tbuckley/cabot-search huggingface dataset:
Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer
Authors: Jenna N Sjoerdsma, Emily K Bromley, Jaeho Shin, Tyvette Hilliard, Yueying Liu, Caitlin Horgan, Gyoyeon Hwang, Michael Bektas, David Omstead, Tanyel Kiziltepe, M Sharon Stack, Basar Bilgicer
Journal: Journal of Controlled Release (2024)
Global, regional, and national burdens of acne vulgaris in adolescents and young adults aged 10-24 years from 1990 to 2021: a trend analysis
Authors: Zhou Zhu, Xiaoying Zhong, Zhongyu Luo, Mingjuan Liu, Hanlin Zhang, Heyi Zheng, Jun Li
Journal: British Journal of Dermatology (2024)

Abstract Background Acne vulgaris is a common skin condition affecting adolescents and young adults worldwide, yet data on its burden and trends remain limited. We aimed to investigate trends in the burden of acne vulgaris among adolescents and young adults aged 10-24 years at global, regional, and national levels. Methods We retrieved data from the Global Burden of Disease Study (GBD) 2021 for individuals aged 10-24 years in 204 countries and territories from 1990 to 2021. We analyzed the numbers, age-standardised rates, and average annual percentage changes (AAPCs) of the prevalence, incidence, and disability-adjusted life-years (DALYs) for acne vulgaris at the global, regional, and national levels. Additionally, we examined these global trends by age, gender, and Socio-demographic Index (SDI). Results Globally, the age-standardised prevalence rate of acne vulgaris among adolescents and young adults increased from 8,563.4 per 100,000 population (95% UI 7,343.5-9,920.1) in 1990 to 9,790.5 (95% UI 8,420.9-11,287.2) per 100,000 population in 2021, with an AAPC of 0.43 (95% CI 0.41-0.46). The age-standardised incidence rate and age-standardised DALY rate also showed a similar upward trend. Regionally, Western Europe had the highest age-standardised prevalence, incidence, and DALY rates, while North Africa and the Middle East had the largest increase in these rates. By SDI quintile, the high SDI region had the highest age-standardised prevalence, incidence, and DALY rates from 1990 to 2021, whereas the low-middle SDI region had the lowest burden of acne vulgaris but experienced the most significant increase in these rates. Globally, the age-standardised prevalence rate of acne vulgaris in 2021 was approximately 25% higher in females than in males (10,911.8 per 100,000 population vs. 8,727.8 per 100,000 population). Among all age groups, adolescents aged 15-19 years had the highest age-specific prevalence rate, while adolescents aged 10-14 years experienced the largest increase from 1990 to 2021 (AAPC = 0.50, 95% CI 0.48-0.52). Conclusions The burden of acne vulgaris among adolescents and young adults has continued to increase in nearly all countries since the 1990s. Managing this condition remains a significant challenge, necessitating more effective and targeted interventions to control the acne burden.
NCCN guideline-concordant cancer care in Sub-Saharan Africa A population-based multi-country study of five cancers
Authors: Nikolaus Christian Simon Mezger, Tobias Paul Seraphin, Robert Ballé, Mirko Griesel, Yvonne Walburga Joko-Fru, Lucia Hämmerl, Jana Feuchtner, Biying Liu, Annelle Zietsman, Bakarou Kamaté, Freddy Houéhanou Rodrigue Gnangnon, Franck Gnahatin, Dimitry Moudiongui Mboungou, Mathewos Assefa, Phoebe Mary Amulen, Gladys Chesumbai, Tatenda Chingonzoh, Cesaltina Feirreira Lorenzoni, Anne Korir, Pablo S Carvalho Santos, Jörg Michael Mezger, Haifa Kathrin Al-Ali, Rafael Mikolajczyk, Donald Max Parkin, Ahmedin Jemal, Eva Johanna Kantelhardt
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background To assess population-based quality of cancer care in sub-Saharan Africa and to identify specific gaps and joint opportunities, we assessed concordance of diagnostics and treatments with National Comprehensive Cancer Network Harmonized Guidelines for leading cancer types in 10 countries. Methods Adult patients with female breast cancer, cervical cancer, colorectal cancer, non-Hodgkin lymphoma, and prostate cancer were randomly drawn from 11 population-based cancer registries. Guideline concordance of diagnostics and treatment was assessed using clinical records. In a subcohort of 906 patients with potentially curable cancer (stage I-III breast cancer, cervical cancer, colorectal cancer, prostate cancer, aggressive non-Hodgkin lymphoma [any stage]) and documentation for more than 1 month after diagnosis, we estimated factors associated with guideline-concordant treatment or minor deviations. Results Diagnostic information based on guidelines was complete for 1030 (31.7%) of a total of 3246 patients included. In the subcohort with curable cancer, guideline-concordant treatment was documented in 374 (41.3%, corresponding to 11.7% of 3246 patients included in the population-based cohort): aggressive non-Hodgkin lymphoma (59.8%/9.1% population based), breast cancer (54.5%/19.0%), prostate cancer (39.0%/6.1%), colorectal cancer (33.9%/9.5%), and cervical cancer (27.8%/11.6%). Guideline-concordant treatment was most frequent in Namibia (73.1% of the curable cancer subcohort/32.8% population based) and lowest in Kampala, Uganda (13.5%/3.1%). Guideline-concordant treatment was negatively associated with poor ECOG-ACRIN performance status, locally advanced disease stage, origin from low Human Development Index countries, and a diagnosis of colorectal cancer or cervical cancer. Conclusions The quality of diagnostic workup and treatment showed major deficits, with considerable disparities among countries and cancer types. Improved diagnostic services are necessary to increase the share of curable cancer in sub-Saharan Africa. Treatment components within National Comprehensive Cancer Network Guidelines for several cancers should be prioritized.
Abstract C034: MUC1 positive extracellular vesicles play an important role on gemcitabine resistance in PDAC
Authors: Ying Huang, Dezhen Wang, Chunbo He, Bo Tu, Kamiya Mehla, Pankaj K. Singh, Michael A. Hollingsworth
Journal: Cancer Research (2024)

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. The high death rate caused by PDAC results from complex factors, including difficulties in diagnosing early-stage disease, increased metastatic potential, and resistance to traditional therapies. Mucin1 (MUC1) is one of the transmembrane mucins typically expressed on the apical surface of epithelial cells but is not apically restricted and upregulated dramatically in pancreatic cancer cells. Our study showed that MUC1CT positive EVs promote tumor cell proliferation and migration in vitro, in vivo tumor growth, and metastasis. Moreover, MUC1 increases glucose metabolism in pancreatic cancer cell to resistance gemcitabine though stabilizing HIF-1α. However, the role of MUC1 in gemcitabine resistance has not been well studied and understood. Methods We used CRISPR-Cas9 to knockout MUC1 in pancreatic cancer cells to investigate MUC1 effects on chemotherapy resistance. EVs were isolated from MUC1 positive cells and MUC1 knockout cells by a sequence of centrifugation and ultracentrifugation steps. Proteomics and liquid chromatography-mass spectrometry-based metabolomics were performed to identify specific proteins and metabolites in MUC1-associated EVs. To evaluate the cargo of MUC1+ EVs and MUC1- EVs on chemotherapy resistance, 13C- labeled glucose with metabolomics was applied to trace glucose-related metabolites when the cells were treated with or without gemcitabine and EVs. Results We identified that MUC1 increased gemcitabine resistance in pancreatic cancer cells. MUC1 positive EVs could increase gemcitabine resistance in MUC1 knockout cells. Unique protein cargo in MUC1-positive EVs was enriched in DNA replication and DNA repair pathways. Phosphogluconate dehydrogenase (PGD) was packaged in MUC1-positive EVs, which helped glucose-derived ribose to increase MUC1 knockout cell gemcitabine resistance. Metabolomics in EVs showed that pyrimidine and purine nucleotides biosynthetic pathway-related metabolites are enriched in MUC1-positive EVs. Uridine is one of the important metabolites in MUC1-positive EVs. Our data showed that the pentose phosphate pathway (PPP) and pyrimidine metabolism were involved in MUC1- positive EV-induced gemcitabine resistance. Citation Format: Ying Huang, Dezhen Wang, Chunbo He, Bo Tu, Kamiya Mehla, Pankaj K. Singh, Michael A. Hollingsworth. MUC1 positive extracellular vesicles play an important role on gemcitabine resistance in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C034.
Abstract PR-03: Canonical Notch signaling in cancer-associated fibroblasts supports an immunosuppressive pancreatic tumor microenvironment
Authors: Allison Bischoff, Wei Yan, Filip Bednar, Marina Pasca di Magliano
Journal: Cancer Research (2024)

Abstract Notch is a contact-dependent signaling pathway that plays critical roles in spatiotemporal patterning during embryogenesis. Beyond its role in development, Notch signaling can regulate tissue patterning in adult organs in response to tissue injury or cancer. In pancreatic cancer, Notch signaling drives pancreatic tumor epithelial growth and regulates myeloid function in the tumor microenvironment (TME). Its role in pancreatic cancer-associated fibroblasts (CAFs) is less clear. CAFs are a central component of the pancreatic TME and demonstrate significant phenotypic and functional differences depending on their spatial arrangement in pre-neoplastic and tumor tissue. Using Notch signaling reporter mice CBF: H2B-Venus bred into KC (Ptf1a cre/+;Kras LSL-G12D/+) and KPC (Ptf1a cre/+;Kras LSL-G12D/+;p53 flox/+) backgrounds, we demonstrate that canonical Notch signaling is activated in CAFs at different stages of neoplastic progression. Notably, Notch signaling appears to be most active in aSMA+ CAFs spatially located adjacent to pre-neoplastic/cancer cells, suggesting that Notch ligands expressed by pre-neoplastic/cancer cells are critical for this activation. To test the functional role of canonical Notch signaling in CAFs, we generated a fibroblast-specific, tamoxifen-inducible model of Notch inhibition that utilizes a dominant-negative form of the Notch transcriptional co-activator MAML1 (PDGFRa CreERT2/+ ,Rosa26 LSL-DNMAML). Using an orthotopic model of pancreatic cancer (50,000 cells; KPC) we demonstrate that inhibition of Notch signaling in CAFs results in smaller tumors. These CAFs expressed lower levels of the myofibroblastic marker aSMA+. Additionally, tumors from PDGFRa CreERT2/+, Rosa26 LSL-DNMAML mice had fewer Arg1+ macrophages and a dramatic influx of CD8+ T cells. Collectively, these results suggest that Notch signaling in CAFs regulates their phenotype and supports tumor progression by inducing an immunosuppressive tumor microenvironment. Citation Format: Allison Bischoff, Wei Yan, Filip Bednar, Marina Pasca di Magliano. Canonical Notch signaling in cancer-associated fibroblasts supports an immunosuppressive pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-03.
Abstract C078: Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes
Authors: Kevin MacPherson-Hawthorne, Jason M. Link, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelle, John Muschler, Andrew Adey, Rosalie Sears
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) disease progression involves complex cell state transitions in both malignant and non-malignant populations within the tumor microenvironment. To uncover PDAC cell states and epigenetic features associated with clinical outcome, we profiled 40 tumor samples (33 primary tumors and 7 metastases) from 39 patients with single cell ATAC-seq, along with 10 sample-matched single cell RNA-seq profiles. Through topic modeling of high dimensional chromatin data, we uncovered distinct cis-regulatory networks underlying the classical and basal-like molecular subtypes of PDAC, which showed differential activity in basal-classical hybrid cells. Furthermore, delineation of epigenetic alterations by basal, classical, and hybrid subtypes revealed a core set of chromatin regions opened in all PDAC subtypes relative to ductal and acinar cells. These universally open regions showed striking overlap with gastrointestinal enhancers, highlighting a common endoderm lineage infidelity process across pancreatic tumors. Within the stromal compartment, we identified novel regulators of myofibroblastic cancer-associated fibroblasts (myCAFs) and inflammatory CAFs (iCAFs) from enhancer networks active in each CAF subtype. Importantly, our data uncover a highly prognostic gene program active in only one of two distinct myCAF chromatin states found in our data, highlighting a putative tumor-promoting myCAF subpopulation. Our work provides a high-resolution description of epigenetic cell state heterogeneity in PDAC, revealing novel regulators and gene programs associated with PDAC subtypes and clinical outcome. Citation Format: Kevin MacPherson-Hawthorne, Jason M. Link, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelle, John Muschler, Andrew Adey, Rosalie Sears. Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C078.
Abstract B089: Identification of novel drivers of gemcitabine resistance in pancreatic cancer
Authors: Amina D Bilalbegovic, Bowen Fu, Zeribe Nwosu
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is an aggressive disease with limited therapeutic options. Gemcitabine is a clinically used chemotherapy for pancreatic cancer treatment but has limited efficacy. The molecular mechanisms responsible for gemcitabine resistance in pancreatic cancer are still unclear. Here, we analyzed the genomics of drug sensitivity in cancer dataset and identified various pancreatic cancer cells with distinct sensitivity to gemcitabine. Validation with proliferation and clonogenic assays confirmed that while CFPAC1 and PANC0327 are highly gemcitabine-sensitive, ASPC1 and PANC1 display intrinsic gemcitabine resistance. Analysis of the gene expression profile of these cells identified several genes that are differentially upregulated in resistant versus sensitive cells. Pathway enrichment analysis using the differential genes revealed the upregulation of Hippo, Wnt, MAPK signaling pathways as well as autophagy and glutathione metabolism in the resistant cells. Using quantitative PCR, immunoblotting and biochemical assays, and extracellular flux analysis methods, we have characterized the molecular distinctions between gemcitabine sensitive and resistant cells. Our results provide insight on the molecular mechanisms driving gemcitabine resistance in pancreatic cancer and could lead to novel therapeutic strategies to overcome resistance and improve patients’ treatment. Citation Format: Amina D Bilalbegovic, Bowen Fu, Zeribe Nwosu. Identification of novel drivers of gemcitabine resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B089.
Abstract A035: 3D High-Density Collagen I Improves the Modeling of Aggressive Pancreatic Cancer
Authors: Kim Nguyen-Ta, Sural Ranamukhaarachchi, Jeffrey Turner, Utsav Joshi, Himangshu Sonowal, Jorge de la Torre Medina, Herve Tiriac, Stephanie Fraley, Rebekah White
Journal: Cancer Research (2024)

Abstract Background: Fibrillar collagen type I constitutes the majority of the extracellular matrix in pancreatic ductal adenocarcinoma (PDAC), yet most in vivo murine models involve the use of basement membrane extracts, which instead contain collagen type IV, as matrices to embed PDAC cells. Type I collagen in the PDAC tumor microenvironment has been associated with worse prognosis. Our hypothesis is that PDAC cells grown in 3D high-density collagen I (HDC) gels behave more aggressively compared to the same cells grown using conventional basement membrane matrix (BMM). Methods: The KPC1199 2D cell line was previously generated from a tumor-bearing male KPC mouse. KPC1199 cells were cultured in vitro in HDC or BMM for one week. Orthotopic tumors were established by embedding KPC1199 cells in HDC (N=10) or BMM (N=10) in the pancreatic tail of syngeneic C57BL/6J mice via laparotomy. Half of the tumors were collected five weeks after tumor implantation, and the other half utilized for a survival study. Collagen was imaged by second harmonic generation (SHG) microscopy. Results: In vitro imaging of single KPC1199 cells grown in HDC revealed an aggressive phenotype with clonal network-like structures compared to a spheroidal, non-aggressive phenotype for cells grown in BMM over the course of seven days. SHG imaging confirmed consistent formation and organization of collagen in HDC tumors but minimal to faint collagen formation in BMM tumors. Gross examination of HDC mice showed 60% with visible liver metastasis compared with none in the BMM mice. In the survival study, the entire HDC group died before the BMM group (p-value &amp;lt; 0.01). Conclusions: Our pilot study is the first, to our knowledge, to successfully generate orthotopic PDAC tumors using 3D high-density collagen I in a mouse model. KPC1199 cells embedded in HDC showed an aggressive phenotype in vitro, and resultant tumors demonstrated more robust collagen organization compared to the same cells grown in the BMM substrate. This aggressive phenotype translated to visible liver metastasis within five weeks in the HDC mice and prior to death from primary tumor burden. This is not typical for most KPC-derived cell lines but is typical for human PDAC patients. Our preliminary findings support the use of HDC as an alternative substrate for better modeling of this aggressive cancer. Citation Format: Kim Nguyen-Ta, Sural Ranamukhaarachchi, Jeffrey Turner, Utsav Joshi, Himangshu Sonowal, Jorge de la Torre Medina, Herve Tiriac, Stephanie Fraley, Rebekah White. 3D High-Density Collagen I Improves the Modeling of Aggressive Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A035.
Abstract A036: The role of hypoxia in CD8+ T cell localization and function in pancreatic cancer
Authors: Ashley M. Mello, Tenzin Ngodup, Katelyn L. Donahue, Marina Pasca Di Magliano, Kyoung Eun Lee
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy characterized by poor response to existing therapeutic options. This resistance to treatment is partly due to its extensive inflammatory, desmoplastic stromal response, along with a hypoxic microenvironment. Although tumor hypoxia induces adaptive responses in both cancer cells and the surrounding stroma, most studies on the role of hypoxia in tumorigenesis have focused on cancer cell-intrinsic properties. The impact of hypoxia on stromal cells themselves and their interactions with cancer cells has remained largely unknown. We previously showed that inflammatory cancer-associated fibroblasts (iCAFs), which express high levels of cytokines and chemokines, are preferentially located in hypoxic regions of PDAC, and that hypoxia promotes an inflammatory fibroblast phenotype. The iCAF phenotype has been correlated with highly immunosuppressive features of PDAC. These findings and our preliminary observation that CD8+ T cells are largely excluded from hypoxic PDAC regions, raise the possibility that hypoxia suppresses the infiltration and activation of CD8+ T cells by modulating their interactions with inflammatory fibroblasts. By culturing CD8+ T cells under hypoxia with conditioned media from co-cultures of pancreatic cancer cells and fibroblasts, we have found that cancer cells and fibroblasts decrease CD8+ T cell proliferation and cytotoxic activity under low oxygen conditions. We are working to elucidate the mechanism by which hypoxia regulates CD8+ T cell infiltration and activation through cancer cell-fibroblast crosstalk. Citation Format: Ashley M. Mello, Tenzin Ngodup, Katelyn L. Donahue, Marina Pasca Di Magliano, Kyoung Eun Lee. The role of hypoxia in CD8+ T cell localization and function in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A036.
Abstract A084: CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer
Authors: Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Keisuke Tateishi, Mitsuhiro Fujishiro
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited therapies. In our screening using patient-derived organoids, we identified cyclin-dependent kinase 12 (CDK12) as a promising target in a subset of PDAC. Both pharmacological and genetic inhibition of CDK12 exerted potent antitumor activity in vitro and in vivo, inducing double-strand DNA breaks and apoptosis. CDK12 is a member of cyclin-dependent kinases that is involved in gene expression regulations at multiple levels. Recently, CDK12 has gained attention as a therapeutic target in several types of cancers including triple-negative breast cancer and Ewing sarcoma. However, little is known about the impact and possibility of CDK12 inhibition in pancreatic cancer treatment. As the lack of specific inhibitors that selectively target CDK12, studying CDK12 has long been challenging. To overcome this, we used CRISPR-Cas9 mediated genome editing to generate FKBP12F36V (dTAG) knock-in PDAC cell lines, enabling rapid elimination of endogenous CDK12 using a degrader against dTAG (dTAG-13). Quantitative-image-based cytometry and time lapse imaging showed that CDK12 ablation induces mitotic arrest, DNA damage and apoptosis (mitotic catastrophe). Specifically, loss of CDK12 kinase activity in the S phase was sufficient to slow DNA replication speed, leading to spindle assembly checkpoint activation and mitotic catastrophe. Importantly, cells that escaped mitotic death accumulate micronuclei, triggering immune response signaling that is mediated by the cGAS-STING-type I interferon pathway. Our results suggest that CDK12 is a promising target in a subset of PDAC patients, where CDK12 inhibition exerts antitumor activity both in cell autonomous and non-cell autonomous ways through inducing mitotic catastrophe as well as triggering immune response. Citation Format: Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Keisuke Tateishi, Mitsuhiro Fujishiro. CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A084.