Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV-related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells (PBMCs) from chronically infected patients is mainly associated with CD19+ B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected PBMCs from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers, but also in HCV recovered patients and HCV negative healthy blood donors and that the serum components were heat labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti-complement C3 antibodies. In experiments with complement-depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti-CD21 and anti-CD35 antibodies could block the binding of patient-derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B cell line derived from Burkitt´s lymphoma.CONCLUSION:In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. This article is protected by copyright. All rights reserved.Fil: Wang, Richard. National Institutes of Health; Estados UnidosFil: Baré, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. National Institutes of Health; Estados UnidosFil: De Giorgi, Valeria. National Institutes of Health; Estados UnidosFil: Matsuura, Kentaro. Nagoya City University Graduate School of Medicine; Japón. National Institutes of Health; Estados UnidosFil: Salam, Kazi Abdus. National Institutes of Health; Estados Unidos. University of Rajshahi; IndiaFil: Grandinetti, Teresa. National Institutes of Health; Estados UnidosFil: Schechterly, Cathy. National Institutes of Health; Estados UnidosFil: Alter, Harvey J.. National Institutes of Health; Estados Unido

Darolutamide in hormone-sensitive and castration-resistant prostate cancer

Introduction: Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide.Areas covered:This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones.Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.</p

Identification of murine phosphodiesterase 5A isoforms and their functional characterization in HL-1 cardiac cell line

Phosphodiesterase 5A (PDE5A) specifically degrades the ubiquitous second messenger cGMP and experimental and clinical data highlight its important role in cardiac diseases. To address PDE5A role in cardiac physiology, three splice variants of the PDE5A were cloned for the first time from mouse cDNA library (mPde5a1, mPde5a2 and mPde5a3). The predicted amino acidic sequences of the three murine isoforms are different in the N-terminal regulatory domain. mPDE5A isoforms were transfected in HEK293T cells and they showed high affinity for cGMP and similar sensitivity to sildenafil inhibition. RT-PCR analysis showed that mPde5a1, mPde5a2 and mPde5a3 had differential tissue distribution. In the adult heart, mPde5a1 and mPde5a2 were expressed at different levels whereas mPde5a3 was undetectable. Overexpression of mPDE5As induced an increase of HL-1 number cells which progress into cell cycle. mPDE5A1 and mPDE5A3 overexpression increased the number of polyploid and binucleated cells, mPDE5A3 widened HL-1 areas and modulated hypertrophic markers more efficiently respect to the other mPDE5A isoforms. Moreover, mPDE5A isoforms had differential subcellular localization: mPDE5A1 was mainly localized in the cytoplasm, mPDE5A2 and mPDE5A3 were also nuclear localized. These results demonstrate for the first time the existence of three PDE5A isoforms in mouse and highlight their potential role in the induction of hypertrophy. This article is protected by copyright. All rights reserved

A Feasible Methodological Approach to Estimate the Burden of Autism Spectrum Disorder: Results from the EPI-ASD Study in the Province of Lecce (Southern Italy)

Diagnoses of Autism Spectrum Disorder (ASD) have rapidly increased globally. However, the lack of comprehensive epidemiological surveys and surveillance systems, able to provide official data at a national or European level is one of the main issues in the monitoring of this condition. The present study aimed to estimate the prevalence of ASD in children and adolescents aged 3-18 years old living in the province of Lecce (Southern Italy) through official data provided by the Local Health Authority of Lecce (ASL/LE) up to 31 October 2020, and compare it with school-based data concerning the number of students needing support for ASD. Based on data provided by the ASL/LE, in 2020 there were 509 cases of ASD among children and adolescents aged 3-18 years old, corresponding to a prevalence of 0.46%. A total of 408 (80.2%) were boys and 101 (19.8%) were girls. In relation to their age, 155 ASD cases (0.90%) were diagnosed in the 3-5 age group, while 222 (0.55%) in the 6-11 age group and 132 (0.25%) in the 12-18 age group. Prevalence of ASD assessed by school-based dataset was underestimated in the 3-5 age group, while the 6-11 and 12-18 age groups were consistent with the official data provided by the ASL/LE

Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls.</p> <p>Methods</p> <p>Gene expression profiling of liver tissues has been performed using a high-density microarray containing 36'000 oligos, representing 90% of the human genes. Samples were obtained from 14 patients affected by HCV-related HCC and 7 HCV-negative non-liver-cancer patients, enrolled at INT in Naples. Transcriptional profiles identified in liver biopsies from HCC nodules and paired non-adjacent non-HCC liver tissue of the same HCV-positive patients were compared to those from HCV-negative controls by the Cluster program. The pathway analysis was performed using the BRB-Array- Tools based on the "Ingenuity System Database". Significance threshold of <it>t</it>-test was set at 0.001.</p> <p>Results</p> <p>Significant differences were found between the expression patterns of several genes falling into different metabolic and inflammation/immunity pathways in HCV-related HCC tissues as well as the non-HCC counterpart compared to normal liver tissues. Only few genes were found differentially expressed between HCV-related HCC tissues and paired non-HCC counterpart.</p> <p>Conclusion</p> <p>In this study, informative data on the global gene expression pattern of HCV-related HCC and non-HCC counterpart, as well as on their difference with the one observed in normal liver tissues have been obtained. These results may lead to the identification of specific biomarkers relevant to develop tools for detection, diagnosis, and classification of HCV-related HCC.</p

BASES EPIDEMIOLÓGICAS Y ESTRATEGIAS DE SANITIZACIÓN DE SARNA EN PERA WILLIAM'S EN EL ALTO VALLE DE RIO NEGRO Y NEUQUÉN

Con el propósito de vislumbrar el comportamiento de la sarna de peral causada por Venturia pirina, y avanzar en el manejo de la enfermedad en la región (Río Negro y Neuquén), los objetivos de este estudio fueron: (i) Evaluar la liberación y captura de esporas en relación a las condiciones climáticas (CC) y presencia de síntomas de la enfermedad, en dos huertos comerciales de pera William’s con antecedentes, y (ii) comparar la degradación de hojarasca entera y triturada en combinación con urea y bioformulados i.a. Trichoderma, como estrategia de sanitización. Las CC y capturas se monitorearon durante septiembre a diciembre 2022. La captura de ascosporas se registró con eventos de rocío, precipitaciones y horas de hoja mojada, aumentado la incidencia de la enfermedad en enero, resultando los conidios el principal inóculo. La degradación de hojarasca evaluada de junio a octubre 2022 como pérdida de peso (%) a los 60, 90 y 120 días de inicio del ensayo, fue significativamente mayor con la trituración para todas las combinaciones

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.)

Bases epidemiológicas y estrategias de sanitización de sarna en pera William's en el alto valle de Rio Negro y Neuquén

Con el propósito de vislumbrar el comportamiento de la sarna de peral causada por Venturia pirina, y avanzar en el manejo de la enfermedad en la región (Río Negro y Neuquén), los objetivos de este estudio fueron: (i) Evaluar la liberación y captura de esporas en relación a las condiciones climáticas (CC) y presencia de síntomas de la enfermedad, en dos huertos comerciales de pera William’s con antecedentes, y (ii) comparar la degradación de hojarasca entera y triturada en combinación con urea y bioformulados i.a. Trichoderma, como estrategia de sanitización. Las CC y capturas se monitorearon durante septiembre a diciembre 2022. La captura de ascosporas se registró con eventos de rocío, precipitaciones y horas de hoja mojada, aumentado la incidencia de la enfermedad en enero, resultando los conidios el principal inóculo. La degradación de hojarasca evaluada de junio a octubre 2022 como pérdida de peso (%) a los 60, 90 y 120 días de inicio del ensayo, fue significativamente mayor con la trituración para todas las combinaciones.Fil: Vexenat De Giorgi, Leticia. Universidad Nacional del Comahue. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; Argentina.Fil: Vexenat De Giorgi, Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Lutz, M. Cecilia. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; Argentina.Fil: Lutz, M. Cecilia. Universidad Nacional del Comahue. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; Argentina.Fil: Lutz, M. Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Reyes, Fernanda. Universidad Nacional del Comahue. Instituto deTierras, Agua y Medio Ambiente; Argentina.Fil: Reyes, Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Basso, Carla N. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; Argentina.Fil: Basso, Carla N. Universidad Nacional del Comahue. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; Argentina.Fil: Basso, Carla N. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Blackhall, Valeria. Universidad Nacional del Comahue. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; Argentina.Fil: Blackhall, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Sosa, M. Cristina. Universidad Nacional del Comahue. Facultad de Ciencias Agrarias; Argentina.Fil: Sosa, M. Cristina. Universidad Nacional del Comahue. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; Argentina.Fil: Sosa, M. Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

An immunologic portrait of cancer

The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior

The stable traits of melanoma genetics: an alternate approach to target discovery

<p>Abstract</p> <p>Background</p> <p>The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number.</p> <p>Results</p> <p>Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including <it>MITF</it>, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis.</p> <p>Conclusions</p> <p>This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.</p