RESUMEN
BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function. METHODS: Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot. RESULTS: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation. CONCLUSIONS: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.
RESUMEN
Chronic viral hepatitis is caused by hepatitis B virus, hepatitis C virus or hepatitis D virus (HBV, HCV, and HDV). Despite different replication strategies, all these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions and HBV subviral particles. Moreover, in a cohort of people with hepatitis B a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis.
RESUMEN
The hepatitis C virus (HCV) relies on cellular lipid pathways for virus replication and also induces liver steatosis, but the mechanisms involved are not clear. We performed a quantitative lipidomics analysis of virus-infected cells by combining high-performance thin-layer chromatography (HPTLC) and mass spectrometry, using an established HCV cell culture model and subcellular fractionation. Neutral lipid and phospholipids were increased in the HCV-infected cells; in the endoplasmic reticulum there was an ~four-fold increase in free cholesterol and an ~three-fold increase in phosphatidyl choline (p < 0.05). The increase in phosphatidyl choline was due to the induction of a non-canonical synthesis pathway involving phosphatidyl ethanolamine transferase (PEMT). An HCV infection induced expression of PEMT while knocking down PEMT with siRNA inhibited virus replication. As well as supporting virus replication, PEMT mediates steatosis. Consistently, HCV induced the expression of the pro-lipogenic genes SREBP 1c and DGAT1 while inhibiting the expression of MTP, promoting lipid accumulation. Knocking down PEMT reversed these changes and reduced the lipid content in virus-infected cells. Interestingly, PEMT expression was over 50% higher in liver biopsies from people infected with the HCV genotype 3 than 1, and three times higher than in people with chronic hepatitis B, suggesting that this may account for genotype-dependent differences in the prevalence of hepatic steatosis. PEMT is a key enzyme for promoting the accumulation of lipids in HCV-infected cells and supports virus replication. The induction of PEMT may account for virus genotype specific differences in hepatic steatosis.
Asunto(s)
Hígado Graso , Hepatitis C Crónica , Hepatitis C , Humanos , Hepacivirus/genética , Hepacivirus/metabolismo , Transferasas/metabolismo , Hepatitis C/genética , Hígado Graso/patología , Replicación Viral , Genotipo , Colesterol/metabolismo , Fosfatidilcolinas/metabolismo , Fenotipo , Fosfatidiletanolamina N-Metiltransferasa/genéticaRESUMEN
Community-based organizations (CBOs) are integral to achieving the goal of Ending the HIV epidemic (EHE). Their familiarity with and proximity to communities position them to effectively implement strategies necessary to address determinants of health through their formal and informal medical and social services. However, structural inequities have contributed to the demise of many organizations that were instrumental in early responses to the HIV epidemic. We define structural inequities for HIV CBOs as systems in which policies, institutional practices, organizational (mis)representations, and other norms work to produce and maintain inequities that affect CBOs' ability to survive and thrive. In this discussion, we describe the organizational threats to grassroots HIV CBOs and the risks to livelihood and longevity, including examples. The invaluable role of HIV CBOs in EHE and their role in responding to existing and novel infectious diseases like COVID-19 should not be overlooked. Recommendations to promote structural equity are offered. (Am J Public Health. 2022;112(3):417-425. https://doi.org/10.2105/AJPH.2021.306688).
Asunto(s)
Redes Comunitarias/organización & administración , Infecciones por VIH/epidemiología , Organizaciones sin Fines de Lucro/organización & administración , Epidemias , Humanos , Organizaciones sin Fines de Lucro/economíaRESUMEN
Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/inmunología , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Masculino , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Mieloides/enzimología , Metástasis de la Neoplasia/tratamiento farmacológico , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Direct acting antiviral therapies rapidly clear chronic hepatitis C virus (HCV) infection and restore natural killer (NK) cell function. We investigated NK-cell memory formation following HCV clearance by examining NK-cell phenotype and responses from control and chronic HCV patients before and after therapy following sustained virologic response at 12 weeks post therapy (SVR12). NK-cell phenotype at SVR12 differed significantly from paired pretreatment samples, with an increase in maturation markers CD16, CD57, and KLRG1. HCV patients possessed stronger cytotoxic responses against HCV-infected cells as compared to healthy controls; a response that further increased following SVR12. The antigen-specific response was mediated by KLRG1+ NK cells, as demonstrated by increased degranulation and proliferation in response to HCV antigen only. Our data suggest that KLRG1+ HCV-specific memory NK cells develop following viral infection, providing insight into their role in HCV clearance and relevance with regard to vaccine design.
Asunto(s)
Antivirales , Hepatitis C Crónica , Células de Memoria Inmunológica/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Antivirales/uso terapéutico , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Células de Memoria Inmunológica/virología , Interferones , Células Asesinas Naturales/virología , Lectinas Tipo C , Receptores InmunológicosRESUMEN
OBJECTIVE: Vaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection. DESIGN: NK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals. RESULTS: NK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels. CONCLUSIONS: Our data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.
Asunto(s)
Vacunas contra Hepatitis B/inmunología , Hepatitis B/inmunología , Memoria Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Inmunidad Adaptativa/inmunología , Anticuerpos Antivirales/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Antígenos de la Hepatitis B/inmunología , Antígenos del Núcleo de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/prevención & control , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHODS: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, nâ =â 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (nâ =â 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a nâ =â 18/18, GT1b nâ =â 2/4), 89% in GT3 (nâ =â 59/66) and 100% in GT6 (nâ =â 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSIONS: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.
Asunto(s)
Hepatitis C Crónica , Hepatitis C , Ácidos Aminoisobutíricos , Antivirales/efectos adversos , Carbamatos , Ciclopropanos , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Quinoxalinas , Sofosbuvir/efectos adversos , Sulfonamidas , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Natural killer (NK) cells are primary innate effector cells that play an important role in the control of human viral infections. During chronic viral infection, NK cells undergo significant changes in phenotype, function and subset distribution, including the appearance of CD56-CD16+ (CD56-) NK cells, previously identified in chronic human immunodeficiency virus (HIV) and hepatitis C virus infection. However, the presence of CD56- NK cells in the pathogenesis of chronic hepatitis B (CHB) remains unknown. METHODS: Phenotype and function of CD56- NK cells from patients with CHB (n = 28) were assessed using flow cytometry and in vitro stimulation with HBV antigen. RESULTS: CHB patients had a higher frequency of CD56- NK cells compared to healthy controls in peripheral blood (6.2% vs 1.4%, P < .0001). Compared to CD56+ NK cells, CD56- NK cells had increased expression of inhibitory receptors, and reduced expression of activating receptors, as measured by MFI and qPCR. CD56- NK cells were less responsive to target cell and cytokine stimulation compared to their CD56+ counterparts. In addition, CD56- NK cells demonstrated defective dendritic cells (DCs) interactions resulting in reduced DCs maturation, lower expression of NK CD69 and impaired capacity of NK cells to eliminate immature DCs in co-culture studies. Finally, frequency of CD56- NK cells was positively correlated with serum HBV DNA levels. CONCLUSION: Chronic HBV infection induces the expansion of highly dysfunctional of CD56- NK cells that likely contribute to inefficient innate and adaptive antiviral immune response in chronic HBV infection.
Asunto(s)
Hepatitis B Crónica , Antivirales/uso terapéutico , Recuento de Células , Citometría de Flujo , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Células Asesinas NaturalesRESUMEN
To determine the epidemiology of coronavirus disease (COVID-19) in a remote region of China, far from Wuhan, we analyzed the epidemiology of COVID-19 in Gansu Province. From January 23 through February 3, 2020, a total of 35 (64.8%) of 54 reported cases were imported from COVID-19-epidemic areas. Characteristics that differed significantly during the first and second waves of illness in Gansu Province were mean patient age, occupation, having visited epidemic areas, and mode of transportation. Time from infection to illness onset for family clusters was shorter in Gansu Province than in Wuhan, consistent with shortened durations from onset to first medical visit or hospitalization. Spatial distribution pattern analysis indicated hot spots and spatial outliers in Gansu Province. As a result of adequate interventions, transmission of the COVID-19 virus in Gansu Province is decreasing.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus , COVID-19 , Niño , Preescolar , China/epidemiología , Femenino , Sistemas de Información Geográfica , Hospitalización , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Análisis Espacial , Factores de Tiempo , Adulto JovenRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1006750.].
RESUMEN
Hepatitis B virus (HBV) is a ubiquitous viral pathogen associated with large-scale morbidity and mortality in humans. However, there is considerable uncertainty over the time-scale of its origin and evolution. Initial shotgun data from a mid-16th century Italian child mummy, that was previously paleopathologically identified as having been infected with Variola virus (VARV, the agent of smallpox), showed no DNA reads for VARV yet did for hepatitis B virus (HBV). Previously, electron microscopy provided evidence for the presence of VARV in this sample, although similar analyses conducted here did not reveal any VARV particles. We attempted to enrich and sequence for both VARV and HBV DNA. Although we did not recover any reads identified as VARV, we were successful in reconstructing an HBV genome at 163.8X coverage. Strikingly, both the HBV sequence and that of the associated host mitochondrial DNA displayed a nearly identical cytosine deamination pattern near the termini of DNA fragments, characteristic of an ancient origin. In contrast, phylogenetic analyses revealed a close relationship between the putative ancient virus and contemporary HBV strains (of genotype D), at first suggesting contamination. In addressing this paradox we demonstrate that HBV evolution is characterized by a marked lack of temporal structure. This confounds attempts to use molecular clock-based methods to date the origin of this virus over the time-frame sampled so far, and means that phylogenetic measures alone cannot yet be used to determine HBV sequence authenticity. If genuine, this phylogenetic pattern indicates that the genotypes of HBV diversified long before the 16th century, and enables comparison of potential pathogenic similarities between modern and ancient HBV. These results have important implications for our understanding of the emergence and evolution of this common viral pathogen.
Asunto(s)
ADN Antiguo/química , Evolución Molecular , Genoma Viral , Virus de la Hepatitis B/genética , Modelos Genéticos , Momias/virología , Secuencia de Bases , Teorema de Bayes , Preescolar , Secuencia de Consenso , ADN Antiguo/aislamiento & purificación , Biblioteca de Genes , Virus de la Hepatitis B/aislamiento & purificación , Virus de la Hepatitis B/metabolismo , Virus de la Hepatitis B/ultraestructura , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Italia , Microscopía Electrónica de Rastreo , Mutación , Filogenia , Reproducibilidad de los Resultados , Alineación de Secuencia , Virión/genética , Virión/aislamiento & purificación , Virión/metabolismo , Virión/ultraestructuraRESUMEN
Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was â¼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Neoplasias Hematológicas/tratamiento farmacológico , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/administración & dosificación , Purinas/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Fosfatidilinositol 3-Quinasa Clase Ib , Femenino , Neoplasias Hematológicas/enzimología , Neoplasias Hematológicas/patología , Humanos , Isoquinolinas/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Purinas/farmacología , Seguridad , Distribución TisularRESUMEN
Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/administración & dosificación , Purinas/farmacocinética , Neoplasias Cutáneas/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Fosfatidilinositol 3-Quinasa Clase Ib , Femenino , Humanos , Isoquinolinas/farmacología , Linfoma Cutáneo de Células T/enzimología , Linfoma Cutáneo de Células T/patología , Linfoma de Células T Periférico/enzimología , Linfoma de Células T Periférico/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Purinas/farmacología , Seguridad , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Distribución TisularRESUMEN
The pandemic of coronavirus disease 2019 (COVID-19), with rising numbers of patients worldwide, presents an urgent need for effective treatments. To date, there are no therapies or vaccines that are proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection. The most promising therapy to date is remdesivir, which is US Food and Drug Administration (FDA) approved for emergency use in adults and children hospitalized with severe suspected or laboratory-confirmed COVID-19. Herein we summarize the general features of SARS-CoV-2's molecular and immune pathogenesis and discuss available pharmacological strategies, based on our present understanding of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Finally, we outline clinical trials currently in progress to investigate the efficacy of potential therapies for COVID-19.
Asunto(s)
Inmunidad Adaptativa , Betacoronavirus/fisiología , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Humanos , Inmunoterapia , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Sistemas de Lectura Abierta/genética , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/terapia , Neumonía Viral/virología , SARS-CoV-2RESUMEN
BACKGROUND & AIMS: Natural killer (NK) cells are known to exert strong antiviral activity. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is expressed by terminally differentiated NK cells and KLRG1-expressing lymphocytes are known to expand following chronic viral infections. We aimed to elucidate the previously unknown role of KLRG1 in the pathogenesis of chronic hepatitis B (CHB). METHODS: KLRG1+ NK cells were taken from the blood and liver of healthy individuals and patients with CHB. The phenotype and function of these cells was assessed using flow cytometry and in vitro stimulation. RESULTS: Patients with CHB had a higher frequency of KLRG1+ NK cells compared to healthy controls (blood 13.4 vs. 2.3%, pâ¯<0.0001 and liver 23.4 vs. 2.6%, pâ¯<0.01). KLRG1+ NK cells were less responsive to K562 and cytokine stimulation, but demonstrated enhanced cytotoxicity (9.0 vs. 4.8%, pâ¯<0.05) and IFN-γ release (8.0 vs. 1.5%, pâ¯<0.05) via antibody dependent cellular cytotoxicity compared to their KLRG1- counterparts. KLRG1+ NK cells possessed a mature phenotype, demonstrating stronger cytolytic activity and IFN-γ secretion against hepatic stellate cells (HSCs) than KLRG1- NK cells. Moreover, KLRG1+ NK cells more effectively induced primary HSC apoptosis in a TRAIL-dependent manner. Increased KLRG1+ NK cell frequency in the liver and blood was associated with lower fibrosis stage (F0/F1) in patients with CHB. Finally, the expression of CD44, degranulation and IFN-γ production were all increased in KLRG1+ NK cells following stimulation with osteopontin, the CD44 ligand, suggesting that HSC-derived osteopontin may cause KLRG1+ NK cell activation. CONCLUSIONS: KLRG1+ NK cells likely play an antifibrotic role during the natural course of CHB infection. Harnessing this antifibrotic function may provide a novel therapeutic approach to treat liver fibrosis in patients with CHB. LAY SUMMARY: Individuals that are chronically infected with hepatitis B virus (HBV) possess an increased number of immune cells, called natural killer (NK) cells expressing the surface marker KLRG1 in the blood and liver. Here, we demonstrate that these specific NK cells are able to kill activated stellate cells in the liver. Because activated stellate cells contribute to liver scarring, i.e. fibrosis, and subsequent liver dysfunction in individuals with chronic HBV infection, KLRG1+ NK cells are a novel immune cell type that can limit liver scarring.
Asunto(s)
Virus de la Hepatitis B/genética , Hepatitis B Crónica/inmunología , Células Asesinas Naturales/inmunología , Lectinas Tipo C/metabolismo , Cirrosis Hepática/inmunología , Receptores Inmunológicos/metabolismo , Adulto , Apoptosis , Células Cultivadas , ADN Viral/sangre , Femenino , Células Estrelladas Hepáticas/metabolismo , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/virología , Humanos , Interferón gamma/metabolismo , Cirrosis Hepática/etiología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
The efficiency of the electrocoagulation method to remove boron from synthetic and mining effluents was investigated in this study. Different parameters were tested using boric acid solution and effluent collected from a mining company located in the city of Vitória-ES. The results showed a percentage of boron removal of over 60% for the synthetic and mining effluents, using aluminum electrodes, pH 7.5, current density of 14.82 mA cm-2, and supporting electrolyte of 0.200 mol L-1. The electrocoagulation and chemical coagulation methods were also compared, in which the percentage obtained by electrocoagulation was 56.30% higher for the mining effluent. Thus, electrocoagulation was more efficient in boron removal, especially when appropriate parameters are applied.
RESUMEN
Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression-free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high-risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.
Asunto(s)
Isoquinolinas/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Purinas/administración & dosificación , Adulto , Anciano , Exantema/inducido químicamente , Femenino , Humanos , Isoquinolinas/toxicidad , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/toxicidad , Análisis de Supervivencia , Transaminasas/efectos de los fármacos , Resultado del TratamientoRESUMEN
Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.
Asunto(s)
Isoquinolinas/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Purinas/administración & dosificación , Adulto , Anciano , Femenino , Humanos , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/efectos adversos , Purinas/farmacocinética , Inducción de Remisión/métodos , Transaminasas/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163-levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS: We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first-generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS: Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION: sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response.