicating insertion of Badan into the hydrophobic interior of the lipid bilayers. However, the increase in fluorescence was completely dependent on the interaction of Badan-labeled LukF with the gamma-hemolysin second component. Individual spots of Badan fluorescence on erythrocyte membranes were visualized that were associated with single pores. Analyses of the intensities of these fluorescent spots and their photobleaching independently showed that a single pore contained 3-4 LukF molecules. Thus, environment-sensitive fluorophore signals can be used to study the insertion of specific protein domains into cell membranes at the single-molecule lever, and the use of this approach in the present study revealed that a single gamma-hemolysin pore opening contains at least three LukF molecules.


Assuntos
2-Naftilamina/análogos & derivados , Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/farmacologia , Membrana Celular/metabolismo , Corantes Fluorescentes/metabolismo , 2-Naftilamina/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Eritrócitos/metabolismo , Proteínas Hemolisinas , Interações Hidrofóbicas e Hidrofílicas , Leucocidinas , Microscopia de Fluorescência , Modelos Biológicos , Estrutura Terciária de Proteína , Staphylococcus aureus/metabolismo
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