Targeting internal ribosome entry site (IRES)-mediated translation to block hepatitis C and other RNA viruses

A number of RNA-containing viruses such as hepatitis C (HCV) and poliovirus (PV) that infect human beings and cause serious diseases use a common mechanism for synthesis of viral proteins, termed internal ribosome entry site (IRES)-mediated translation. This mode of translation initiation involves entry of 40S ribosome internally to the 5' untranslated region (UTR) of viral RNA. Cap-dependent translation of cellular mRNAs, on the other hand, requires recognition of mRNA 5' cap by the translation machinery. In this review, we discuss two inhibitors that specifically inhibit viral IRES-mediated translation without interfering with cellular cap-dependent translation. We present evidence, which suggest that one of these inhibitors, a small RNA (called IRNA) originally isolated from the yeast Saccharomyces cerevisiae, inhibits viral IRES-mediated translation by sequestering both noncanonical transacting factors and canonical initiation factors required for IRES-mediated translation. The other inhibitor, a small peptide from the lupus autoantigen La (called LAP), appears to block binding of cellular transacting factors to viral IRES elements. These results suggest that it might be possible to target viral IRES-mediated translation for future development of therapeutic agents effective against a number of RNA viruses including HCV that exclusively use cap-independent translation for synthesis of viral proteins

Describes the experience of nursing students in a center of testing na counseling that offers anti-HIV test

Relata-se a experiência de graduandos de enfermagem num Centro de Orientação e Apoio Sorológico (COAS) para a realização do teste anti-HIV. Objetivos: descrever a experiência; identificar fatores dificultadores e facilitadores na realização do aconselhamento. As dificuldades: o preparo insuficiente para abordar aspectos sobre a sexualidade, a insegurança na tomada de condutas, o preconceito frente a diferentes práticas sexuais, o tempo exíguo para o estabelecimento de vínculos e a ansiedade ao comunicar os resultados positivos. As facilidades: a receptividade da equipe, sua disponibilidade para descrever o funcionamento do serviço, orientar e esclarecer dúvidas surgidas durante o desenvolvimento do trabalho; a realização das palestras, bem como a existência de impressos utilizados no aconselhamento pré e pós teste e a disponibilidade de recursos educativos, como as fitas de vídeo.Se relata la experiencia de estudiantes de enfermería en un Centro de Orientación y Apoyo (COAS) para la realización de la prueba anti-HIV. Objetivos: Describir la experiencia, identificar factores limitantes y facilitadores en la realización de la consejería. Las dificultades: La preparación insuficiente para abordar aspectos sobre la sexualidad, la inseguridad en la toma de conductas, el preconcepto frente a diferentes prácticas sexuales, el poco tiempo para el establecimiento de vínculos y la ansiedad al comunicar los resultados positivos. Las facilidades: La receptividad del equipo, su disponibilidad para describir el funcionamiento del servicio, orientar y establecer dudas surgidas durante el desarrollo del trabajo; la realización de las charlas educativas, así como también la existencia de material impreso utilizado en la consejería antes y después de la prueba y la disponibilidad de recursos educativos, tales como, películas de vídeo.The paper describes the experience of undergraduated nursing students in a Center of Testing and Counseling (CTA), that offers anti-HIV test. There were identifed the facilities and the difficulties faced in the accomplishment of the counseling before and after-test, for five months, aiming to propose strategies to surmount them

Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443

Indicators to assess the quality of programs to prevent occupational risk for tuberculosis: are they feasible?

Objetivo: analisar a viabilidade de indicadores de qualidade para avaliação de programas hospitalares de prevenção de tuberculose ocupacional. Método: estudo descritivo transversal. Testaram-se indicadores de avaliação de programas de prevenção de tuberculose ocupacional em seis hospitais. O critério para definir a viabilidade foi o tempo necessário para aplicar os indicadores. Resultados: o tempo necessário para avaliar os indicadores variou de 02'52'' até 15h11'24''. O indicador para a avaliação da estrutura demandou menor tempo; o maior tempo foi utilizado com os indicadores de processo, incluindo a observação das práticas dos trabalhadores de saúde em relação ao uso de máscaras N95. Um dos indicadores de resultados de tuberculose deixou de ser testado em cinco situações devido à falta de uso do teste tuberculínico nessas instituições. O tempo necessário para aplicar indicadores em relação aos resultados de tuberculose ocupacional depende em grande parte do nível da organização da estrutura administrativa para a coleta de dados. Conclusões: os indicadores de avaliação da estrutura de prevenção de tuberculose ocupacional são altamente viáveis. No entanto, a viabilidade de aplicação dos indicadores de processo e de resultado é limitada devido a variações relevantes em questões administrativas nas instituições de saúde.Objetivo: analizar la viabilidad de los indicadores de calidad de la evaluación de los programas hospitalarios para la prevención de la tuberculosis en el trabajo. Metodología: estudio descriptivo transversal. Se probaron los indicadores dirigidos a evaluar los programas para la prevención de la tuberculosis laboral en seis hospitales. El criterio para definir la viabilidad fue el tiempo para aplicar los indicadores. Resultados: el tiempo empleado para la evaluación de los los indicadores varió desde 02'52 '' hasta 15h11'24 ''. El indicador para la evaluación de la estructura requiere menos tiempo; se invirtió más tiempo en los indicadores de proceso, lo que incluye la observación de las prácticas de los empleados del cuidado de salud en relación con el uso de máscaras N95. No se pudo probar uno de los indicadores de resultados de tuberculosis en cinco situaciones debido a la falta de uso de la prueba de la tuberculina en estas centros. El tiempo necesario para aplicar los indicadores en relación con los resultados por tuberculosis laboral depende en gran medida del nivel de organización de la estructura administrativa para la recopilación de datos. Conclusiones: los indicadores para evaluar la estructura para la prevención de la tuberculosis laboral son altamente factibles. Sin embargo, la viabilidad de aplicación de los indicadores de proceso y el resultado es limitada debido a las variaciones relevantes en cuestiones administrativas en los centros sanitarios.Objective: to analyze the feasibility of quality indicators for evaluation of hospital programs for preventing occupational tuberculosis. Method: a descriptive cross-sectional study. We tested indicators for evaluating occupational tuberculosis prevention programs in six hospitals. The criterion to define feasibility was the time spent to calculate the indicators. Results: time spent to evaluate the indicators ranged from 2h 52min to 15h11min 24sec. The indicator for structure evaluation required less time; the longest time was spent on process indicators, including the observation of healthcare workers' practices in relation to the use of N95 masks. There was an hindrance to test one of the indicators for tuberculosis outcomes in five situations, due to the lack of use of tuberculin skin test in these facilities. The time requires to calculate indicators in regarding to the outcomes for occupational tuberculosis largely depends upon the level of organizational administrative structure for gathering data. Conclusions: indicators to evaluate the structure for occupational tuberculosis prevention are highly feasible. Nevertheless, the feasibility of indicators for process and outcome is limited due to relevant variations in administrative issues at healthcare facilities

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant

Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1–4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1]. Here, we present updated results from the ACE-LY-004 study after a median 26-month follow-up. Eligibility criteria and study design were published previously (Supplementary methods) [1]. Analysis of minimal residual disease (MRD) was conducted after complete response (CR) or partial response (PR) was achieved using the quantitative ClonoSEQ next-generation sequencing (5 × 10−6 ) assay (Adpative Biotechnologies, Seattle, WA, USA) in consenting patients with available paired archival tumor and whole blood samples. Data are updated as of February 12, 2018

Genetic Diversity of EBV-Encoded LMP1 in the Swiss HIV Cohort Study and Implication for NF-Κb Activation

Epstein-Barr virus (EBV) is associated with several types of cancers including Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane protein 1 (LMP1), a multifunctional oncoprotein, is a powerful activator of the transcription factor NF-κB, a property that is essential for EBV-transformed lymphoblastoid cell survival. Previous studies reported LMP1 sequence variations and induction of higher NF-κB activation levels compared to the prototype B95-8 LMP1 by some variants. Here we used biopsies of EBV-associated cancers and blood of individuals included in the Swiss HIV Cohort Study (SHCS) to analyze LMP1 genetic diversity and impact of sequence variations on LMP1-mediated NF-κB activation potential. We found that a number of variants mediate higher NF-κB activation levels when compared to B95-8 LMP1 and mapped three single polymorphisms responsible for this phenotype: F106Y, I124V and F144I. F106Y was present in all LMP1 isolated in this study and its effect was variant dependent, suggesting that it was modulated by other polymorphisms. The two polymorphisms I124V and F144I were present in distinct phylogenetic groups and were linked with other specific polymorphisms nearby, I152L and D150A/L151I, respectively. The two sets of polymorphisms, I124V/I152L and F144I/D150A/L151I, which were markers of increased NF-κB activation in vitro, were not associated with EBV-associated HL in the SHCS. Taken together these results highlighted the importance of single polymorphisms for the modulation of LMP1 signaling activity and demonstrated that several groups of LMP1 variants, through distinct mutational paths, mediated enhanced NF-κB activation levels compared to B95-8 LMP1

Indicators to assess the quality of programs to prevent occupational risk for tuberculosis: are they feasible?

Abstract Objective: to analyze the feasibility of quality indicators for evaluation of hospital programs for preventing occupational tuberculosis. Method: a descriptive cross-sectional study. We tested indicators for evaluating occupational tuberculosis prevention programs in six hospitals. The criterion to define feasibility was the time spent to calculate the indicators. Results: time spent to evaluate the indicators ranged from 2h 52min to 15h11min 24sec. The indicator for structure evaluation required less time; the longest time was spent on process indicators, including the observation of healthcare workers' practices in relation to the use of N95 masks. There was an hindrance to test one of the indicators for tuberculosis outcomes in five situations, due to the lack of use of tuberculin skin test in these facilities. The time requires to calculate indicators in regarding to the outcomes for occupational tuberculosis largely depends upon the level of organizational administrative structure for gathering data. Conclusions: indicators to evaluate the structure for occupational tuberculosis prevention are highly feasible. Nevertheless, the feasibility of indicators for process and outcome is limited due to relevant variations in administrative issues at healthcare facilities

Gravitational Test beyond the First Post-Newtonian Order with the Shadow of the M87 Black Hole

The 2017 Event Horizon Telescope (EHT) observations of the central source in M87 have led to the first measurement of the size of a black-hole shadow. This observation offers a new and clean gravitational test of the black-hole metric in the strong-field regime. We show analytically that spacetimes that deviate from the Kerr metric but satisfy weak-field tests can lead to large deviations in the predicted black-hole shadows that are inconsistent with even the current EHT measurements. We use numerical calculations of regular, parametric, non-Kerr metrics to identify the common characteristic among these different parametrizations that control the predicted shadow size. We show that the shadow-size measurements place significant constraints on deviation parameters that control the second post-Newtonian and higher orders of each metric and are, therefore, inaccessible to weak-field tests. The new constraints are complementary to those imposed by observations of gravitational waves from stellar-mass sources