bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B076: Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma
Authors: Ju Jingfang
Published: January 2024

Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with PDAC in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a new treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a). In a panel of PDAC cell lines, we found that Gem-miR-15a induces cell cycle arrest and apoptosis, and these mimics are potent inhibitors with single digit nM IC50 up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a. Compared to Gem, we also found that our Gem-modified miRNA mimics exhibit enhanced efficacy by over several hundred fold less than Gem in patient-derived PDAC organoids. Gem-miR-15a was able to eliminate Gem resistant PDAC cells and organoids. In addition, Gem-miR-15a was able to be delivered to PDAC cells without the aid of delivery vehicle, a major advancement in nucleic acid based medicine. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of muti-targeted Gem-modified miRNAs as a novel treatment strategy for PDAC.

Citation Format: Jingfang Ju. Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B076.
Abstract B078: A complex of NF1 and SPRED2 non-canonically behave as tumor promoters in pancreatic cancer
Authors: Kim Sun , Ting Hsiu-Chi , Deschenes Astrid , Kastan Jonathan , Park Youngkyu , Tuveson David
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. >90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. We find that both knockout of either NF1 or SPRED2 in PDAC organoids induces a substantial growth defect in vivo. Our preliminary data suggests that NF1 and SPRED2 support KRAS activity in mouse pancreatic cancer in vivo. Moreover, both SPRED2 and NF1 KO show decreased proliferation, invasion, and attachment on collagen family members in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and SPRED2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities.

Citation Format: Sun Kim, Hsiu-Chi Ting, Astrid Deschenes, Jonathan Kastan, Youngkyu Park, David Tuveson. A complex of NF1 and SPRED2 non-canonically behave as tumor promoters in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B078.
Abstract C041: Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts
Authors: Woogeng Ivo N. , Han Lu , Saberi Samaneh , Bumbleburg Cameron , Beaudet Joseph , Sharma Sudarshana , Ostrowski Michael
Published: January 2024

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy with poor prognosis and treatment options. Cancer associated fibroblasts (CAFs) play a complex role in the PDAC tumor microenvironment (TME), contributing significantly to the progression of the tumor and the dense desmoplastic stroma. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss in both the tumor and in CAFs is associated with increased tumor aggressiveness and resistance to therapy. Our group previously demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which correlated with worsened outcomes. In addition, PTEN expression was lost in 80% of SMA+ CAFs in mouse PDAC models. Genetic or pharmacologic inhibition of the hedegehog pathway leads to ubiquitin-dependent destruction of PTEN by the proteosome. However, little is known of the signals produced by tumor cells that trigger PTEN degradation in CAFs. In order to address this problem, we developed an in vitro assay system based on wild type murine PDAC-CAFs that expresses a PTEN-GFP fusion protein. Initially, we focused on IL6 and IL6 family members Leukemia Inhibitory Factor (LIF) and Oncostatin-M (OSM) and Transforming Growth Factor beta 1 (TGFb1). The SMO inhibitor GDC-0449 was used as a positive control. PTEN stability was evaluated using the LSM 880 confocal microscope and GFP+ cells were quantified with QuPath-0.4.3 and analyzed with GraphPad Prism. Among the repertoire of secreted factors, we found that only OSM and TGFb1 could destabilize PTEN after 48H of treatment. When queried against the single cell RNA sequence dataset produced by our lab, we observed that CD45+ leukocytes were the likely source of OSM whereas TGFb1 was produced by tumor cells, fibroblasts, and immune cells. In conclusion, OSM and TGFb1 can downregulate PTEN in CAFs in vitro. Current efforts are aimed at testing whether inhibition of these pathways can restore PTEN expression in mouse PDAC models, and in identifying signaling pathways and E3-ligases that mediate PTEN destruction. These pathways and interactions could be further exploited for selective inhibition aimed at therapeutic benefits in curbing PDAC progression.

Citation Format: Ivo N. Woogeng, Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma, Michael Ostrowski. Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C041.
Abstract C063: Keratin 17 as a predictor of chemotherapy response in pancreatic ductal adenocarcinoma
Authors: Oblein Lyanne , Roa Lucia , Babu Sruthi , Horowitz Michael , Petricoin Emanuel , Matrisian Lynn M. , Blais Edik , Marchenko Natalia , Allard Felicia , Alkalin Ali , Jiang Wei , Larson Brent , Hendifar Andrew , Picozzi Vincent , Choi Minsig , Escobar-Hoyos Luisa , Shroyer Kenneth
Published: January 2024

Background: Two chemotherapies based on either gemcitabine- or 5-fluorouracil (5-FU) remain standard-of-care for pancreatic ductal adenocarcinomas (PDACs). Patients, however, differ in response and thus many clinical trials for experimental drugs have failed. Therefore, there is an urgent need to establish clinically deployable and rapid biomarkers to decide the best chemotherapeutic regimen for subgroups of patients and prevent toxic side effects. We previously reported that keratin 17 (K17) expression, detected at either the level of messenger RNA or protein by immunohistochemistry (IHC), is as accurate as molecular subtyping to identify subgroups of PDAC patients with shortest survival. In this work, we determined the predictive value of K17 testing for both chemotherapeutic approaches to treat PDAC. Methods: We profiled keratin 17 (K17) expression, a hallmark biomarker of the basal molecular subtype of PDAC, using immunohistochemistry in two cohorts of formalin-fixed paraffin-embedded PDACs (total n=305). These cases were collected through the Know Your Tumor® initiative and three high-volume treating institutions in the U.S. We performed multivariate predictive analyses and determined the threshold to define positive vs negative test. Results: Patients with advance stage disease, low K17, and treated with 5-FU- chemotherapy had three-times longer survival rates compared to counterparts treated with gemcitabine-based chemotherapy. These results contrast to those found in cases with high K17, where no differences were seen with either regimen. Based on RECIST, 72% of low K17 cases responded to treatment compared to 24% of high K17 cases. Predictive value of K17 was independent of mutation status and clinical variables. Conclusions: Our findings indicate that 5-FU-, rather than gemcitabine- based therapies are more likely to extend survival for patient's tumors expressing low rather than high K17. A K17 IHC test rapid test in PDACs has been patented (US11,092,603) and it is currently being tested in prospective phase II clinical trials (NCT04469556, NCT02047474 and NCT03991962). Results from these trials will test the presented findings.

Citation Format: Lyanne Oblein, Lucia Roa, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn M. Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Luisa Escobar-Hoyos, Kenneth Shroyer. Keratin 17 as a predictor of chemotherapy response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C063.
Abstract C103: Differential acquisition of extracellular lipid correlates with pancreatic cancer subtype and metastatic tropism
Authors: Rademaker Gilles , Hernandez Grace A. , Qiu Longhui , Wen Kwun W. , Jain Aakriti , Kim Grace A. , Zoncu Roberto , Perera Rushik M.
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, and the third leading cause of cancer-related death with a 5-year overall survival rate of less than 5%. Recent studies have identified two major subtypes of pancreatic cancer, basal and classical, that are predictive of patient prognosis, with basal tumors corresponding with more aggressive disease. While transcriptional signatures define basal and classical tumors and cell lines, little is known regarding the metabolic vulnerabilities linked to the basal versus classical state. Using unbiased computational interrogation to uncover metabolic genes correlating with known markers of classical PDAC, we identified high expression of Proprotein convertase subtilisin/kexin type-9 (PCSK9) – a negative regulator of receptor mediated uptake of cholesterol containing low-density lipoprotein (LDL) – as correlating with several established markers of classical PDAC. In contrast, PCSK9 expression is suppressed in Basal PDAC. Accordingly, basal PDAC uptake high levels of LDL, are sensitive to LDL depletion and show higher dependence on cholesterol uptake, relative to classical PDAC. As lipoproteins are produced in the liver, we hypothesized that basal PDAC cells may more efficiently seed and grow within the liver. Consistent with this hypothesis, low PCSK9 expression is correlated with liver metastasis in mouse models of PDAC and patient PDAC specimens. Ongoing studies will interrogate the role of PCSK9 and cholesterol uptake and utilization in metastatic tropism, and uncover unique features and vulnerabilities of the most aggressive variant of PDAC.

Citation Format: Gilles Rademaker, Grace A. Hernandez, Longhui Qiu, Kwun W. Wen, Aakriti Jain, Grace A. Kim, Roberto Zoncu, Rushik M. Perera. Differential acquisition of extracellular lipid correlates with pancreatic cancer subtype and metastatic tropism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C103.
Abstract C107: Use of spatial transcriptomics to identify molecular features associated with African American heritage in pancreatic cancer
Authors: Wu Yuesong , Xie Aoqi , Loveless Ian , George Madison , Gartrelle Kendyll , Clark Julie , Salas-Escabillas Daniel , Shah Rupen , Kwon David , Francescone Ralph , Vendramini Costa Débora B. , Crawford Howard , Theisen Brian , Cui Yuehua , Huang Ling , Steele Nina G.
Published: January 2024

Pancreatic cancer is the third leading cause of cancer-related deaths in the US, with a 5-year survival rate of 12%. Black or African American patients (BAA) have a 20% higher incidence of pancreatic cancer, and recent studies suggest that there are biological factors that may influence this disparity, in addition to complex socioeconomic factors. Pancreatic tumors are highly enriched with stroma and exhibit significant inter- and intra-patient morphological and molecular heterogeneity. To improve the care for all patients, we need to better understand the disease mechanisms by comprehensively mapping different spatial locations within individual patients’ tumors and determining whether there are common patterns of pathogenesis across diverse patient populations. In this study, we utilized the 10X Visium spatial transcriptomics platform on eight treatment-naïve primary pancreatic tumors. We tested multiple published bioinformatic packages, including SpatialDE, SPARK-X, Spatial PCA, and Cottrazm, and optimized a multi-sample integrated analysis pipeline that allows us to automatically segment tumor lesions, infer major cell types in regions of interest on tissues, detect spatially variant genes, and assess associations between tissue morphological phenotypes and transcriptomic features. Importantly, our study cohort includes four White patients and four BAA patients. Through the comparison of spatial transcriptomes between White and BAA patients, we identified several genes displaying differential expression in tumor lesions of distinct racial groups, including Trefoil Factor 1 (TFF1) and CYP3A5. These genes present potential candidates for further investigation to elucidate the biological mechanisms underlying racial disparities in pancreatic cancer.

Citation Format: Yuesong Wu, Aoqi Xie, Ian Loveless, Madison George, Kendyll Gartrelle, Julie Clark, Daniel Salas-Escabillas, Rupen Shah, David Kwon, Ralph Francescone, Débora B. Vendramini Costa, Howard Crawford, Brian Theisen, Yuehua Cui, Ling Huang, Nina G. Steele. Use of spatial transcriptomics to identify molecular features associated with African American heritage in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C107.
Abstract IA13: Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer
Authors: Califano Andrea
Published: January 2024

Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of regulatory protein activity in single cells identified three PDA Developmental Lineages (PDLs), coexisting in virtually all tumors, whose transcriptional states are mechanistically driven by aberrant activation of Master Regulator (MR) proteins associated with gastrointestinal lineages (GLS state), morphogen and EMT pathways (MOS state), and acinar-to-ductal metaplasia (ALS state), respectively. Each PDL is further subdivided into sub-states characterized by low vs. high MAPK pathway activity. This taxonomy was remarkably conserved across multiple cohorts, cell lines, and PDX models, and harmonized with bulk profile analyses. Cross-state plasticity and MR essentiality was confirmed by barcode-based lineage tracing, epigenetic profiling, and CRISPR/Cas9 assays, respectively. Indeed, ectopic expression of PDL-specific MRs induced transdifferentiation in vitro and in vivo. Together these data provide a mechanistic foundation for PDA heterogeneity and a roadmap for targeting PDA cellular subtypes.

Citation Format: Andrea Califano. Developmental and MAPK-responsive programs drive distinct malignant subtypes and dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA13.
Abstract IA14: Forecasting pancreatic carcinogenesis through spatial multi-omics
Authors: Fertig Elana J.
Published: January 2024

Combining genomics with mathematical modeling provides a forecast system that can yield computational predictions to anticipate cancer progression and therapeutic response. High-throughput profiling technologies can indicate the molecular and cellular pathways of malignancies, but not the effect of targeting those pathways with therapy. Precision interception requires relating therapies to the cellular phenotypes underlying pancreatic carcinogenesis. This talk presents a hybrid computational and experimental strategy to uncover interactions between neoplastic cells and the microenvironment during pancreatic carcinogenesis. As pancreatic cancer develops, it forms a complex microenvironment of multiple interacting cells. The microenvironment of advanced pancreatic cancer includes a heterogeneous and dense population of cells, such as macrophages and fibroblasts, that are associated with immunosuppression. New single-cell and spatial molecular profiling technologies enable unprecedented characterization of the cellular and molecular composition of the microenvironment. These technologies provide the potential to identify candidate therapeutics to intercept immunosuppression in pancreatic cancer. State-of-the-art mathematical approaches in computational biology are essential to uncover mechanistic insights for high-throughput data for these precision interception strategies. We have recently applied new machine learning techniques to integrate imaging and spatial transcriptomics to enable comprehensive characterization of the pancreatic precancer microenvironment. Developing targets for interception requires determining which of these cellular and molecular pathways drive subsequent development of cancer. Relating the transcriptional programs in premalignant lesions to carcinogenesis requires mapping their temporal changes across disease stages. To integrate the spatial molecular data from premalignancies and single-cell RNA-seq reference atlases, we developed a transfer learning approach. This integrated analysis identified a switch between fibroblast-induced inflammatory signaling and cellular proliferation in pancreatic cancer cells. We confirmed these transitions also occur in pancreatic cancer patient derived organoids co cultured with fibroblasts using transfer learning from the reference scRNA-seq atlases of pancreatic tumors. This approach demonstrates the potential of computational analysis of multi-omics data in human tissue with organoid models for bidirectional bench to bedside research.

Citation Format: Elana J. Fertig. Forecasting pancreatic carcinogenesis through spatial multi-omics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA14.
Abstract IA15: What the surgeon has learned from pancreas cancer genomics, and vice versa
Authors: Gallinger Steven
Published: January 2024

Recent advances in molecular profiling and fundamental science discoveries are impacting care of PDAC patients, including surgical decision making. Our multidisciplinary group at the Ontario Institute for Cancer Research and the Princess Margaret in Toronto has focused on elucidating both germline and somatic genomic changes in PDAC, with aims to understand genetic predisposition to the disease, foster early detection and conduct trials for improved selection of standard and novel therapies. Using laser capture microdissection overseen by expert pathologists, seamless tumor banking and aggressive biopsy of chemo-naïve and progressive metastases, we have generated high epithelial tumor cell content whole genomes and transcriptomes (WGTS) on over 600 PDAC patients with all stages of the disease. Germline sequencing of all PDAC patients should be considered standard of care to detect patients with uniquely actionable genomic changes due to less common mutational pathways. The genetic basis of familial pancreas cancer remains elusive and we continue to collaborate with the PACGENE Network spearheaded by colleagues at Mayo, Hopkins and McGill to discover novel genes in high risk cases. Our genomic work and others explains the clinical conundrum of late presentation of PDAC due to rapid punctuated evolution which challenges the ‘holy grail’ of early detection. Thus, screening high risk groups is still within the realm of investigational studies such as the PRECEDE consortium, of which we are an active member. Focused clinical trials (eg COMPASS and PASS-01) using WGTS has revealed both large scale changes in genomes (eg. HRD, tandem duplicators, etc) and transcriptomes (the Moffit ‘continuum’) and discreet mutations (eg BRAF mutations in Kras wild type tumors) that are important to identify as early as possible in the patient’s clinical course. Subspecialty PDAC surgeons need to keep abreast of recent developments of both prognostic and predictive transcriptomic biomarkers that will soon be important in selecting appropriate patients for appropriate neoadjuvant therapies. A few clinical vignettes will be shown to provide evidence for the importance of WGTS and other profiling approaches for almost all PDAC patients.

Citation Format: Steven Gallinger. What the surgeon has learned from pancreas cancer genomics, and vice versa [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA15.
Abstract IA20: Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
Authors: Han Jincheng , Xu Jiaqian , Liu Yonghong , Liang Shaoheng , LaBella Kyle A. , Chakravarti Deepavali , Spring Denise J. , Xia Yan , DePinho Ronald A.
Published: January 2024

Oncogenic KRAS (KRAS*) is a signature mutation in pancreatic ductal adenocarcinoma (PDAC). While genetic extinction or pharmacological inhibition of KRAS* elicits anti-tumor responses in preclinical models and patients, we and others have identified cancer cell intrinsic (YAP, RTKs) and paracrine immune-mediated (TGFb) mechanisms enabling KRAS* bypass and tumor recurrence. Here, we explored the potential role of cancer associated fibroblasts (CAFs) as contributors to mechanisms driving KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent tumor regrowth is supported. We showed that genetic extinction or pharmacological inhibition of KRAS* results in upregulation of ERBB2 and ERBB3 expression in human and murine cancer cell models. We demonstrated that CAF-derived NRG1 supports KRAS*-dependent tumor growth. These insights prompted genetic depletion or pharmacological inhibitions studies targeting ERBB2/3 or NRG1, which showed abolition of KRAS* bypass and synergy with KRASG12D inhibitor in mouse and human PDAC models. Thus, CAFs via the NRG-ERBB2/3 paracrine axis provide yet another mechanism enabling KRAS* inhibitor therapy resistance, providing a highly actionable combination therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.

Citation Format: Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A. LaBella, Deepavali Chakravarti, Denise J. Spring, Yan Xia, Ronald A. DePinho. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr IA20.
Abstract PR13: Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer
Authors: Rajbhandari Nirakar , Hamilton Michael , Reya Tannishtha
Published: January 2024

The detailed understanding of the molecular basis of tumor initiation and progression is essential for the effective management and treatment of any cancer, including pancreatic cancer. To determine if the stem and progenitor cells can serve as cells of origin for pancreatic cancer, we have created a new mouse strain in which tamoxifen inducible Cre (CreERT2) is knocked into the endogenous locus encoding the stem cell regulator Musashi2 (Msi2). When crossed to a Cre-regulatable Myc transgenic (CAG-LSL-MycT58A) strain, Msi2-CreERT2 mice develop multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), and acinar cell carcinoma (ACC) following Myc activation in Msi2+ cells in the adult stage. A combination of single-cell genomics with computational analysis of developmental states and lineage trajectories of tumors in our model suggests that oncogenic Myc preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage potential. These pre-cancer cells subsequently take distinct fates within the same mice by activation of distinct transcriptional programs and large-scale genomic changes. Additionally, combining transcriptomic and functional genomic approaches, we have identified hyaluronan-mediated motility receptor (HMMR) as a potential novel dependency in mouse and human ASCP cells, providing a framework to develop interception strategies for this lethal disease. In summary, our study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer.

Citation Format: Nirakar Rajbhandari, Michael Hamilton, Tannishtha Reya. Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR13.
Portuguese Pancreatic Club Perspective on the Surveillance Strategy for Pancreatic Neuroendocrine Tumours: When and How to Do It?
Authors: Bispo Miguel , Marques Susana , Fernandes Alexandra , Rodrigues-Pinto Eduardo , Vilas-Boas Filipe , Rio-Tinto Ricardo , Devière Jacques ,   specialized section of the Portuguese Society of Gastroenterology.
Published: January 2024

Background: Pancreatic neuroendocrine tumours (pNETs) are a highly heterogeneous group of tumours with widely variable biological behaviour. The incidence of pNETs has risen exponentially over the last three decades, particularly for asymptomatic small pNETs (≤2 cm), due to the widespread use of cross-sectional imaging in clinical practice. Summary: Current consensus guidelines suggest that incidentally discovered pNETs ≤2 cm can be selectively followed due to the overall low risk of malignancy. Nevertheless, the “watch-and-wait” management strategy for small asymptomatic pNETs is still not widely accepted due to the lack of long-term data on the natural history of these small lesions. Additionally, it is clear that a subset of small pNETs may show malignant behaviour. Key Message: Given the non-negligible risk of malignancy even in small pNETs, it is of the utmost importance to identify other preoperative factors, other than size, that may help to stratify the risk of malignant behaviour and guide clinical management. In this article, the Portuguese Pancreatic Club reviews the importance of risk stratification of pNETs and presents an updated perspective on the surveillance strategy for sporadic well-differentiated pNETs.
Mask Continuous Positive Airway Pressure Increases Diaphragm Thickening Fraction in Healthy Subjects
Authors: Lindner Simon , Teichert Jan , Hoermann Clara , Michels Julia D. , Herth Felix J.F. , Duerschmied Daniel , Britsch Simone
Published: January 2024

Introduction: The most widespread treatment for obstructive sleep apnoea and obesity hypoventilation syndrome is continuous positive airway pressure (CPAP). The addition of inspiratory support is a potential alternative. This is a physiological study to determine the effect of CPAP and inspiratory support pressure on respiratory effort measured by diaphragm thickening fraction (DTF) in healthy volunteers. Methods: DTF was measured in spontaneously breathing, healthy volunteers during 4 phases: (I) without connection to a ventilator, (II) on a ventilator without any applied pressures, (III) with a CPAP of 5 cmH2O, and (IV) with an additional inspiratory support pressure of 5 cmH2O. Results: Twenty-nine individuals agreed to participate. DTF was similar during the first two phases (32 ± 13% and 35 ± 22%). A considerable increase in DTF to 51 ± 21% was noted in phase III. The introduction of inspiratory support pressure during phase IV led to a reduction in DTF back to 36 ± 23% (p < 0.001). Tidal volume and minute ventilation were both slightly higher in phase IV compared to phase III. Conclusion: CPAP without inspiratory support pressure increases respiratory effort measured by DTF in healthy subjects. Further research is required to investigate this phenomenon in a clinical setting.
O Rabinal-achí em perspectiva: uma análise comparativa de suas diversas versões escritas
Authors: Pasquali Bruno Tomazela
Published: January 2024

Este artigo tem como objetivo analisar as versões impressas do Rabinal-Achí, uma obra de origem indígena guatemalteca, catalogada pelo abade francês Charles Étienne Brasseur de Bourbourg entre 1855 e 1856. Para compreender as motivações do abade e a forma como o texto foi transposto para o papel, o artigo apresenta uma breve biografia contextualizada do autor, utilizando como fontes seus próprios trabalhos autorais e demais cartas de contemporâneos. Como contraponto, na segunda seção do artigo se analisam as adaptações do Rabinal-Achí oriundas do Manuscrito Pérez de 1917, um documento redigido em idioma maia-achí que tem sido identificado como uma produção genuinamente indígena e isenta de influências europeias. O objetivo é desconstruir a narrativa que retrata o Rabinal-Achí como uma manifestação impoluta e idílica da cultura indígena mesoamericana, apresentando as influências que tal tradição sofreu ao longo do tempo nas diversas manifestações culturais catalogadas. Por fim, o artigo apresenta as novas concepções e interpretações geradas a partir dessas influências nos variados suportes em que foram concebidas.
Marxismo, teología y política: Enrique Dussel
Authors: Ortega Reyna Jaime , Wesche Rodrigo
Published: January 2024

Este texto aborda, en forma de un homenaje póstumo, tres elementos claves del pensamiento de Enrique Dussel. Por un lado, el marxismo, del cual se destaca su perspectiva a propósito de la exterioridad del “trabajo vivo”; la teología y su crítica del fetichismo mercantilizante; y la dimensión política militante. Enrique Dussel murió en 2023 y dejó tras de sí un legado escrito que tendrá que ser valorado en su justa dimensión. Los autores sugieren que
O avesso do mesmo lugar
Authors: Imbrizi Jaquelina , Bartsch Julia , Binkowski Gabriel , Broide Emilia
Published: January 2024

Neste artigo, parte-se das experiências de fronteira de dois meninos. Uma é a narrativa de Zain, no filme Cafarnaum, anterior à sua migração do Líbano; a outra, o caso clínico de Túlio, construído por um grupo de supervisão em serviço de medidas socioeducativas em São Paulo. Abordaremos o laço social nesses distintos contextos, observando subjetividades singulares e universais de adolescentes marcados por desigualdade e injustiça social. O objetivo é interrogar a psicanálise diante da condição de desenraizamento imposta ao sujeito na contemporaneidade. O cinema, objeto da cultura, evoca a nossa responsabilidade ética ao aproximar ficção e realidade, denunciando violências de gênero e situações desumanas oferecidas aos imigrantes e às infâncias subalternizadas. Há o convite para a criação de dispositivos clínicos que ofereçam a hospitalidade como operador conceitual diante das urgências sociais.
Construção de um circuito no tratamento do autista
Authors: Nogueira Isabela de Lima , Lemos Jéssyca Carvalho , Calzavara Maria Gláucia Pires
Published: January 2024

A partir da apresentação de fragmentos de um caso clínico de autismo infantil, busca-se discutir possibilidades de manejo da voz, do olhar e do corpo do analista no trabalho com sujeitos autistas. Com o referencial da psicanálise, analisam-se algumas estratégias utilizadas pelas analistas na condução do caso bem como seus efeitos na construção do corpo da criança. Assim, considera-se que o analista, ao se portar como um parceiro no trabalho de construção já realizado pelo autista, pode acolher suas dificuldades e reconhecer seus interesses particulares, a fim de estabelecer uma prática clínica que o ajude a se regular e a construir formas menos angustiantes de estar no mundo e de se relacionar.
Projeto de automatização do processo de produção de comidas em rede de fast-food a partir de um sistema a eventos discretos
Authors: Dacca Danilo Patah , Aquino Pedro Bianco de , Kassab Vítor Aun
Published: January 2024

O projeto de automação proposto visa aprimorar a eficiência da produção em um ambiente de fast-food, especificamente na fabricação de hambúrgueres, batatas fritas e nuggets. Utilizando a metodologia de Sistemas a Eventos Discretos (SED), a abordagem emprega uma arquitetura física que incorpora dispositivos de detecção, monitoramento, comando e atuação, todos conectados a um Controlador Lógico Programável (CLP). A norma IEC 61131-3 guia a programação dos CLPs, empregando a linguagem Ladder Diagram (LD) para traduzir os modelos de rede de Petri para a lógica de controle do sistema. A modelagem do comportamento do sistema é realizada por meio da metodologia Production Flow Schema (PFS) e redes de Petri,  proporcionando uma representação visual clara dos subprocessos, incluindo a produção de cada item e os intertravamentos necessários. A validação do controle é executada por simulações utilizando o software PIPE 4.3, permitindo ajustes antes da conversão para LD. Os resultados esperados abrangem uma melhoria substancial na eficiência operacional. A automação busca garantir consistência na qualidade do produto, redução de erros e aumento da capacidade produtiva. Ao minimizar a intervenção humana, o sistema também pretende otimizar a produção, proporcionando benefícios tanto para a empresa quanto para a experiência do cliente. O desenvolvimento do projeto segue uma metodologia de cinco etapas, que englobam desde a definição da arquitetura física até o comissionamento das Entradas/Saídas no sistema real. A transcrição da Rede de Petri para a linguagem de programação é realizada por meio do isomorfismo, facilitando a implementação prática do controle. Em síntese, a integração de SED, metodologia PFS, modelagem de redes de Petri e programação conforme a norma IEC 61131-3 oferece uma abordagem robusta para o desenvolvimento de sistemas de automação complexos, proporcionando melhorias significativas na eficiência e na qualidade da produção em um ambiente de fast-food.
Abstract 14594: Dual Contrast-Enhanced Micro-Computed Tomography for Simultaneous Characterization of Macrocalcification and Tri-Layered Structural Remodeling in Explanted Human Aortic Valves
Authors: El Zeini Mustapha , Kabiri Angela , Vailionis Arturas , Perrino John , Jensen Kristin C , Burdon Thomas A , Shudo Yasuhiro , Boyd Jack , Woo Y Joe , Marie-Joubert Lydia , Chen Ian Y
Published: January 2024

Background:
Micro-computed tomography (microCT) is excellent for detecting macrocalcification but ineffective at revealing other pathologically relevant structural details in the valves affected by aortic stenosis (AS). Here, we aimed to develop a dual contrast-enhanced microCT technique to simultaneously assess macrocalcification and layer-specific remodeling in diseased human aortic valves.

Methods:
Diseased (n=15) and normal (n=9) aortic valve leaflets were obtained from human subjects undergoing aortic valve replacement for AS and heart transplantation/autopsy, respectively. Leaflets were fixed (4% paraformaldehyde and 2% glutaraldehyde), stained with dual contrast (1% osmium tetroxide and 1% uranyl acetate), and embedded in epoxy resin. Additional unstained leaflets (n=3 diseased, n=3 normal), similarly processed otherwise, served as staining controls. MicroCT of embedded leaflets was performed using a ZEISS Xradia 520 Versa scanner, with low energy beam (80 kVp, 5 W, LE4 filter) and high-resolution acquisitions (15 μm x 15 μm, 5 sec exposure x 1601 projections). Reconstructed images were analyzed for leaflet/layer thicknesses at midline and macrocalcification volume using Dragonfly.

Results:
The tri-layered tissue structure was only visualized in stained but not unstained leaflets (
p
=0.002). With staining, each layer was found to be thicker in the diseased than the normal leaflets (0.28±0.13 mm vs 0.18±0.07 mm,
p
=0.0002 for fibrosa; 0.64±0.68 mm vs 0.29±0.19 mm,
p
=0.012 for spongiosa; 0.32±0.16 mm vs 0.16±0.07 mm,
p
<0.0001 for ventricularis). The macrocalcification volume in the diseased leaflets was greater than that in the normal leaflets (84.7±84.4 mm
3
vs 0 mm
3
,
p
<0.0001) and correlated only with the thickness of spongiosa (
r
=0.79,
p
<0.001) but not other layers (
p
=0.67,
p
=0.26). Macrocalcification was as frequently observed in spongiosa as in fibrosa (66.7% vs 66.7% of diseased leaflets,
p
=0.3) but never in ventricularis.

Conclusions:
Dual contrast-enhanced microCT enables high-quality imaging of both macrocalcification and layer-specific remodeling in diseased human aortic valves. The results here suggest an intimate relationship between macrocalcification and spongiosa that warrants further investigation.
Comparative Effectiveness of PET and SPECT MPI for Predicting Cardiovascular Events After Kidney Transplant
Authors: Huck Daniel M. , Weber Brittany , Schreiber Brittany , Pandav Jay , Parks Sean , Hainer Jon , Brown Jenifer M. , Divakaran Sanjay , Blankstein Ron , Dorbala Sharmila , Trinquart Ludovic , Chandraker Anil , Di Carli Marcelo F.
Published: January 2024

BACKGROUND:

Advanced chronic kidney disease is associated with high cardiovascular risk, even after kidney transplant. Pretransplant cardiac testing may identify patients who require additional assessment before transplant or would benefit from risk optimization. The objective of the current study was to determine the relative prognostic utility of pretransplant positron emission tomography (PET) and single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for posttransplant major adverse cardiovascular events (MACEs).

METHODS:

We retrospectively followed patients who underwent MPI before kidney transplant for the occurrence of MACE after transplant including myocardial infarction, stroke, heart failure, and cardiac death. An abnormal MPI result was defined as a total perfusion deficit >5% of the myocardium. To determine associations of MPI results with MACE, we utilized Cox hazard regression with propensity weighting for PET versus SPECT with model factors, including demographics and cardiovascular risk factors.

RESULTS:

A total of 393 patients underwent MPI (208 PET and 185 SPECT) and were followed for a median of 5.9 years post-transplant. Most were male (58%), median age was 58 years, and there was a high burden of hypertension (88%) and diabetes (33%). A minority had abnormal MPI (n=58, 15%). In propensity-weighted hazard regression, abnormal PET result was associated with posttransplant MACE (hazard ratio, 3.02 [95% CI, 1.78–5.11];
P
<0.001), while there was insufficient evidence of an association of abnormal SPECT result with MACE (1.39 [95% CI, 0.72–2.66];
P
=0.33). The explained relative risk of the PET result was higher than the SPECT result (R
2
0.086 versus 0.007). Normal PET was associated with the lowest risk of MACE (2.2%/year versus 3.6%/year for normal SPECT;
P
<0.001).

CONCLUSIONS:

Kidney transplant recipients are at high cardiovascular risk, despite a minority having obstructive coronary artery disease on MPI. PET MPI findings predict posttransplant MACE. Normal PET may better discriminate lower risk patients compared with normal SPECT, which should be confirmed in a larger prospective study.
Coronary Sinus Narrowing Improves Coronary Microcirculation Function in Patients With Refractory Angina: A Multicenter Prospective INROAD Study
Authors: Tebaldi Matteo , Campo Gianluca , Ugo Fabrizio , Guarracini Stefano , Marrone Andrea , Clò Stefano , Abdirashid Mohamed , Di Mauro Michele , Rametta Francesco , Di Marco Massimo , Cocco Marta , Marchini Federico , Penzo Carlo , Erriquez Andrea , Banai Shmuel , Biscaglia Simone
Published: January 2024

BACKGROUND:

The underlying mechanisms responsible for the clinical benefits following coronary sinus narrowing and pressure elevation remain unclear. The present study aims to investigate whether coronary sinus narrowing improves the indexes of coronary microcirculatory function.

METHODS:

Patients with refractory angina who had a clinical indication for reducer implantation underwent invasive physiological assessments before and 4 months after the procedure. The primary outcome was the change in the values of the index of microcirculatory resistance. Secondary end points included changes in coronary flow reserve and the resistive resistance ratio values. Angina status was assessed with the Canadian Cardiology Society class and the Seattle Angina Questionnaire.

RESULTS:

Twenty-four patients with a history of obstructive coronary artery disease and prior coronary revascularization (surgical and percutaneous) treated with reducer implantation were enrolled, and 21 of them (87%) underwent repeated invasive coronary physiological assessment after 4 months. The index of microcirculatory resistance values decreased from 33.35±19.88 at baseline to 15.42±11.36 at 4-month follow-up (
P
<0.001; mean difference, −17.90 [95% CI, −26.16 to −9.64]). A significant (≥20% from baseline) reduction of the index of microcirculatory resistance was observed in 15 (71.4% [95% CI, 47.8%–88.7%]) patients. The number of patients with abnormal index of microcirculatory resistance (≥25) decreased from 12 (57%) to 4 (19%;
P
=0.016). Coronary flow reserve increased from 2.46±1.52 to 4.20±2.52 (mean difference, 1.73 [95% CI, 0.51–2.96]). Similar findings were observed for resistive resistance ratio values. Overall, 16 patients (76.1%) had an improvement of 1 Canadian Cardiology Society class. Seattle Angina Questionnaire summary score increase of around 3 points (3.01 [95% CI, 1.39–4.61]).

CONCLUSIONS:

Coronary sinus reduction implantation is associated with a significant improvement in the parameters of coronary microcirculatory function. These findings provide insights into the improvement of angina symptoms and may have implications for the treatment of coronary microvascular dysfunction.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05174572.
Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure
Authors: Guirette Mélanie , Lan Jessie , McKeown Nicola M. , Brown Michael R. , Chen Han , de Vries Paul S. , Kim Hyunju , Rebholz Casey M. , Morrison Alanna C. , Bartz Traci M. , Fretts Amanda M. , Guo Xiuqing , Lemaitre Rozenn N. , Liu Ching-Ti , Noordam Raymond , de Mutsert Renée , Rosendaal Frits R. , Wang Carol A. , Beilin Lawrence J. , Mori Trevor A. , Oddy Wendy H. , Pennell Craig E. , Chai Jin Fang , Whitton Clare , van Dam Rob M. , Liu Jianjun , Tai E. Shyong , Sim Xueling , Neuhouser Marian L. , Kooperberg Charles , Tinker Lesley F. , Franceschini Nora , Huan TianXiao , Winkler Thomas W. , Bentley Amy R. , Gauderman W. James , Heerkens Luc , Tanaka Toshiko , van Rooij Jeroen , Munroe Patricia B. , Warren Helen R. , Voortman Trudy , Chen Honglei , Rao D.C. , Levy Daniel , Ma Jiantao ,   On behalf of the CHARGE Gene-Lifestyle Interactions Working Group
Published: January 2024

BACKGROUND:

The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP.

METHODS:

We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses.

RESULTS:

We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at
P
interaction
<5e−8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (
P
interaction
=4e−8;
P
for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (
P
interaction
=9.4e−7) and 0.20±0.06 mm Hg (
P
interaction
=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (
P
=4e−273) and cis-DNA methylation quantitative trait loci variants (
P
=1e−300). Although the closest gene for rs117878928 is
MTHFS
, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene
ST20
at 15q25.1.

CONCLUSIONS:

We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.