Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. SIGNIFICANCE: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275.

Arginase 1 is a key driver of immune suppression in pancreatic cancer.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions.

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significance: The causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

A sociogenia fanoniana e a formação em psicologia: uma aposta clínica política e negra / Fanonian sociogeny and training in psychology: a political and black clinical bid / La sociogenia fanoniana y la formación en psicología: una apuesta clínica política y negra

Resumo Em 2020, recebíamos, no Brasil, a tradução do livro Écrits sur l´aliénation et la liberté de Frantz Fanon que, aliado a outras obras como Pele negra, máscaras brancas e Os condenados da terra, apresentava a sociogenia como condição imprescindível para compreensão das vidas negras em sua relação com o sofrimento físico e psíquico e a possibilidade de um fazer clínico que não se pautasse apenas na dimensão filogenética e ontogenética dos estados mentais e físicos. Partindo da sociogenia fanoniana como princípio e método, este artigo objetiva refletir sobre a possibilidade de construção de um processo de formação em Psicologia que tome a dimensão sociogênica como espaço vital para que o cuidado possa ser pensado em relação às comunidades negras nos diferentes contextos brasileiros. Defendemos a necessidade urgente de a formação e a práxis em Psicologia assumirem a discussão da sociogênese fanoniana como imprescindível.

Resumen En 2020 recibimos la traducción brasileña del libro Écrits sur l´aliénation et la liberté, de Frantz Fanon. Combinado con otras obras como Piel negra, máscaras blancas y Los condenados de la tierra, el libro presenta la sociogenia como condición esencial para comprender las vidas negras en su relación con el sufrimiento físico y psíquico y la posibilidad de una práctica clínica que no se basa únicamente en la dimensión filogenética y ontogenética de los estados físicos y mentales. A partir de la sociogenia fanoniana como principio y método, este artículo tiene como objetivo principal reflexionar sobre las posibilidades de construir un proceso de formación en Psicología que aborde la dimensión sociogénica como un espacio vital para pensar el cuidado en relación con las comunidades negras en diferentes contextos brasileños. Defendemos la urgente necesidad de formación y praxis en Psicología para asumir como imprescindible la discusión de la sociogénesis fanoniana.

Abstract In 2020, we received the Brazilian translation of the book Écrits sur l´aliénation et la liberté (Alienation and freedom), by Frantz Fanon. Combined with other works such as Black skin, white masks and The wretched of the earth, the book presents sociogeny as an essential condition for understanding black lives in their relationship with physical and psychological suffering and the possibility of a clinical practice that is not based solely on the phylogenetic and ontogenetic dimension mental and physical states. Starting from Fanonian sociogeny as a principle and method, this paper aims to reflect on the possibility of building a training process in Psychology that takes the sociogenic dimension as a vital space so that care can be thought of in relation to black communities in different Brazilian contexts. We defend the urgent need for training and praxis in Psychology to assume the discussion of Fanonian sociogenesis as essential.

Racismo, Trauma Colonial e Agência Crítica: Fórum Estadual de Mulheres Negras do Rio de Janeiro / Racism, Colonial Trauma, and Agency: The State Forum of Black Women in Rio de Janeiro / Racismo, Trauma Colonial y Agencia Crítica: Fórum Estadual de Mujeres Negras del Río de Janeiro

A relação entre racismo, subjetividade e o trauma colonial tem, cada vez mais, ocupado os debates no campo dos estudos e pesquisas em Psicologia. Este artigo tem como foco os processos de subjetivação, levando em consideração a relação entre racismo, gênero e o trauma colonial, bem como as agências possíveis que emergem nas vidas das mulheres negras ativistas. Adotando a interseccionalidade enquanto lente epistemológica e metodológica negra, os discursos e práticas de mulheres que fazem parte do Fórum Estadual de Mulheres Negras do Rio de Janeiro assumem aqui o protagonismo, compondo um espaço perpassado por agências políticas de re-existência e reivindicação de falas, escutas e ações de mulheres negras. Pode-se considerar, a partir da atuação no Fórum, que a consciência e a participação em uma instituição coletiva política feminina negra atuam como forças impulsionadoras, tanto em espaços públicos, pressionando o poder do Estado, quanto formando as mulheres negras nos/para espaços microcapilares e cotidianos. Foi possível perceber como a agência das mulheres negras possibilita formas de devolver o trauma colonial ao mundo através de uma mística quilombola coletiva pelo bem viver.

The relationship between racism, subjectivity and colonial trauma has increasingly been debated in the field of studies and research in Psychology. This paper focuses on the processes of subjectivation, taking into account the relationship between racism, gender, and colonial trauma, as well as the possible agencies that emerge in the lives of black women activists. We adopt intersectionality as a black epistemological and methodological lens. The discourses and practices of women who are part of the State Forum of Black Women of Rio de Janeiro assume the leading role in this study, creating a space permeated by political agencies of re-existence and demand for black women's voices, listening, and actions. It can be considered, from the performance in the forum, that consciousness and participation in a collective black female political institution act as a driving force both in public spaces, as pressure on the power of the State, as well as preparing black women for microcapillary and everyday spaces. Therefore, it was possible to perceive how the agency of black women can return the colonial trauma to the world through a collective mystic quilombola for "good living".

La relación entre racismo, subjetividad y trauma colonial ha ocupado cada vez más los debates dentro del campo de estudios y investigaciones en Psicologia. Este artículo tiene por foco los procesos de subjetivación, tomando en cuenta la relación entre racismo, género y trauma colonial, así como las agencias críticas posibles que emergen en la vida de las mujeres negras activistas. Tomando la interseccionalidad como lente epistemológica y metodológica negra, los discursos y prácticas de mujeres que hacen parte del Fórum Estadual de Mujeres Negras de Rio de Janeiro asumen aquí el protagonismo, formando un espacio, permeado por agencia política de re-existencia y reivindicación de palabras, escuchas y acciones de mujeres negras. Se puede considerar a partir de la actuación en el Fórum que la consciencia y participación en una institución colectiva política femenina negra, actúan como fuerzas impulsoras tanto en espacios públicos, presionando el poder del Estado, así como formando mujeres negras en y para espacios microcapilares y cotidianos. Fue posible percibir como la agencia crítica de mujeres negras posibilita formas de devolver el trauma colonial al mundo a través de una mística cimarrona colectiva por el bien vivir.

Patient blood management in a Cardiac Surgery Center, how to start?

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MHC Class II Expression Influences the Composition and Distribution of Immune Cells in the Metastatic Colorectal Cancer Microenvironment.

Despite advances in therapy over the past decades, metastatic colorectal cancer (mCRC) remains a highly morbid disease. While the impact of MHC-I on immune infiltration in mCRC has been well studied, data on the consequences of MHC-II loss are lacking. Multiplex fluorescent immunohistochemistry (mfIHC) was performed on 149 patients undergoing curative intent resection for mCRC and stratified into high and low human leukocyte antigen isotype DR (HLA-DR) expressing tumors. Intratumoral HLA-DR expression was found in stromal bands, and its expression level was associated with different infiltrating immune cell makeup and distribution. Low HLA-DR expression was associated with increased intercellular distances and decreased population mixing of T helper cells and antigen-presenting cells (APC), suggestive of decreased interactions. This was associated with less co-localization of tumor cells and cytotoxic T lymphocytes (CTLs), which tended to be in a less activated state as determined by Ki67 and granzyme B expression. These findings suggest that low HLA-DR in the tumor microenvironment of mCRC may reflect a state of poor helper T-cell interactions with APCs and CTL-mediated anti-tumor activity. Efforts to restore/enhance MHC-II presentation may be a useful strategy to enhance checkpoint inhibition therapy in the future.

Improving Awareness about Patient Blood Management in Portugal: A Call for Action Arising from a Delphi Panel.

INTRODUCTION: Anaemia and iron deficiency are associated with increased mortality and poor surgical outcomes. Consensus in their definitions is expected to optimize their management, which is encompassed by patient blood management, providing patient-centred care while improving patient safety and clinical outcomes. Patient blood management implementation is even more relevant in contingency times and faces barriers due to lack of standardization, among others. The aim is to establish a consensus on these diagnoses and implement patient blood management principles in clinical practice in Portugal. MATERIAL AND METHODS: Eight experts in Transfusion Medicine, Haematology, Anaesthesiology, Internal Medicine, and Obstetrics/Gynaecology were assembled; a focus group was conducted, defining 33 statements. A Delphi panel was conducted, with experts from the clinical specialities named above as well as from General Surgery, Urology, and Orthopaedics. RESULTS: The Delphi panel's rounds had 70 (Round 1) and 46 (Round 2) respondents. Specialists were consensual in only two statements, on the existence of a preoperative patient blood management consultation for candidates to elective surgeries in which the use of blood derivatives is anticipated and, on the importance of the correction of postoperative anaemia and iron deficiency. Of the remaining 31 statements, 27 reached high agreement or disagreement by the respondents. CONCLUSION: Consensus was reached in only two (6%) of the 33 statements. There was a consensual agreement on the relevance of establishing patient blood management as the standard of care and of valuing preoperative and postoperative patient blood management interventions. Nevertheless, our results point to the lack of awareness regarding patient blood management principles - which could result in better postoperative outcomes, shorter hospitalizations, reduced costs and increased availability of beds. Training and literacy initiatives could help further implement patient blood management standards in Portuguese hospitals.

Introdução: A anemia e ferropenia estão associadas a um aumento da mortalidade e a piores resultados no período pós-operatório. Consensualizar as suas definições permitirá otimizar a sua gestão. O patient blood management engloba essa gestão, com relevo acrescido em situações de contingência, focado nos cuidados centrados no doente e na melhoria da segurança e dos outcomes. As barreiras à implementação de princípios patient blood management prendem-se, entre outras, com falta de padronização. Pretende--se estabelecer um consenso sobre estes diagnósticos e implementação de patient blood management na prática clínica em Portugal. Material e Métodos: Foram reunidos oito especialistas em Imuno-hemoterapia, Hematologia Clínica, Anestesiologia, Medicina Interna e Obstetrícia/ Ginecologia. Foi realizado um focus group, onde foram definidas 33 afirmações. Além disso, foi realizado um painel Delphi, com especialistas das áreas mencionadas acima, assim como de Cirurgia Geral, Urologia e Ortopedia. Resultados: As duas rondas do painel Delphi tiveram, respetivamente, 70 e 46 respondedores. Estes foram consensuais em apenas duas afirmações, na existência de consulta pré-operatória de patient blood management para os candidatos a cirurgias eletivas em que se antecipa o uso de hemoderivados e, na importância da correção da anemia e ferropenia pós-operatórias. Das 31 afirmações restantes, 27 atingiram alta concordância ou discordância pelos respondentes. Conclusão: Foi alcançado consenso em apenas duas (6%) das 33 afirmações. Houve consenso sobre a relevância de estabelecer o patient blood management como standard of care e a valorização das intervenções de patient blood management pré e pós-operatórias. No entanto, os resultados indiciam falta de consciencialização sobre os princípios de patient blood management ­ que poderiam levar a melhores resultados pós-operatórios, com redução do tempo de hospitalização e dos custos e maior disponibilidade de camas. Iniciativas de formação e literacia poderiam ajudar a uma melhor implementação dos princípios de patient blood management nos hospitais portugueses.

Cellular engagement and interaction in the tumor microenvironment predict non-response to PD-1/PD-L1 inhibitors in metastatic non-small cell lung cancer.

Immune checkpoint inhibitors (ICI) with anti-PD-1/PD-L1 agents have improved the survival of patients with metastatic non-small cell lung cancer (mNSCLC). Tumor PD-L1 expression is an imperfect biomarker as it does not capture the complex interactions between constituents of the tumor microenvironment (TME). Using multiplex fluorescent immunohistochemistry (mfIHC), we modeled the TME to study the influence of cellular distribution and engagement on response to ICI in mNSCLC. We performed mfIHC on pretreatment tissue from patients with mNSCLC who received ICI. We used primary antibodies against CD3, CD8, CD163, PD-L1, pancytokeratin, and FOXP3; simple and complex phenotyping as well as spatial analyses was performed. We analyzed 68 distinct samples from 52 patients with mNSCLC. Patients were 39-79 years old (median 67); 44% were male and 75% had adenocarcinoma histology. The most used ICI was atezolizumab (48%). The percentage of PD-L1 positive epithelial tumor cells (EC), degree of cytotoxic T lymphocyte (CTL) engagement with EC, and degree of CTL engagement with helper T lymphocytes (HTL) were significantly lower in non-responders versus responders (p = 0.0163, p = 0.0026 and p = 0.0006, respectively). The combination of these 3 characteristics generated the best sensitivity and specificity to predict non-response to ICI and was also associated with shortened overall survival (p = 0.0271). The combination of low CTL engagement with EC and HTL along with low expression of EC PD-L1 represents a state of impaired endogenous immune reactivity. Together, they more precisely identified non-responders to ICI compared to PD-L1 alone and illustrate the importance of cellular interactions in the TME.

DNA-PK Inhibition and Radiation Promote Antitumoral Immunity through RNA Polymerase III in Pancreatic Cancer.

Targeting the DNA damage response in combination with radiation enhances type I interferon (T1IFN)-driven innate immune signaling. It is not understood, however, whether DNA-dependent protein kinase (DNA-PK), the kinase critical for repairing the majority of radiation-induced DNA double-strand breaks in cancer cells, is immunomodulatory. We show that combining radiation with DNA-PK inhibition increases cytosolic double-stranded DNA and tumoral T1IFN signaling in a cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-independent, but an RNA polymerase III (POL III), retinoic acid-inducible gene I (RIG-I), and antiviral-signaling protein (MAVS)-dependent manner. Although DNA-PK inhibition and radiation also promote programmed death-ligand 1 (PD-L1) expression, the use of anti-PD-L1 in combination with radiation and DNA-PK inhibitor potentiates antitumor immunity in pancreatic cancer models. Our findings demonstrate a novel mechanism for the antitumoral immune effects of DNA-PK inhibitor and radiation that leads to increased sensitivity to anti-PD-L1 in poorly immunogenic pancreatic cancers. IMPLICATIONS: Our work nominates a novel therapeutic strategy as well as its cellular mechanisms pertinent for future clinical trials combining M3814, radiation, and anti-PD-L1 antibody in patients with pancreatic cancer.

Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming.

BACKGROUND & AIMS: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. METHODS: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. RESULTS: We have discovered that non-cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. CONCLUSIONS: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB-Mediated Production of CXCL1.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in ApoE-/- mice showed reduced tumor growth in ApoE-/- mice. Histologic and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8+ T cells in tumors in ApoE-/- mice. Mechanistically, ApoE induced pancreatic tumor cell expression of Cxcl1 and Cxcl5, known immunosuppressive factors, through LDL receptor and NF-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment. SIGNIFICANCE: This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival.See related commentary by Sherman, p. 4186.

Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages.

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients.

Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. EXPERIMENTAL DESIGN: We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. RESULTS: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. CONCLUSIONS: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

Thermoregulatory capacity of Santa Inês hair ewes of different genotypes associated with coat colors raised in a hot environment.

The relationship between hair color characteristics and thermoregulatory responses in ewes raised in hot environment were evaluated. 15 Santa Inês hair ewes of different genotypes associated with coat colors (light brown, dark brown and black) with body weight of 41.2 ± 8.1 kg were evaluated during three consecutive days. Rectal temperature (RT, °C) and coat surface temperature (CST, °C) of seven anatomical points (front, back, croup, loin, side, thigh, and belly) were measured during the morning and afternoon periods. Thermoregulatory responses were recorded along with meteorological variables. Heat tolerance index (HTI) and thermal gradient (TG, °C) were estimated for each genotype. RT and CST were influenced by periods of the day (P < 0.05), being higher in the afternoon, but TG did not differ (P > 0.05) between periods. HTI, CST, and TG were equal (P > 0.05) among the three genotypes. Only RT was higher in animals with dark brown coats compared to light brown, but equal to the black coat. It was observed that animals with black or dark brown hairs have a strong association between the CST under study, and yet these had an inverse behavior with the RT. Animals with a darker coat tend to trigger heat dissipation in various anatomical regions of the body, presenting dynamics in thermoregulatory responses in relation to those with lighter coats. Santa Inês ewes have heat dissipation mechanisms as a function of different genotypes associated with coat colors, but have the same thermoregulatory aspects to maintain homeostasis, demonstrating an excellent adaptive mechanism in a hot environment.

Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8+ T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8+ T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.

Adaptive profile of dairy cows in a tropical region.

The objectives of this study were to determine the main variables which act in the adaptive profile and the dynamic of the thermoregulatory responses of Sindi and Girolando dairy cows in tropical conditions using multivariate analyses as the auxiliary method. Thirty dairy cows were evaluated, in which the data were collected monthly during 12 months. Rectal temperature (RT) and respiratory rate (RR) were measured twice a day (morning and afternoon), along with meteorological variables (air temperature, relative humidity, and wind speed), and later the Black Globe and Humidity Index and Radiant Heat Load were calculated. Blood samples were collected for estimating the levels of triiodothyronine (T3), thyroxine (T4), hemoglobin concentration (HC), red blood cells (RBC), packet cell volume (PCV), mean corpuscular volume (MCV), white blood cells (WBC), glucose (GLU), cholesterol (CHO), triglycerides (TRI), creatinine (CRE), total protein (TP), urea (URE), albumin (ALB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The more active variables in the adaptive profile for Sindi cows were T4, PCV, RBC, WBC, TRI, CRE, HC, T3, and URE, while PCV, RBC, ALB, TP, RT, RR, URE, ALT, and AST variables were more active for Girolando cows. All animals were classified according to their corresponding group when considering all variables under study. The classification error percentage was > 40% in the Sindi cows when the physiological responses were considered, whereas an 80% success rate was observed in Girolando cows in the winter and summer seasons. The physiological responses of the dairy cows are similar in winter and distinct in summer in tropical conditions.

Trauma, colonialidade e a sociogenia em Frantz Fanon: os estudos da subjetividade na encruzilhada / Trauma, coloniality, and Frantz Fanon's sociogenesis: studying subjectivities at the crossroads / Trauma, colonialidad y sociogenia en Frantz Fanon: los estudios de la subjetividad en la encrucijada

Partindo das discussões sobre trauma colonial e da ideia de sociogenia no pensamento de Frantz Fanon, a noção de sujeito e de subjetividade, produzidas no âmbito de matrizes eurocentradas, são interpeladas, tornando visível e dizível a insuficiência no entendimento dos processos subjetivos que atravessam as diferentes experiências de/em viver enquanto negras/os. A hegemonia branca aparece como o contraponto para compreensão do que podemos chamar de eventos traumáticos nas vidas negras. Faz-se urgente, nas experiências negras, descolonizar o eu e o mundo, conjurando a violência da colonialidade, possibilitando que negras/os se constituam enquanto sujeitos e não mais como a/o outra/o da branquitude.

Grounded on recent discussions about the colonial trauma and on Frantz Fanon's concept of sociogenesis, this paper problematizes the notions of subject and subjectivity as they have been produced by Eurocentric lenses. The aim is to bring these notions to the level of visibility and sayability with a view to highlighting their inability to understand the subjective processes of living while Black. White hegemony is paramount for us to understand what we may call traumatic events in/of Black experiences. I argue for the urgency of decolonizing the I and the world. This can only be done through a critique of colonial violence. Such a critique aims to open affordances for Black people to constitute themselves as subjects own their own rights rather than as the Other of whiteness.

A partir de las discusiones sobre el trauma colonial y de la idea de sociogenia en el pensamiento de Frantz Fanon, se cuestionan la noción de sujeto y subjetividad, producidas en el ámbito de las matrices eurocentradas, haciendo visible y decible la insuficiencia en el entendimiento de los procesos subjetivos que atraviesan las diferentes experiencias de/en vivir como persona negra. La hegemonía blanca aparece como el contrapunto para comprender lo que podemos llamar de eventos traumáticos en las vidas negras. Es urgente, en las experiencias negras, descolonizar el yo y el mundo, conjurando la violencia de la colonialidad, permitiendo que la persona negra se constituya como sujeto y no más como el otro de la blanquitud.

Takayasu's Arteritis and Cardiac Surgery: an Anaesthetic Challenge.

Takayasu's arteritis (TA) is a rare inflammatory vascular disease, which causes a chronic progressive pan-endarteritis involving the aorta and its main branches, leading to persistent and uncontrolled hypertension and symptoms related to ischemia such as claudication, visual disturbances, stroke and transient ischemic attack. Limited information is available concerning anaesthetic management. We present the successful anaesthetic management of a 55 years old woman with TA scheduled for mitral valve replacement, tricuspid valve annuloplasty and coronary artery bypass grafting (CABG). The choice of anaesthetic technique took into consideration mainly the maintenance of blood pressure in the intraoperative and postoperative periods. According to our monitoring records, we can say that our choice enabled a safe and stable anaesthetic procedure.