Agora

People facing incurable cancer need appropriate informal psychosocial care. This study examines the experiences and needs of visitors of IPSO centers (psychosocial supporting centers for life with and after cancer) for people facing incurable cancer in order to optimize the services provided by IPSO centers for this group. Semi-structured interviews were conducted with visitors of IPSO centers, both patients and relatives facing incurable cancer. The interviews were analyzed thematically. Eight themes and two sub themes were identified. In total, 18 patients and 13 relatives and bereaved relatives were interviewed. Participants expressed a strong need for understanding, exchanging information and finding ways to fill their days. They appreciated IPSO's non-obligatory approach and highlight the value of sharing stories with others. Many participants experienced mixed peer groups including both people facing curable and incurable cancer, as uncomfortable. They emphasized the benefit of having separate peer groups for those facing incurable cancer, including able to talk openly about end of life and a deeper sense of understanding and connection. A few participants found these groups inaccessible due to a specific setup. Visitors also experience unpredictability and uncertainty from their illness, making planning difficult, which also affect their IPSO visit. IPSO centers play a crucial role in supporting people facing incurable cancer. To best meet their needs, it is essential to facilitate peer contact by organizing special peer groups or by introducing those facing incurable cancer to each other in another way. It is important to take into account accessibility. Further research should focus on individuals who need IPSO's informal care but are not able to benefit from it due to their burden of disease.

Abstract Antiretroviral therapy (ART) halts HIV-1 replication, reducing plasma virus levels to below the limit of detection, but it is not curative due to a reservoir of latently infected CD4 + T cells. In some people living with HIV-1 (PLWH), plasma HIV-1 RNA becomes persistently detectable despite optimal ART. This nonsuppressible viremia (NSV) is characterized by identical, non-evolving HIV-1 RNA variants expressed from infected CD4 + T cell clones. The mechanisms driving persistent virus production from a specific population of infected cells are poorly understood. We hypothesized that proviruses in cells responding to chronic immunologic stimuli, including self-associated antigens, may drive viral gene expression and NSV. Here, we demonstrate that stimulation of CD4 + T cells with autologous cell lysates induces virus production in an MHC-II-dependent manner. In 7 of 8 participants with NSV, we recovered viral RNA released ex vivo in response to autologous cell lysates that matched plasma virus. This process involves both defective and replication-competent proviruses residing in conventional T cells, and is also observed in PLWH with undetectable viremia. These findings suggest that recognition of self-associated antigens is an important cause of HIV-1 reservoir expression, which can contribute to persistent systemic inflammation and potential rebound upon ART interruption. One sentence summary HIV-1 viremia not suppressed by effective ART can be caused by proviruses in CD4 + T cells reactive to autologous antigens.

Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for most non-malignant cell types frequently observed in the microenvironment of human tumors. We then integrate these data into the EPIC deconvolution framework (Racle et al., 2017) to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a human breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes.

Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and other diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to antibodies to enable cell-type-specific delivery. Our antibody-peptide inhibitor conjugates specifically blocked the activity of cathepsins in different cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in cancer and other diseases.

Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for all major cancer-relevant cell types. We then capitalize on the EPIC deconvolution framework (Racle et al. 2017) previously shown to accurately predict cell-type composition in tumor bulk RNA-Seq data and integrate our markers and reference profiles to EPIC to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes.

Andrey Rolyenok’s conversation/correspondence with David Ames Curtis on Cornelius Castoriadis’s legacy, its preservation, promotion, and critical updating in the context of the current socio-political situation took place in January–March 2023. The contribution of the Agora International Association to the development and extension of Castoriadis’s work is considered in the interview. The origins of Castoriadis’s thought (break with Marxism, revision of psychoanalysis, influence of Martin Heidegger’s ideas, return to ancient philosophy, etc.) are evoked. Key ideas of Castoriadis are reconstructed and contextualized (the project of individual and collective autonomy, creativity, and the rising tide of insignificancy). The problem of the reception and critique of Castoriadis’s ideas in contemporary social thought is articulated (e.g. in Zygmunt Bauman’s theory of liquid modernity).

Devido ao crescente uso farmacológico de progestógenos ao longo da gravidez para a prevenção do parto prematuro, a relação entre esses hormônios e o diabetes gestacional requer atenção. A morte de células beta-pancreáticas está associada aos diabetes tipo I e tipo II, mas ainda precisa ser melhor compreendida no contexto do diabetes gestacional. Para investigar este problema, experimentos de microarray foram conduzidos com células da linhagem RINm5F submetidas à progesterona em três doses (0,1 M, 1 M e 100 M) e dois tempos (6h e 24h). A análise de agrupamento em dados de expressão gênica é amplamente utilizada para auxiliar no entendimento da função dos genes e tem sido consistentemente aplicada na literatura. No entanto, diante da variedade de técnicas de agrupamento existentes, a escolha daquela mais adequada a determinado problema torna-se um desafio. O estudo desenvolvido por Saelens, Cannoodt e Saeys, em 2018, buscou preencher tal lacuna avaliando, segundo índices de validação externa e com base em módulos conhecidos, vários métodos de agrupamento e propondo uma metodologia para a realização de estudos comparativos que envolvam detecção de módulos em dados de expressão gênica. No entanto, em cenários do mundo real, o pesquisador muitas vezes só tem à sua disposição os índices de validação internos, não dispondo de módulos conhecidos a respeito dos genes, como no caso do presente trabalho. Desta forma, para proceder com a análise de agrupamento dos dados das células beta-pancreáticas submetidas à progesterona, fez-se necessário estender o estudo mencionado para incluir índices de avaliação internos, de modo a selecionar a técnica e os parâmetros adequados ao problema. Ao fim dos experimentos, foram selecionados para a análise de enriquecimento funcional os resultados de agrupamento de acordo com as pontuações baseadas nos índices de validação externos e internos. Do ponto de vista da compreensão do problema, o resultado mais significativo foi aquele obtido por meio de índices internos, revelando que o gene TXNIP é relevante para a compreensão do diabetes gestacional

CD4+ T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. While multiple CD4+ T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+ T cell transcriptional states. In addition, the progressive changes affecting CD4+ T cell subtypes during and after immune responses remain poorly defined. Using single-cell transcriptomics, we characterized the diversity of CD4+ T cells responding to self-resolving and chronic viral infections in mice. We built a comprehensive map of virus-specific CD4+ T cells and their evolution over time, and identified six major cell states consistently observed in acute and chronic infections. During the course of acute infections, T cell composition progressively changed from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, in persistent infections T cells acquired distinct, chronicity-associated programs. By single-cell T cell receptor (TCR) analysis, we characterized the clonal structure of virus-specific CD4+ T cells across individuals. Virus-specific CD4+ T cell responses were essentially private across individuals and most T cells differentiated into both Tfh and Th1 subtypes irrespective of their TCR. Finally, we showed that our CD4+ T cell map can be used as a reference to accurately interpret cell states in external single-cell datasets across tissues and disease models. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+ T cells responding to viruses and provides a new computational resource for CD4+ T cell analysis.

Le poids de la Seconde Guerre mondiale continue de peser sur l’Allemagne. L’utilisation de la puissance militaire y est considérée avec circonspection, tant par les élites politiques que par une partie importante de la population. La dégradation du contexte stratégique incite toutefois les dirigeants à repenser le rôle de la Bundeswehr. Le budget de la Défense augmente et les effectifs des armées sont amenés à croître significativement dans les prochaines années.