Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer

BACKGROUND Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer. METHODS Using orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD). RESULTS We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy. CONCLUSIONS These findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy

COVID-19 bei einer Großveranstaltung: Erfahrungen aus der Kieler Woche 2022

Im Juni 2022 fand die Kieler Woche ohne pandemiebedingte einschränkende Maßnahmen statt. Im Anschluss daran verdreifachte sich binnen weniger Tage die lokale Sieben-Tage-Inzidenz der SARS-CoV-2-Infektionen. Im selben Zeitraum war bei den COVID-19-bedingten Hospitalisierungen, schweren Erkrankungen und Todesfällen allenfalls ein schwacher Anstieg zu verzeichnen. Dagegen kam es aufgrund der Absonderungsmaßnahmen zu umfangreichen Personalausfällen unter anderem in Krankenhäusern sowie damit auch zu einem starken Rückgang der Anzahl der belegbaren Krankenhausbetten auf Normalstationen. Der Erfahrungsbericht fasst die verfügbaren, quantifizierbaren epidemiologischen Auswirkungen der Kieler Woche 2022 zusammen.Peer Reviewe

Active monitoring of tuberculosis cases during the Covid-19 pandemic in a general hospital for acute patients in Buenos Aires City

A pesar de la existencia de un tratamiento efectivo, la persistencia de la tuberculosis (TB) en la Ciudad de Buenos Aires (CABA) señala los obstáculos presentes en la accesibilidad a los servicios de salud y la necesidad de visibilizar los determinantes sociales en la adherencia a los tratamientos antituberculosos. El contexto de la pandemia de covid-19 y del aislamiento social preventivo y obligatorio (ASPO) implicaron un fuerte desafío para reorganizar los servicios de salud y afecta de manera exacerbada a los grupos en situación de pobreza y vulnerabilidad social. Este artículo se propone señalar los principales resultados de la implementación de una modalidad de seguimiento activo de los casos de tuberculosis en un hospital general de agudos de CABA entre 2020 y 2021. Se utilizó un diseño de investigación en implementación con una metodología cuantitativa y cualitativa para reconocer los principales obstáculos en el seguimiento y la adherencia a los tratamientos antifímicos en el contexto de la pandemia de covid-19. Se identificaron los grupos sociales afectados por la TB con mayor vulnerabilidad social para el seguimiento: población en situación de calle, con consumo problemático de sustancias y población transfemenina. Se señala el armado de redes comunitarias con referentes de organizaciones de la sociedad civil como una estrategia efectiva para acompañar a esta población.Despite an effective treatment, the persistence of tuberculosis (TB) in the City of Buenos Aires (CABA, its acronym in Spanish) indicates the obstacles in accessibility to health services and the need to make the social determinants of adherence to the tuberculosis treatments visible. The covid-19 pandemic together with the preventive and compulsory social isolation (ASPO, its acronym in Spanish) mean a strong challenge for reorganizating health services and exacerbate the problems of poor and socially vulnerable groups. This article aims to show the main results of implementing an active follow-up modality of TB cases in a general hospital for acute patients in CABA in 2020-2021. The main obstacles in the follow-up and adherence to anti-fimic treatments in the context of the covid-19 pandemic were identified through a research design with quantitative and qualitative methodology. Social groups affected by TB and higher social vulnerability were identified for the follow-up: homeless, those with problematic substance use, and trans-female. Setting community networks with mentors from civil society organizations were an effective strategy for accompanying these populations.Fil: Pereyra, Andrés Martín. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Barrios, Rocio. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Aranda, Jimena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Herrero, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Longordo, Marina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Hering, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Ben, Graciela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Koufios, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Marcuzz, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Camera, Eugenia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Catalano, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Paz, Enroque. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentin

Protein tyrosine phosphatase non-receptor type 2 controls colorectal cancer development

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC) as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. Particularly, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T-cells and increased PTPN2 levels negatively correlated with PD1, CTLA4, STAT1 and granzyme A. In vivo, T-cell and dendritic cell-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T-cells, as well as CD8+ T-cell infiltration and cytotoxicity into the tumor. In direct relevance to CRC treatment, T-cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced anti-tumor memory formation upon tumor re-challenge in vivo. Our data suggest a role for PTPN2 in suppressing anti-tumor immunity and promoting tumor development in CRC patients. Our in vivo results uncover PTPN2 as a key player in controlling immunogenicity of CRC, with the strong potential to be exploited to promote cancer immunotherapy

Plants in aquatic ecosystems: current trends and future directions

Aquatic plants fulfil a wide range of ecological roles, and make a substantial contribution to the structure, function and service provision of aquatic ecosystems. Given their well-documented importance in aquatic ecosystems, research into aquatic plants continues to blossom. The 14th International Symposium on Aquatic Plants, held in Edinburgh in September 2015, brought together 120 delegates from 28 countries and six continents. This special issue of Hydrobiologia includes a select number of papers on aspects of aquatic plants, covering a wide range of species, systems and issues. In this paper we present an overview of current trends and future directions in aquatic plant research in the early 21st century. Our understanding of aquatic plant biology, the range of scientific issues being addressed and the range of techniques available to researchers have all arguably never been greater; however, substantial challenges exist to the conservation and management of both aquatic plants and the ecosystems in which they are found. The range of countries and continents represented by conference delegates and authors of papers in the special issue illustrate the global relevance of aquatic plant research in the early 21st century but also the many challenges that this burgeoning scientific discipline must address

Editorial. Raza: Perspectivas transatlánticas

Dos mujeres bajo un parasol rojo. Una de ellas, blanca; la otra, negra. La esclava porta la sombrilla para proteger a su ama de los efectos del sol. Todo ocurre en un mercado, en medio de la vida cotidiana en las Antillas. Esta circunstancia hace parte de algo más amplio. En un primer plano aparecen seres de diferentes colores, mercancías de consumo, textiles, arte, animales y, nuevamente, esclavos o pardos libres. En un segundo plano, incluso más extenso, se divisa el mar insinuando una red de comercio transatlántico. En medio de ese acontecimiento congelado se intuyen aspectos, aunque sin representación evidente. Muchos los sentían y vivían: prejuicios, estereotipos y jerarquías sociales que juntos formaban una poderosa matriz social del mundo colonial. La imagen es sin duda solo un fragmento del día a día. No hace falta decirlo, se trata de la portada del presente número, una pintura de Agostino Brunias de finales del siglo xviii que comentamos como abrebocas para el nuevo dossier en manos del lector

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

Background/Aims Knockdown of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) exaggerates IFN-γ-induced intestinal barrier defects, but mice constitutively lacking PTPN2 in epithelial cells (PTPN2xVilCre mice) do not show changes in epithelial function or enhanced susceptibility to experimental colitis. Here, we investigated whether PTPN2 modulates the expression of related tyrosine phosphatases. Methods PTPN2 knockdown in HT-29 cells was induced using siRNA constructs. Acute colitis in PTPN2xVilCre mice was induced by 2% dextran sulfate sodium (DSS) in drinking water for 7 days. Colitis-associated tumors were induced by injection of azoxymethane prior to treatment with DSS for 3 consecutive cycles. Results In HT-29 cells, PTPN2 depletion resulted in enhanced mRNA expression of PTPN11 and PTPN23 and in parallel to upregulation of IL-18 mRNA upon treatment with TNF for 24 h. DSS treatment of PTPN2-deficient mice resulted in a strong induction of Ptpn23 mRNA in colon tissue in vivo. In the tumor model, Ptpn23 mRNA was again clearly upregulated in nontumor tissue from PTPN2-deficient mice; however, this was not observed in tumor tissue. Conclusions Our experiments show that PTPN23 function might, at least partially, compensate lack of PTPN2 in epithelial cells. Upregulation of PTPN23 might therefore crucially contribute to the lack of a colitis phenotype in PTPN2-VilCre mice

Prospective Memory & External Clock Manipulation

AbstractThe present dataset comprises the data used for the paper called "The role of internal time processing in time monitoring and time-based prospective memory: Evidence from external clock manipulation" (current status: under review; Journal of Experimental Psychology: Learning, Memory, and Cognition). In this study, we investigated whether a manipulation of the external time affected time monitoring and time-based prospective memory (TBPM) performance in a sample of young adults (age range: 18 - 35). Participants performed two identical TBPM tasks: a baseline TBPM block with no clock speed manipulation followed by a second experimental TBPM block, where the clock speed was manipulated in three conditions: faster versus slower versus external-regular clock. Regardless of the condition, the actual digits displayed on the clock did not change in both baseline and experimental TBPM blocks (the tasks appeared to have the same duration)

Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner

The gut microbiota is crucial for our health, and well-balanced interactions between the host's immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host's response to the intestinal microbiota