Macrophage re-programming by JAK inhibitors relies on MAFB.

Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3ß, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.

Residential Greenness, Lifestyle, and Vitamin D: A Longitudinal Cohort of South Asian Origin and Caucasian Ethnicity Women Living in the South of the UK.

The global population is at risk of vitamin D deficiency due to low exposure to sunlight and low intake of the vitamin through diet. The aim of this study was to investigate in women the association between vitamin D status and parathyroid hormone (PTH), ultraviolet radiation, lifestyle, ethnicity, social conditions, and residential greenness. A 1-year longitudinal study assessed vitamin D status in 309 women living at latitude 51°14' N. Blood samples were taken four times throughout the year for analysis of 25(OH)D and serum PTH concentration. After each seasonal visit, the individuals completed 4-day diet diaries and used two dosimeter badges for 1 week to estimate weekly UVR exposure. A questionnaire was applied to provide information about lifestyle and their ethnicity. Residential greenness was measured by Normalized Difference Vegetation Index (NDVI), within a 1000 m radius around each participant's home address. Women living in greener spaces were more likely to have improved vitamin D status (RR: 1.51; 95%CI: 1.13-2.02), as well as those who were more exposed to UVR (RR: 2.05; 95%CI: 1.44-2.92). Our results provide an insight into the connection between residential greenness, lifestyle, and vitamin D status comparing two ethnicities in a country with a temperate climate and with a high degree of urbanization.

MAFB shapes human monocyte-derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression.

Monocyte-derived macrophages, the major source of pathogenic macrophages in COVID-19, are oppositely instructed by macrophage CSF (M-CSF) or granulocyte macrophage CSF (GM-CSF), which promote the generation of antiinflammatory/immunosuppressive MAFB+ (M-MØ) or proinflammatory macrophages (GM-MØ), respectively. The transcriptional profile of prevailing macrophage subsets in severe COVID-19 led us to hypothesize that MAFB shapes the transcriptome of pulmonary macrophages driving severe COVID-19 pathogenesis. We have now assessed the role of MAFB in the response of monocyte-derived macrophages to SARS-CoV-2 through genetic and pharmacological approaches, and we demonstrate that MAFB regulated the expression of the genes that define pulmonary pathogenic macrophages in severe COVID-19. Indeed, SARS-CoV-2 potentiated the expression of MAFB and MAFB-regulated genes in M-MØ and GM-MØ, where MAFB upregulated the expression of profibrotic and neutrophil-attracting factors. Thus, MAFB determines the transcriptome and functions of the monocyte-derived macrophage subsets that underlie pulmonary pathogenesis in severe COVID-19 and controls the expression of potentially useful biomarkers for COVID-19 severity.

GSK3ß Inhibition Prevents Macrophage Reprogramming by High-Dose Methotrexate.

Methotrexate (MTX) is an antifolate drug used as a chemotherapeutic agent for acute lymphoblastic leukemia, where MTX improves patients' prognosis. Macrophage reprogramming is being increasingly assessed as an antitumor therapeutic strategy. However, and although MTX limits the pathogenic action of macrophages in chronic inflammatory diseases, its effects on tumor-promoting macrophages have not been previously explored. We now report that MTX shapes the transcriptional and functional profile of M-CSF-dependent human macrophages, whose transcriptome is highly enriched in the gene signature that defines pathogenic tumor-associated macrophages ("large TAM"). Specifically, MTX prompted the acquisition of the gene signature of antitumoral "small TAM" and skewed macrophages toward an IL-6high IFNß1high IL-10low phenotype upon subsequent stimulation. Mechanistically, the MTX-induced macrophage reprogramming effect correlated with a reduction of the M-CSF receptor CSF1R expression and function, as well as a diminished expression of MAF and MAFB transcription factors, primary determinants of pro-tumoral macrophages whose transcriptional activity is dependent on GSK3ß. Indeed, the ability of MTX to transcriptionally reprogram macrophages toward an antitumoral phenotype was abrogated by inhibition of GSK3ß. Globally, our results establish MTX as a macrophage reprogramming drug and indicate that its ability to modulate macrophage polarization may also underlie its therapeutic benefits. Since GSK3ß inhibition abrogates the reprogramming action of MTX, our results suggest that the GSK3ß-MAFB/MAF axis constitutes a target for the macrophage-centered antitumor strategies.

Análise de dados fora do padrão sobre a água de abastecimento da região metropolitana de Salvador / Data analysis out of standard about water supply in the metropolitan region of Salvador / Análisis de los datos fuera del estándar sobre el suministro de agua en la región metropolitana de Salvador, Brasil

Os sistemas de informação do Ministério da Saúde são importantes ferramentas de planejamento das ações de saúde no território brasileiro. O Sistema de Informação de Vigilância da Qualidade da Água para Consumo Humano (Sisagua) oferece para toda a população dados sobre a situação do abastecimento de água para consumo humano, juntamente com eventuais problemas de qualidade que possam existir. É imprescindível para os gestores da área da saúde entender os maiores problemas de cada prestador de serviço de abastecimento a fim de oferecer água de boa qualidade para todas as pessoas, pois, uma vez que se trata de um bem público, todos têm direito à água de qualidade independentemente de sua condição social. Este trabalho averiguou os dados sobre a qualidade da água do estado da Bahia no período de janeiro de 2014 a março de 2022, com o objetivo de observar qual parâmetro de qualidade é responsável pela contaminações do recurso hídrico a ser consumido pelas pessoas, tornando-o fora de padrão conforme a Portaria nº 888/2021 do Ministério da Saúde. Através de gráficos de pizza gerados pelo Excel, foram averiguados os parâmetros que mais levaram a inconformidades. Foram observados, em porcentagem, os municípios que frequentemente ultrapassaram o padrão de potabilidade dentro da região. Dentro da região metropolitana de Salvador, o parâmetro cloro residual livre se destacou, seguido de cor e coliformes totais. A oferta de água doce limpa para a população é um dos pilares da saúde pública, sendo importante a constante evolução dos sistemas de abastecimento.

The information systems of the Ministry of Health are important tools for planning health actions in the Brazilian territory. The Drinking Water Quality Surveillance Information System (SISAGUA) provides the entire population with data on the situation of water supply for human consumption, alongside any water quality problems that may exist. It is essential for health managers to understand the biggest problems of each supply service provider to provide good quality water to all people, since, water being a public good, everyone has the right to quality water regardless of their social status. This work investigated the water quality data of the state of Bahia from January 2014 to March 2022, aiming to observe which quality parameter is most responsible for contaminating the water resource to be consumed by people, turning it non-standard according to Ordinance No. 888/2021 of the Ministry of Health. With pie charts generated by Excel, the parameters that most led to nonconformities were investigated. Municipalities that frequently exceed the standard of potability within the region were also observed in percentage. Within the metropolitan region of Salvador, the parameter free residual chlorine stood out, followed by color, and total coliforms. The supply of clean fresh water to the population is one of the pillars of public health, and the constant evolution of supply systems is important.

Los sistemas de información del Ministerio de Salud son herramientas importantes para planificar acciones de salud en Brasil. El Sistema de Información para la Vigilancia de la Calidad del Agua para Consumo Humano (Sisagua) proporciona a toda la población datos sobre el estado del suministro de agua para consumo humano y posibles problemas de calidad que puedan existir. Es fundamental que los responsables de las áreas de salud conozcan los problemas de cada red de suministro para poder ofrecer agua de buena calidad a todas las personas, ya que debido a este es un bien público, las personas tienen derecho al agua limpia de calidad, independientemente de su condición social. Este trabajo analizó los datos de calidad del agua en el estado de Bahía, en el período de enero de 2014 a marzo de 2022, con el objetivo de observar qué parámetro de calidad indica la contaminación del recurso hídrico a ser consumido por las personas, haciéndolo fuera del estándar desde la Ordenanza n.° 888/2021 del Ministerio de Salud. A partir de gráficos circulares en Excel, se analizaron los parámetros que más generaron las no conformidades. Se observó el porcentaje de los municipios que frecuentemente excedieron el estándar de potabilidad en la región. En la región metropolitana de Salvador destacó el parámetro cloro residual libre, seguido del color y coliformes totales. El suministro de agua dulce limpia a la población es uno de los elementos clave para la salud pública, y es importante la evolución de los sistemas de suministro.

Thymosin α1 continues to show promise as an enhancer for vaccine response.

Thymosin α1 (Tα1) is an immune-modulating peptide that can be expected to improve response to vaccinations, as stimulated dendritic cells and T cells can act in concert to increase antibody production along with an improved cytotoxic response from the T cells themselves. Tα1 demonstrated efficacy in preclinical studies; subsequently, it was shown to enhance response to vaccinations in difficult-to-treat populations, including individuals immune suppressed due to age or hemodialysis, and leading to a decrease in later infections. During the 2009 pandemic outbreak of H1N1 influenza, mouse and ferret studies confirmed that the use of higher doses of Tα1 allowed for fewer injections than those used in the previous clinical studies. In addition, a clinical study with Focetria™ MF59-adjuvanted monovalent H1N1 vaccine showed that treatment with Tα1 twice provided an earlier and greater response to the vaccine (P < 0.01).

Personalized medicine for mucositis: Bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis.

Gamma-D-glutamyl-L-tryptophan (SCV-07) demonstrated an overall efficacy signal in ameliorating oral mucositis (OM) in a clinical trial of head and neck cancer patients. However, not all SCV-07-treated subjects responded positively. Here we determined if specific gene clusters could discriminate between subjects who responded to SCV-07 and those who did not. Microarrays were done using peripheral blood RNA obtained at screening and on the last day of radiation from 28 subjects enrolled in the SCV-07 trial. An analytical technique was applied that relied on learned Bayesian networks to identify gene clusters which discriminated between individuals who received SCV-07 and those who received placebo, and which differentiated subjects for whom SCV-07 was an effective OM intervention from those for whom it was not. We identified 107 genes that discriminated SCV-07 responders from non-responders using four models and applied Akaike Information Criteria (AIC) and Bayes Factor (BF) analysis to evaluate predictive accuracy. AIC were superior to BF: the accuracy of predicting placebo vs. treatment was 78% using BF, but 91% using the AIC score. Our ability to differentiate responders from non-responders using the AIC score was dramatic and ranged from 93% to 100% depending on the dataset that was evaluated. Predictive Bayesian networks were identified and functional cluster analyses were performed. A specific 10 gene cluster was a critical contributor to the predictability of the dataset. Our results demonstrate proof of concept in which the application of a genomics-based analytical paradigm was capable of discriminating responders and non-responders for an OM intervention.

Thymosin alpha 1: past clinical experience and future promise.

Thymosin alpha 1, originally isolated as the compound responsible for reconstitution of immune function in thymectomized animal models, has enjoyed a wide-ranging clinical development program over the past decades, extending across multiple companies, indications, countries, and continents. This paper provides an overview of this complex picture. The extensive clinical studies began with small studies conducted with an impure mixture of peptides under the aegis of physician-sponsored INDs submitted to the US FDA, in subjects with primary immune deficiency such as DiGeorge syndrome. Subsequent studies ranged all the way to large phase-3 trials conducted with synthetically produced thymosin alpha 1 and hundreds of patients, in many countries including the United States, Italy, and China.

A randomized controlled trial of thymalfasin plus transarterial chemoembolization for unresectable hepatocellular carcinoma.

PURPOSE: Patients with advanced hepatocellular carcinoma (HCC) have few treatment options. Thymalfasin (thymosin α-1) is an immunomodulator that may increase response to ablative therapy through direct anti-tumor action or enhanced protection against infections. We compared transarterial chemoembolization (TACE) plus thymalfasin with TACE alone for unresectable HCC. METHODS: In this phase II, randomized trial, 25 patients received either TACE plus thymalfasin (1.6 mg SC, 5 times weekly; n = 14) or TACE alone (n = 11) for 24 weeks. Response was defined as transition to transplant eligibility or lack of disease progression through week 72. Survival was assessed through 24 months post-treatment. RESULTS: Eight of fourteen (57.1%) patients in the TACE + thymalfasin group versus 5 of 11 (45.5%) patients in the TACE-only group became responders (P = 1.0). Four of fourteen TACE + thymalfasin patients versus none of 11 TACE-only patients became eligible for transplant. Median overall survival time was 110.3 weeks for the TACE + thymalfasin group versus 57.0 weeks for the TACE-only group (P = 0.45). Seven patients in each group experienced serious adverse events; there were no bacterial infections in the TACE + thymalfasin group versus 4 in the TACE-only group. There were 3 deaths in the TACE + thymalfasin group and 5 in the TACE-only group. CONCLUSIONS: In patients with unresectable HCC, TACE + thymalfasin resulted in numerically higher rates of survival and tumor response, including transplant candidacy, with fewer bacterial infections, than TACE alone. Treatment regimens for HCC including thymalfasin as an immunomodulator should be evaluated in larger trials.