MARS Code Research Articles

Abstract LB227: Accelerated intra-clonal transcriptomic diversification of hematopoietic stem cells during aging fuels leukemia evolution

Abstract Cancers are diseases of aging. Many cellular processes characteristic of cancer, e.g., epigenetic dysregulation, are similarly observed during aging. Acute myeloid leukemia (AML) is emblematic of this interplay. As a blood cancer stemming from hematopoietic stem and progenitors (HSPC), its median age of diagnosis is 65. AML is linked to age-related clonal hematopoiesis (CH), a condition resulting from the expansion of HSPC, marked by mutations in leukemia-associated genes. We aim to clarify the intrinsic role of aging in HSPC as it causes CH and leukemic transformation. Hypothesis: aging amplifies the heritable phenotypic variations in hematopoietic stem cells (HSC), enhancing epigenetic heterogeneity. This acts as a substrate for natural selection, driving leukemic transformation. Results: We found a significant increase in epigenetic and transcriptomic heterogeneity in long-term HSC (LT-HSC) from old mice compared to their younger counterparts via single-cell RNA-seq (scRNA-seq)s. This process occurs in an aged bone marrow with higher inflammation and altered HSPC support. Of relevance, we previously show that the rise of epigenetic and transcriptomic heterogeneity in HSC with Tet2 loss and Flt3 ITD precedes leukemic transformation. We further employed CellTag Indexing and scRNA-seq to track the fate of specific HSC subclones. We tracked HSPC cell culture (in vitro) after two-weeks and two-months following transplantation into recipient mice of matching ages (in vivo). Cells of the same clone manifest higher transcriptomic similarities than those from different clones, validating CellTag in mapping clonal evolution. We computed the progeny output activity (Ai) by the ratio of clone i abundance in the committed progenitors to its frequency in the HSC compartment. We found that young mice exhibit significantly higher variability and a higher mean of progeny output activity Ai, indicating the efficiency in self-renewal and cell differentiation. While both young and old mice have low-output (higher stemness) clones, only young mice had significant differential expression of key genes in low-output clones compared to high-output clones, e.g., Dpp4, Eps8, and Col5a1. Depite lower progeny output Ai variation, LT-HSCs from older mice exhibited greater clonal transcriptome diversification both in vitro and in vivo , evidenced by intra-clonal transcriptomic correlation. This pattern also existed in ST-HSC and MPP from older mice. Genes with higher expression variability in older mice highlighted pathways pivotal for HSPC fitness, e.g., ribosome synthesis (RS), inflammation response mechanisms (JAK-STAT), hematopoietic cell lineage, AML and cancer pathways (GSEA). The RS pathway were remarkably enriched in the megakaryocytic-erythroid progenitors, directly before differentiation where substantial protein translation is required. Conclusion: our results suggest that the synergy of aging and somatic mutations in epigenetic regulators may enhance cell-to-cell variations, offering additional heritable phenotypic variations. These, in turn, may facilitate clonal hematopoiesis and leukemic transformation. Future work will delineate specific epigenetic and transcriptomic configurations for mutant HSPC clonal expansion. This study provides a cohesive framework, linking the principles governing aging to cancer. Citation Format: Lamis Naddaf, Marco De Dominici, Xiaowen Chen, Travis Roeder, Hideyuki Oguro, Shilpita Karmakar, Eric Pietras, James DeGregori, Sheng Li. Accelerated intra-clonal transcriptomic diversification of hematopoietic stem cells during aging fuels leukemia evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB227.

Abstract A092: Ovarian tumor organotypic slices cultures for functional drug screening (TOSCA)

Abstract A092: Ovarian tumor organotypic slices cultures for functional drug screening (TOSCA)

Impact of annual TB screening on stone quarry workers in high-incidence Portuguese municipalities.

<sec id="st1"><title>SETTING</title>The Portuguese municipalities of Penafiel and Marco de Canaveses are high TB incidence areas, where stone quarry workers represent a vulnerable population.</sec><sec id="st2"><title>OBJECTIVE</title>To assess the annual rate of TB infection (ARI) in stone quarry workers and to compare it with the TB notification rate in the general community.</sec><sec id="st3"><title>DESIGN</title>An annual TB infection screening strategy using interferon-gamma release assay (IGRA) was implemented in 2018 for workers from high-risk stone quarries. A prospective cohort was enrolled and workers screened in periods of 2 years were included. IGRA-positive workers were referred for preventive treatment. ARI was calculated as the proportion of workers with IGRA conversion.</sec><sec id="st4"><title>RESULTS</title>Of the 232 IGRA-negative workers in 2018, 20 tested positive in 2019 (8.6% ARI). Of 171 IGRA-negative workers in 2019, eight tested positive in 2021 (4.7% in 2 years). Two of the 150 IGRA-negative workers in 2021 tested positive in 2022 (1.3% ARI). ARI decreased by 84.9% between 2019 and 2022. In the two municipalities, the TB notification rate declined 23.9% between 2018 and 2021.</sec><sec id="st5"><title>CONCLUSION</title>A more pronounced reduction in ARI was observed among stone quarry workers regularly screened for TB infection compared to the notification rate among the general population in high-incidence municipalities. A screening strategy for high-risk populations, together with enforced community measures, could foster risk reduction in the community.</sec>.

Uses for Wines and Vinegars from Marco de Jerez: Between Culinary Tradition and Haute Cuisine

An analysis of the wines and vinegars from the city of Jerez de la Frontera, center of a tradition that dates backs hundreds of years in the viticultural area of Marco de Jerez. Ethnography was resorted to as a method, describing the culinary processes which make use of such products, either in traditional or haute cuisines, and assessing the consumers’ perceptions regarding these uses. The results exhibit the deep meaning and importance of the culinary uses of wine and vinegar from Jerez in everyday cooking and haute cuisine, and also the exporting and international vocation of the place, with a background of social agents with opposing positions and preferences, where the interests of large corporations prevail over local preferences.

Community-Based Action Research Intervention to Promote Occupational Health Nursing of Portuguese Quarry Workers.

The northern region of Portugal has the largest number of companies manufacturing granite and stone products, which has become the region's trademark. In the municipalities of Marco de Canaveses and Penafiel, the economic activity of this area is important. However, the lack of attractiveness of this activity, combined with the high prevalence of silicosis and tuberculosis in this population, has led to a growing shortage of labor. In order for this project to be the result of collaborative, integral work centered on the people who are the target of health promotion, we used the Participatory Health Research (PHR) approach, based on the PRECEDE-PROCEED model, to implement a mixed-methods study, including participant observation, interviews and document analysis. These data were used to co-create a study design. In 2021, a total of 102 interviews were carried out and self-completion surveys were distributed: the Fantastic Lifestyle Questionnaire (FLQ) and the EQ-5D-3L. Within the scope of occupational health nursing and in the field of action of public health nurses, with the interviews and self-completed surveys carried out, we identified potential focuses for occupational health nursing intervention to promote the health of stone industry workers: adherence to protective measures, energy balance deficit, tobacco and alcohol consumption and access to health services. Data analysis made it possible to assess the prevalence of risk behaviors by order and to involve managers and workers in the co-creation of a health promotion program. The accurate identification of the focuses for nursing intervention not only improves the effectiveness of occupational health services, allowing for targeted interventions adapted to workers' needs, but also contributes considerably to health promotion in the workplace, resulting in safer working environments, a reduction in occupational diseases and, consequently, a healthier and more productive workforce. This protocol of this study was not registered.

Abstract B031: Accelerated intra-clonal diversification of hematopoietic stem cells during aging fuels leukemia evolution

Abstract Cancer are diseases of aging. Many cellular processes characteristic of cancer, e.g., epigenetic dysregulation, are similarly observed during aging. Acute myeloid leukemia (AML) is emblematic of this interplay. As a blood cancer stemming from hematopoietic stem and progenitors (HSPC), the median age of AML diagnosis is 65. This is linked to age-related clonal hematopoiesis (CH), a condition resulting from the expansion of hematopoietic stem and progenitor cells, typically marked by mutations in leukemia-associated genes. Our investigation thus seeks to clarify the intrinsic role of aging in HSPCs as they relate to CH and leukemic transformation. Hypothesis: Aging amplifies the inheritable phenotypic variations in hematopoietic stem cells, enhancing epigenetic heterogeneity. This acts as a substrate for natural selection, driving leukemic transformation. HSPC Epigenomic and transcriptomic heterogeneity increase in old age: we profiled the single-cell transcriptome (scRNA-seq) and single-nuclear ATAC-seq (snATAC-seq) data from Lineage-c-Kit+ HSPCs isolated from mice at two age groups. Applying Shannon entropy, our analysis revealed a significant increase in epigenetic and transcriptomic heterogeneity in middle-aged LT-HSC compared to their younger counterparts. This process occurs in an aged bone marrow (BM) microenvironment characterized by inflammation and altered HSPC support. Interestingly, we previously show that the rise of epigenetic and transcriptomic heterogeneity in HSC with Tet2 loss (Tet2 MT) and Flt3 ITD precedes leukemic transformation. Diversification of LT-HSC Transcriptome: We employed CellTag Indexing to track the fate of specific HSC subclones. With a barcode detection rate of 80%, our findings indicate that a significant majority (97%) of clones emerged from an HSC. Furthermore, we observed that cells of the same clone manifest higher transcriptomic similarities than those from different clones, underscoring the technique's capability in mapping HSPC clonal evolution. Then we applied scRNA-seq to tagged HSPCs after 16 days of ex vivo expansion. We found that LT-HSCs from older mice exhibited greater clonal diversification, evidenced by intra-clonal transcriptomic correlation. ST-HSC and MPP from older mice also exhibt this pattern. Functional Relevance: Our GSEA analysis of genes with increased expression variability in older mice highlighted several pathways pivotal for HSPC fitness, encompassing ribosome synthesis, inflammation response mechanisms (e.g., JAK-STAT), hematopoietic cell lineage, and AML/cancer pathways. Conclusion: our results suggest that the combined effects of aging and somatic mutations in epigenetic regulators may enhance cell-to-cell variations, offering additional heritable phenotypic variations. These, in turn, may facilitate clonal hematopoiesis and leukemic transformation. Future work will delineate specific epigenetic and transcriptomic configurations that enable mutant HSPC clonal expansion. This study provides a cohesive framework, linking the principles governing aging to cancer. Citation Format: Lamis Naddaf, Marco De Dominici, Xiaowen Chen, Parveen Kumar, James Chavez, Travis Roeder, Shilpita Karmakar, Eric Pietras, Hideyuki Oguro, James DeGregori, Sheng Li. Accelerated intra-clonal diversification of hematopoietic stem cells during aging fuels leukemia evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B031.

Abstract 4422: Evaluation of immune response to tumor associated antigens in patients with high grade serous ovarian cancer vaccinated intra-dermally with DCP-001, an allogeneic, cancer cell-based vaccine

Abstract Treatment of high grade serous ovarian cancer (HGSOC) after debulking and chemotherapy remains challenging. This phase 1 trial (NCT04739527) evaluates the use of a cell-based relapse vaccine, DCP-001, to prevent disease recurrence after primary treatment. Previous data in acute myeloid leukemia, has shown that DCP-001 induces an immune responses to tumor associated antigens, like WT1 and PRAME, frequently upregulated in HGSOC. In NCT04739527, DCP-001 is given four times biweekly (week 0, 2, 4 and 6) at a dose of 25 million cells/vaccination (vc), followed by 2 monthly boosters (week 14 and 18) of 10 million cells/vc, after primary debulking and chemotherapy. IFNγ ELISpot is performed on peripheral blood mononuclear cells after restimulation with WT1, PRAME, MAGEA3/4 and NY-ESO1. Vaccine induced T-cell response (VIR) at any point after week 0 are calculated as at least a 2-fold increase of the mock-corrected baseline response. Sustained VIR are counted if a VIR to the same antigen is observed in at least 2 timepoints after start of DCP-001. Flow cytometry is performed using a 40-marker panel to evaluate the immune profiles of innate and adaptive immune system, as well as activation and exhaustion markers and memory profiles. At present, a total of 7 patients have been included and 6 have completed the full vaccination schedule (week 22). DCP-001 is well-tolerated, with only mild to moderate adverse events, mainly related to local injection side reactions, or systemic discomfort with fatigue, diarrhea, temperature elevation and headache. Immune responses have been evaluated in 5 patients by IFNy ELISPOT. VIR were detected in a range of 0-8, and all but 1 patient had at least one sustained VIR to either of the 4 antigens. One patient had no VIR, however this patient had already high baseline responses to all 4 antigens. Flow cytometry showed changes during the vaccination in the immune profiles of these patients, with in general an activation of the innate and adaptive immune system. Detailed analysis is currently ongoing. Finally, at the week 22 visit, 2 patients had progressed during the treatment and 4 had no clinical signs of progressive disease. Taken together, initial data from the phase I trial demonstrate that DCP-001 is safe and well-tolerated and induces durable T-cell responses to tumor associated antigens in OC patients. The study will continue to enroll new patients, follow-up for progression and overall survival and will further analyze the immune responses induced by DCP-001. Citation Format: Marco De Bruyn, Annegé Vledder, Rob ten Pas, Anneke Eerkens, Koen Brummel, Hester van Zeeburg, Jeroen Rovers, Hans Nijman. Evaluation of immune response to tumor associated antigens in patients with high grade serous ovarian cancer vaccinated intra-dermally with DCP-001, an allogeneic, cancer cell-based vaccine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4422.

Abstract PR001: Dissecting the role of aging and inflammation on clonal hematopoiesis

Abstract Aging is associated with the appearance in multiple tissues of somatic mutant clones often harboring mutations observed in cancers. In the hematopoietic system this phenomenon is named clonal hematopoiesis of indeterminant potential (CHIP) or “age-related clonal hematopoiesis”. The incidence of CHIP increases exponentially with aging, and has been associated with increased risk of myeloid malignancies, cardiovascular disease, and overall mortality. While mutations are thought to be acquired at a constant rate during life, whether aging plays a role in driving the expansion of these mutant clones is of crucial importance, as it can inform on the potential to prevent or halt the expansion of CHIP clones by intervening with the specific hallmark of aging fueling such expansion. To determine the effect of aging on the expansion of CHIP clones, we have established a method that relies on in vitro manipulation of mouse hematopoietic stem and progenitor cells (HSPC) in order to introduce by CRISPR-Cas9 selected mutations, followed by transplant into young and old recipient mice. Our method has several advantages: i) it allows rapid introduction of the desired mutations from mice of any background, including aged mice, bypassing the need to create transgenic lines; ii) by expanding the cultured cells in previously developed PVA media, it allows efficient engraftment in mildly (busulfan) conditioned recipient mice, avoiding the damaging effects on the bone marrow microenvironment that result from irradiation; iii) by manipulating HSPC with gRNAs targeting either the gene of interest (GFP tagged) or the safe harbor Rosa26 locus (dTomato tagged) prior to pooling, we can assess the competitive advantage of the mutation of interest relative to the Rosa26 control cells and determine their fitness advantage at various time points. We used this technique to generate Dnmt3a and Tet2 mutant clones and tested their expansion in young and aged recipient mice. Our data reveal that Dnmt3a exhibits a relatively mild fitness advantage and no difference in the rate of expansion between young and aged mice. By contrast Tet2-KO HSPC show a significantly faster expansion in old compared to young recipient mice, indicating a greater fitness advantage in the aged background. Tet2 mutant HSPC were previously shown to preferentially expand in inflammatory conditions such as stimulation with microbial products, IL-6 and TNFa. We have preliminary data that shows that co-housing old mice with young syngeneic mice alters their gut microbiome and results in a reduction of inflammation and restoration of more youthful gene expression profiles in stem and progenitor cells in the bone marrow. We are currently testing whether altering the gut microbiome or applying genetic models of reduced inflammation prevents the expansion of Tet2-KO cells, with associated “omics” analyses to explore underlying mechanisms. In all, these studies should contribute to our understanding of the aging-dependent occurrence of CHIP and suggest potential interventions to limit its prevalence. Citation Format: Marco De Dominici, Johannes Menzel, James V. DeGregori. Dissecting the role of aging and inflammation on clonal hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR001.

La fortuna indiana. El patrocinio artístico de Marcos de Torres. Nuevas aportaciones

"The idea of emigration has always been present throughout history. from the 17th and 18th centuries, many tried to seek their fortune in the new world. one of the most outstanding was the icodense Marcos de Torres, known for the foundation of the hermitage of angustias, image he brought from america along with all the pieces of the trousseau and ornament of the temple. but he not only endowed this enclosure but he made other important works for the history of the region, benefiting its neighbors and enriching the temples of icod, remaining as the personality who met all the requirements to enlarge the myth of the emigrant who returns with fortune"

New types of organic wines with Pedro Ximenez variety grown in the Marco de Jerez Sherry region

The Pedro Ximénez grape variety is one of the authorised varieties in the Jerez-Xérès-Sherry DO, although it currently occupies only 1% of the region's total cultivated area. With the intention of promoting its cultivation, as well as diversifying production in a historic wine-growing area such as the Marco de Jerez (Spain), work is currently being carried out through a research project in which both public and private entities are participating. This project focuses, among other aspects, on the organic cultivation of this minor grapevine variety in the region, as well as on the production of naturally sweet wines. In this research, the results of the characterisation of the grape musts of overripe Pedro Ximénez grapes are presented, as well as the monitoring of its fermentation and the characterisation of the wines obtained. The resulting wines show how the over-ripening technique is presented as a viable alternative for the production of new types of wines in a warm climate area such as the Marco de Jerez.

Analytical, Chemometric and Sensorial Characterization of Oloroso and Palo Cortado Sherries during Their Ageing in the Criaderas y Solera System.

Oloroso and Palo Cortado are two types of sherry wines, produced in the Sherry Wine Region in Southern Spain, known as Marco de Jerez, where it is aged following the traditional Criaderas y Solera system. All of them are aged through oxidative ageing, even though the peculiar Palo Cortado Sherry wine is also aged biologically under a veil of flor yeasts in the first stage. Total dry extract, organic acids, aldehydes, esters, higher alcohols and phenolic compounds in these sherry wines evolve during their ageing as a consequence of evaporation and/or perspiration processes, chemical reactions, extraction of compounds from oakwood and microbiological activity. Sherry wines develop their characteristic organoleptic profile during their ageing, as could be proven through their tasting sessions. According to the sherry type, some natural groupings of the wines could be observed after their principal component analysis. Furthermore, by multiple linear regression methods, an important correlation between the parameters that were analyzed and the ageing of each specific wine has been confirmed, which allowed us to establish two different models, each corresponding to the sherry type in question. Only five of the variables that were investigated were required to successfully estimate each wine's age at over 99% confidence. This represents a rather convenient tool for wineries to monitor the ageing of these sherry wines.

5-Hydroxyindoleacetic acid, a new ligand for GPR35, plays an important role in inflammatory disease.

Marco De Giovanni et al. recently found that the 5-hydroxyindoleacetic acid (5-HIAA) from platelet and mast cell is a new ligand for G Protein-Coupled Receptor 35 (GPR35) and promotes neutrophil recruitment to inflamed tissues. Although some endogenous ligands of GPR35 have been reported, GPR35 is still officially defined as an orphan receptor. We believe that this study makes a significant contribution to the literature because it details the new mechanism by which platelets and mast cells promote neutrophil recruitment and expands the diagnostic and therapeutic value of inflammatory and vascular diseases.

MARS-CUPID 연계코드를 이용한 피동원자로건물냉각계통 격납건물 내부 열수력거동 분석

A passive containment cooling system (PCCS) has been designed to effectively remove the energy released to a containment by using condensation heat during a loss of coolant accident (LOCA) in a nuclear reactor. During the past few years, thermal-hydraulic performance of the PCCS has been analyzed using system scale codes, MARS and GOTHIC codes. In this work, thermal-hydraulic performance of the PCCS was analyzed again using the MARS-CUPID coupled code, which is a combinded code of the system scale and component scale, respectively. For a more realistic simulation, we modified Uchida correlation to take into account the effect of pressure in the MARS-CUPID coupled code. The simulation result showed the peak pressure of 4.31 bar, which is similar to the peak pressure obtained using the GOTHIC code. In this study, thermal-hydraulic performance of the PCCS considering uncertainty parameters, such as mass&energy release, heat transfer coefficient, and heat sink area, is also discussed.

Contributo da comunicação visual na simbiose entre espaço e tecnologia: o caso Zora

Visual communication is a key factor for the graphic development of a project. The association Zora, in the scope of the event “De cor”, has as main goal to establish the communication of the event, as well as the connection between the public and the city of Marco de Canaveses. With this focus, the use of Motion Graphics, and its application in Video Mapping, prove to be the most suitable visual communication elements to generate empathy with the target audience.The research is structured through the study of concepts in communication and visual identity, its evolution, in its various forms of intervention, from animation to the emergence of Motion Graphics. In this context, Video Mapping is approached as a visual communication platform for cultural events. An analysis of the designer’s role in the conception and development of visual communication is also promoted. Case studies are used to investigate the contribution of typography and technologies to the development of communication for cultural events.In the development of the empirical work, use was made of projectual methodologies informed by design involving a varied set of steps, processes, techniques, and methods, seeking to respond to the general objective of the study.This project allowed the reflection on the importance and efficiency of the use of new technological instruments in the visual communication of an event of social and cultural importance, revealing itself as an enhancer of the message to communicate to the target audience.

Actions for the confirmation of the continuous improvement plan for the Educational Program in Chemical Engineering at UAEMéx

The objective of this work was to reflect on the responsibility that the educational program in Chemical Engineering at UAEMex has in translating its intentions into actions, as well as establishing an organised process for continuous planning and systemic evaluation which is reflected in a continuous improvement plan. This process entails the inclusion of tools that permit the evaluation or self-evaluation of the measurements and forms in which the educational program is improving its actions in achieving the criteria established by the acreditory organisation Consejo de Acreditación de la Enseñanza de la Ingeniería (CACEI) (Accreditation Board for the Teaching of Engineering) in their Marco de Referencia (Frame of Reference) 2018 in the international context.

The UAZ in the University Network of Arts, RUA (Red Universitaria de Artes): presence and development perspectives

The University Network of Arts was created in Havana, (2014) to promote cooperation among university arts instructors and to improve artistic quality and its academic specificity (University Network of Arts [RUA], 2014). Since its inception, the network has been formed by university students and arts professionals who have represented dozens of institutions in America, Africa and Europe. The UAZ, based on the Academic Collaboration Framework Agreement (Convenio Marco de Colaboración Académica) signed with the Higher Institute of Arts of the Republic of Cuba (Instituto Superior de Artes de la República de Cuba) (2011), became a founding member, through various Academic Groups. The UAZ-CA 219 “Music and interdisciplinarity”, formed by the authors of this article, has actively taken part in meetings of the RUA, contributing proposals for its expansion and consolidation. Despite this, the results are rarely communicated. In this sense, this work has as its main objective to spread the importance of the University Network of Arts, RUA and disclose some ideas about its possible development perspectives, increasing the participation of the UAZ, from its institutional Academic Groups focused on art, culture and sustainable development, and its capacity for social and inter-institutional bonding.

Abstract 6156: High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor

Abstract Introduction and Objective High-fat diet (HFD) induce prostate inflammation and promote cancer growth. However, the mechanism of this inflammation has not been entirely clear. We provide the evidence of new histamine-mediated mechanism and the crucial role of the gut microbiota on HFD-induced prostate cancer (PCa) growth. Methods We compared between HFD-fed and control diet (CD)-fed prostate-specific Pten KO mice at 22 weeks of age as PCa models. HFD-fed mice were given histamine receptor antagonist. Tumor growth was evaluated by prostate weight and Ki67 staining. Gut microbiota compositions were analyzed by 16S rRNA gene sequencing. Histamine signaling in PCa was assessed at gene and protein level. Results HFD significantly increased prostate weight (0.25 vs. 0.46g, P = 0.01) and Ki67-positive cancer cell ratio (0.15 vs. 0.36, P = 0.01). cDNA microarray of PCa showed that expression of Hdc encoding histidine decarboxylase (HDC), which is responsible for histamine production, was upregulated in HFD-fed mice (Fold change = 2.71). The elevated expression of Hdc was also confirmed by quantitative PCR (P &amp;lt; 0.01). Infiltrating mast cells highly produced HDC protein, and mast cell counts around cancer foci were significantly increased in HFD-fed mice. Fexofenadine (Fexo), an H1 blocker, inhibited HFD-induced PCa growth, while ranitidine, an H2 blocker, had no inhibitory effect. Fexo reduced MDSC counts and suppressed IL6-STAT3 signaling in PCa of HFD-fed mice. In vitro, both histamine and Fexo did not affect the proliferation of DU145. HFD altered the composition of gut microbiota, and Shannon index suggesting diversity of gut microbiota was reduced in HFD-fed mice. Serum lipopolysaccharide (LPS) levels were elevated in 11-week-old HFD-fed mice, and LPS injection resulted in upregulation of Hdc in PCa. Conclusions We found that HFD caused gut microbiota dysbiosis and elevated systemic LPS level, which could promote inflammatory PCa progression through mast cells and histamine H1 receptor signaling. These results suggest the existence of “Gut-Prostate Axis.” Citation Format: Kazutoshi Fujita, Makoto Matsushita, Daisuke Motooka, Takuaki Hase, Eri Banno, Marco De Velasco, Taigo Kato, Atsunari Kawashima, Motohide Uemura, Shota Nakamura, Kazutake Tsujikawa, Eiichi Morii, Kazuhiro Yoshimura, Hirotsugu Uemura. High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6156.

Improvement of the critical heat flux correlation in a thermal-hydraulic system code for a downward-flow narrow rectangular channel

Several critical heat flux (CHF) correlations including the look-up table in the MARS code have been assessed for the prediction of CHF in a downward-flow narrow rectangular channel. For the assessment, we built an experiment database that covers pressures between 1.01 and 39.0 bar, gap sizes between 1.09 and 6.53 mm, mass fluxes up to 25,772 kg/m2s, and under one-sided and two-sided heating conditions. The results of the assessment showed that the Kaminaga correlation has the best overall prediction compared to others. However, because the correlation uses global variables, such as inlet and outlet subcooling and total heat transfer area, it is difficult to use in a system code. A new CHF correlation is then proposed by replacing the global variables in the Kaminaga correlation with local ones and adding correction factors to consider the effect of gap size, mass flux, and the number of heating walls. Additional correction factor is added to consider the effect of inlet subcooling. It is shown that the new one is better than the Kaminaga correlation and it is easy to implement to any system code.

The 1624 Tumult of Mexico in Perspective (c. 1620–1650): Authority and Conflict Resolution in the Iberian Atlantic

Angela Ballone's book is an example of how a specific case can offer a new historiographical perspective. Among Ballone's main contributions is her emphasis that the assertion of royal authority was the primary expression of the spread of a common legal culture in the Iberian Atlantic. The 1624 tumult in Mexico City and its resolution constituted a critical and radical example of Spanish American elites' strength, but this strength was always circumscribed within the framework of respect for the king's authority as the source of all rights. This allows us to discard the traditional anachronistic theses about the opposition between creoles and Iberians and about the weakness of the royal authority during the seventeenth century.Another central contribution of the book is its attention to the apostolic character of the church's defense and the role of the two Mexico City archbishops involved in the crisis triggered by the 1624 uprising. Chapter 5’s second section persuasively demonstrates the degree to which the sources of law (doctrine, legislation, jurisprudence, custom) supported the positions held by the representatives of both royal and ecclesiastical authority. Thus the Marquess of Gelves, as well as his respective predecessor and successor as viceroy, the Marquess of Guadalcázar and the Marquess of Cerralvo, defended the preeminence of the viceroy by pointing to the realm of royal powers. However, the arguments of Archbishop Juan Pérez de la Serna and his successor, Francisco Manso y Zúñiga, showed the malleability of canon law for defending ecclesiastical prerogatives and invoking for archbishops greater legitimacy, as representatives of the king's priestly character and as depositaries of the apostolic tradition.In this sense, Ballone's treatment of the Mexican archbishops' actions confirms the desire of New Spain's diocesan prelates for preeminence. As pointed out by Óscar Mazín, Pérez de la Serna and Manso y Zúñiga provided precedent for an episcopacy in northern Spanish America faced with the greater power wielded by the viceroys of Peru, the most famous of such prelates being Pedro Moya de Contreras and Juan de Palafox y Mendoza. This aspect of the 1624 conflict and its resolution is central to Ballone's perspective, since if the crown never again used the real audiencia to substitute for a viceroy in New Spain, there were occasions when bishops exercised viceregal authority on an interim basis or by appointment: examples of this include the governments of Marcos de Torres y Rueda, Diego Osorio de Escobar y Llamas, Payo Enríquez de Rivera, and Juan de Ortega y Montañés.Ballone makes an extraordinary contribution in documenting the constitution and functioning of a junta del tumulto that worked until 1648 within the Madrid court. The meticulous attention to Mexican affairs among the members of the Councils of Castile and the Indies who constituted that extraordinary committee shows the extent to which the tumult had judicial consequences for the ministers and royal officials involved and the importance of Mexican affairs in the royal court. Especially revealing is Ballone's discovery of the sentence leveled against the relatives of the Marquess of Gelves. The junta's lengthy deliberations reveal the profound impact of events in the Indies on the royal court's decisions. Ballone raises interesting questions about how government and justice were modeled in the monarchy's various latitudes.These central contributions of documentation and interpretation underpin Ballone's balanced treatment of the historiography. Her generous review includes the unpublished theses that at the time constituted her monograph's antecedents. This book on the 1624 tumult also fits with Ballone's work on Juan de Solórzano Pereira, legal literature in Spanish America, and the legal aspects of the labor conditions in Indigenous societies. With subtlety and sobriety, Ballone has contributed to renewing the Atlantic history promoted by the historians of the British Empire and the European Hispanists. The book under review draws on the great lines of interpretation established by, among others, Horst Pietschmann, John Elliott, David Armitage, and Harald Braun. Simultaneously, Ballone's book complicates the multiplicity of problems that the Atlantic scale entails to place the making of royal authority in local settings, in consonance with the local-global explanations of imperial phenomena, while still admitting that Madrid was the court and Mexico the seat of a distant viceroyalty. With this, Ballone distances herself from the imperialistic character attributed to Atlantic history and instead deals with the specific aspects of the continuities within the Iberian worlds, particularly the cocreation of a common legal culture between rulers and ruled.In the finest tradition of Atlantic history, Angela Ballone's monograph about the 1624 tumult of Mexico City brings us a broader understanding of how royal authority was made in New Spain and Spanish America.

Analytical and Chemometric Characterization of Fino and Amontillado Sherries during Aging in Criaderas y Solera System.

Fino and Amontillado are Sherry wines, produced in Marco de Jerez area (southern Spain), and aged in Criaderas y Solera system. Fino Sherry wine follows a biological aging process, under a veil of flor yeasts, while Amontillado Sherry wine shares the same biological aging firstly, followed by oxidative aging, which gives them special features. Organic acids, esters, higher alcohols, phenolic compounds and total dry extract of Sherries evolve during aging due to evaporation processes, physical-chemical reactions, wood contributions and microbiological activity. During aging, Sherry wines improve their organoleptic profile, as could be proved in the tasting sessions. Hierarchical Cluster Analysis and Factor Analysis with factor extraction using Principal Components of Sherry wines studied were carried out and natural groupings of the wines according to the type of aging and their age were observed. A strong correlation between the parameters analyzed and the aging of each wine has been seen in the Multiple Linear Regression studies, establishing two different models, one for each type of Sherry wine, that, with only four of all the variables studied estimated the wine age with more than 99% of confidence. This constitutes a useful tool to control the age of these Sherry wines in the winery.