bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiencia de una unidad aerodigestiva pediátrica en Latinoamérica
Authors: L´opez Forte Rosina , Bravo Maynor , Cuan Shirley , Beltetón Edgar , Farrington Christian
Published: November 2020

Introducción: las unidades aerodigestivas proveen un cuidado complejo coordinado a pacientes pediátricos con condiciones congénitas o adquiridas de grados variables que afectan la vía respiratoria, el tracto gastrointestinal, la deglución y el crecimiento. La primera unidad aerodigestiva de Guatemala fue fundada en el año 2018 en un hospital privado, y por ser la única de su tipo en el país, no se tenían datos locales al respecto. Pacientes y métodos: se llevó a cabo un estudio retrospectivo cuantitativo; se analizó el total de casos reportados en la unidad aerodigestiva pediátrica desde el 1 de enero de 2018 hasta el 31 de mayo de 2019, se contó con un total de 69 casos. Resultados: el 79% de los pacientes presentaron más de una patología de diferente etiología. La indicación principal para realizar la triple endoscopia fue tos crónica. Los diagnósticos encontrados como comorbilidades con mayor frecuencia fueron bronquitis bacteriana recurrente y enfermedad por reflujo gastroesofágico. Conclusión: la triple endoscopia es útil tanto en el diagnóstico como en la toma de decisiones en el manejo de las patologías aerodigestivas pediátricas de alta complejidad. Es una herramienta útil que pone en evidencia que múltiples etiologías pueden contribuir a síntomas crónicos de la vía aérea, y que estas pueden pasarse por alto si se realiza un solo procedimiento.
Experiencia del internado de medicina durante la pandemia por Covid-19
Authors: Ballart Espinosa María Jesús , González de la Vega Javier Ignacio , Larraín Castellón Sebastián Andrés , Muñoz Ferrada Felipe Ignacio , Pérez Brunet Sebastián Cristóbal , Andresen Max
Published: November 2020

Introducción: la pandemia por SARS-CoV-2 ha causado cambios en la formación médica a nivel mundial. Se han suspendido todas las actividades presenciales buscando reducir el contagio y, además, dada la creciente demanda hospitalaria, ha generado la necesidad de buscar nuevas formas de mantener la docencia y a la vez, balancear ésta con las necesidades hospitalarias. Desarrollo: revisamos la experiencia de estudiantes de medicina en otros países, tanto las similitudes como diferencias respecto a lo vivido en Chile, bajo nuestra formación. El interno de medicina, a diferencia del estudiante o del médico, se encuentra en un rol intermedio como práctica profesional y consideramos que tiene un rol positivo en el apoyo a los servicios de salud durante la crisis actual. Presentamos nuestra experiencia como internos de medicina voluntarios en los distintos campos clínicos que se encuentran bajo el alero de nuestra universidad y como hemos experimentado la creciente sobrecarga hospitalaria, incertidumbre, soledad y experiencia con la muerte en nuestra práctica. Conclusión: la experiencia como internos durante esta pandemia y como voluntarios en los distintos servicios de nuestros campos clínicos ha alterado profundamente nuestra formación médica. Nos ha permitido interiorizarnos no solo en aspectos técnicos, sino también en el área más humana de la medicina, en aprender sobre trabajo en equipo, la incertidumbre y el fin de la vida. Creemos que todo esto nos ha preparado y nos ha dado una experiencia invaluable para nuestra futura práctica médica.
impacto psicológico de la pandemia de COVID-19 en el personal de salud: Un panorama preocupante
Authors: Figueroa Rodrigo
Published: November 2020

La pandemia de COVID-19 ha impactado de manera dramática a la humanidad en casi todas las formas imaginables. A la fecha de la redacción de esta editorial, el SARS-CoV-2  ha cobrado la vida  de casi un millón de personas, y ha contagiado a más de 30 millones (Roser et al., 2020). La mayor parte de los países del mundo ha restringido la movilidad de sus ciudadanos, con algunas excepciones como Corea del Sur (Campbell, (2000), Japón (The associated press, 2020), Suecia ( Birchall, 2020 ), Uruguay ( AFP & Scarpinelli, 2020) y algunos estados de Norte América ( Mervosh, 2020) y Brasil (Araújo, 2020).
Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case–Control Studies
Authors: Yuan Jian-Min , Wang Yue , Wang Renwei , Luu Hung N. , Adams-Haduch Jennifer , Koh Woon-Puay , Gao Yu-Tang , Behari Jaideep , Lotze Michael T.
Published: November 2020

Background:

IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma.

Methods:

Two parallel case–control studies of hepatocellular carcinoma, each with 100 case–control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma.

Results:

The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68–453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81–95.57) in the Shanghai Cohort Study (both Ptrend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30–217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42–1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg.

Conclusions:

Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development.

Impact:

IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
Genetic Predictors of Severe Skin Toxicity in Patients with Stage III Colon Cancer Treated with Cetuximab: NCCTG N0147 (Alliance)
Authors: Labadie Julia D. , Hua Xinwei , Harrison Tabitha A. , Banbury Barbara L. , Huyghe Jeroen R. , Sun Wei , Shi Qian , Yothers Greg , Alberts Steven R. , Sinicrope Frank A. , Goldberg Richard M. , George Thomas J. , Penney Kathryn L. , Phipps Amanda I. , Cohen Stacey A. , Peters Ulrike , Chan Andrew T. , Newcomb Polly A.
Published: November 2020

Background:

Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%–20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity.

Methods:

Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10−8.

Results:

Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47–6.25; P < 7.8 × 10−9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions.

Conclusions:

Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab.

Impact:

Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.
Somatic Epigenetic Silencing of RIPK3 Inactivates Necroptosis and Contributes to Chemoresistance in Malignant Mesothelioma
Authors: Tan Yinfei , Sementino Eleonora , Cheung Mitchell , Peri Suraj , Menges Craig W. , Kukuyan Anna-Mariya , Zhang Ting , Khazak Vladimir , Fox Lauren A. , Ross Eric A. , Ramanathan Suresh , Jhanwar Suresh C. , Flores Raja M. , Balachandran Siddharth , Testa Joseph R.
Published: November 2020

Purpose:

Receptor-interacting protein kinase 3 (RIPK3) phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma is unknown. This study aimed to determine whether RIPK3 functions as a potential tumor suppressor to limit development of malignant mesothelioma.

Experimental Design:

RIPK3 expression was examined in 66 malignant mesothelioma tumors and cell lines. Promoter methylation and DNMT1 siRNA studies were performed to assess the mode of RIPK3 silencing in RIPK3-deficient malignant mesothelioma cells. Restoration of RIPK3 expression in RIPK3-negative malignant mesothelioma cells, either by treatment with 5-aza-2′-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization.

Results:

Loss of RIPK3 expression was observed in 42/66 (63%) primary malignant mesotheliomas and malignant mesothelioma cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative malignant mesothelioma cells treated with 5-aza-2′-deoxycytidine resulted in reexpression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of RIPK3 expression and survival outcomes among patients with malignant mesothelioma available from The Cancer Genome Atlas repository revealed that promoter methylation of RIPK3 is associated with reduced RIPK3 expression and poor prognosis.

Conclusions:

These data suggest that RIPK3 acts as a tumor suppressor in malignant mesothelioma by triggering necroptosis and that epigenetic silencing of RIPK3 by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.
AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer
Authors: Giffin Michael J. , Cooke Keegan , Lobenhofer Edward K. , Estrada Juan , Zhan Jinghui , Deegen Petra , Thomas Melissa , Murawsky Christopher M. , Werner Jonathan , Liu Siyuan , Lee Fei , Homann Oliver , Friedrich Matthias , Pearson Joshua T. , Raum Tobias , Yang Yajing , Caenepeel Sean , Stevens Jennitte , Beltran Pedro J. , Canon Jude , Coxon Angela , Bailis Julie M. , Hughes Paul E.
Published: November 2020

Purpose:

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.

Experimental Design:

AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).

Results:

AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients.

Conclusions:

AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.
IOX1 Suppresses Wnt Target Gene Transcription and Colorectal Cancer Tumorigenesis through Inhibition of KDM3 Histone Demethylases
Authors: Hoyle Rosalie G. , Wang Huiqun , Cen Yana , Zhang Yan , Li Jiong
Published: November 2020

Epigenetic activation of Wnt/β-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers. KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not available. In addition, which family is most responsible for activation of Wnt target genes and Wnt-induced oncogenesis is not well documented, specifically in colorectal cancer. In this study, we characterized the functional redundancy and differences between KDM3 and KDM4 in regard to regulating Wnt signaling. Our data suggest that KDM3 may play a more essential role than KDM4 in regulating oncogenic Wnt signaling in human colorectal cancer. We also identified that IOX1, a known histone demethylase inhibitor, significantly suppresses Wnt target gene transcription and colorectal cancer tumorigenesis. Mechanistically, IOX1 inhibits the enzymatic activity of KDM3 by binding to the Jumonji C domain and thereby preventing the demethylation of H3K9 on Wnt target gene promoters. Taken together, our data not only identified the critical mechanisms by which IOX1 suppressed Wnt/β-catenin signaling and colorectal cancer tumorigenesis through inhibition of KDM3, but also suggested that IOX1 may represent an attractive small molecule lead for future drug design and discovery.
Abstract IA-01: Role of the gut-tumor microbial axis in pancreatic ductal adenocarcinoma (PDAC)
Authors: McAllister Florencia
Published: November 2020

Even though Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of 9%, there is a minority of patients that survive more than 5 years (Long Term Survivors, LTS). Genomic studies have not shown a particular signature on those patients, suggesting the potential relevance of extrinsic non-genetic factors in survival. Also, higher number of tumor infiltrating CD8+T cells and neoantigens with similarities to microbes are predictive of better outcomes. Studies have linked microbiome with tumorigenesis and treatment responses in many cancers, including PDAC, a tumor that contains bacteria. We have analyzed intratumoral microbial content and found that LTS have higher microbial diversity and a unique microbial signature. We have also found that some of the intra-tumoral bacteria originates in the intestines. Fecal microbial transplants resulted in modulation of tumoral microbiome, immune infiltration and tumor growth. Direct bacterial immune activation or indirect effect by bacterial metabolites may be some of the mechanisms implicated. Future clinical work is needed to further understand how to modulate tumors immune status by manipulating bacteria. A clinical trial with this goal is now being developed.

Citation Format: Florencia McAllister. Role of the gut-tumor microbial axis in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-01.
Abstract IA-03: ECM-dependent CAF functions in pancreatic cancer nutritional support & immunosuppression
Authors: Cukierman Edna , Francescone Ralph , Vendramini-Costa Débora Barbosa
Published: November 2020

Pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming the second deadliest cancer in the US. PDAC is characterized by an unusually vast stromal expansion known as desmoplasia. Desmoplasia is a chronic fibrosis-like reaction enriched in cancer associated-fibroblasts (CAFs) and CAF-generated interstitial extracellular matrix (ECM). PDAC associated desmoplasia limits blood-supplied nutrition and is highly immunosuppressive. Understanding the role of CAFs and their ECM in PDAC could lead to the recognition of new therapeutic targets. This seminar will present newly uncovered roles for the desmoplastic ECM-induced expression of a particular protein, which stimulates PDAC tumorigenesis. It will illustrate how the ectopic expression of this protein in CAFs fosters the metabolic support of PDAC cells and propagates immunosuppression. Data presented will help clarify the role that CAFs and their ECM play in PDAC, by defining CAF phenotypes and functions. The discussion will illustrate a newly uncovered ECM-dependent signaling circuit with therapeutic potential.

Citation Format: Edna Cukierman, Ralph Francescone, Débora Barbosa Vendramini-Costa. ECM-dependent CAF functions in pancreatic cancer nutritional support & immunosuppression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-03.
Abstract IA-09: The end of perpetual chemotherapy?
Authors: Reiss Kim A
Published: November 2020

The traditional therapeutic model for patients with metastatic pancreatic cancer is perpetual chemotherapy from diagnosis to death. However, subsets of patients who achieve durable responses to cytotoxic chemotherapy may benefit from a switch maintenance approach. Maintenance therapy with the PARP inhibitor olaparib has recently been established for one such subgroup: Patients with germline BRCA mutations. In this talk we will review the available data and the future directions for maintenance therapy including combination treatments and expanding beyond germline BRCA carriers.

Citation Format: Kim A Reiss. The end of perpetual chemotherapy? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-09.
Abstract IA-14: Understanding inherited risk for pancreatic cancer
Authors: Klein Alison P.
Published: November 2020

Pancreatic cancer is the 3rd leading cause of cancer death in the Unites States and the global burden of pancreatic cancer has more than doubled over the past 25 years. Inherited genetic factors explain 22-36% of pancreatic cancer. This includes both high-risk pathogenic variants in hereditary cancer genes and genes associated with hereditary pancreatitis as well as common variants identified in genome-wide association studies. Environmental factors, including cigarette smoking may influence the impact of these genetic variants. High risk pathogenic variants are present in 5-10% of all pancreatic cancer patients and up to 20% of patients with a family history of pancreatic cancer. Studies to identify the genetic basis of the remaining 80% of families with a clustering of pancreatic cancer are ongoing. Identification of the genetic changes that underlie pancreatic cancer not only provide insight into the etiology of this fatal cancer but also provides an opportunity to guide early detection strategies.

Citation Format: Alison P. Klein. Understanding inherited risk for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-14.
Abstract PO-007: PRMT5 inhibition sensitizes pancreatic cancer to gemcitabine in orthotopic and metastatic murine models
Authors: Kane William J. , Adair Sara J. , Nagdas Sarbajeet , Liu Denis , Wei Xiaolong , Adli Mazhar , Bauer Todd W.
Published: November 2020

Purpose: The purpose of this study was to investigate protein arginine methyltransferase 5 (PRMT5) as a therapeutic target in combination with gemcitabine for pancreatic cancer in preclinical models. Procedures: In an orthotopic xenograft model, PRMT5 wild-type (WT) or knockout (KO) mPanc96 cells were injected into the pancreata of athymic nude mice. Mice were randomized to control or gemcitabine (100 mg/kg) arms. Tumor volume was measured with magnetic resonance imaging (MRI) at 21, 28, and 35 days post-injection. In a liver metastasis model, PRMT5 WT or KO mPanc96 cells were injected into the spleens of athymic nude mice followed by splenectomy after 10 minutes. Mice were randomized to control or gemcitabine (100 mg/kg) arms. Metastatic tumor burden within the liver was measured with in vivo bioluminescence imaging twice weekly for 19 days post-injection. Relative bioluminescence was calculated relative to post-injection day 2. Results: In the orthotopic model, untreated PRMT5 KO tumors exhibited a 46% reduction in tumor volume compared to untreated PRMT5 WT tumors (959 mm−3 vs. 1766 mm−3, p=0.009). Furthermore, gemcitabine-treated PRMT5 KO tumors exhibited a 30% reduction in tumor volume compared to gemcitabine-treated PRMT5 WT tumors (405 mm−3 vs. 579 mm−3, p=0.046). Compared to untreated PRMT5 WT tumors, gemcitabine-treated PRMT5 KO tumors exhibited a 77% reduction in tumor volume (405 mm−3 vs. 1766 mm−3, p=<0.001). In the liver metastasis model, untreated PRMT5 KO cells exhibited a 45% reduction in relative bioluminescence compared to untreated PRMT5 WT metastases (83.3 vs. 152.8, p=0.02). Additionally, gemcitabine-treated PRMT5 KO metastases exhibited a 52% reduction in relative bioluminescence compared to gemcitabine-treated PRMT5 WT metastases (17.2 vs. 36.0, p=0.02). Compared to untreated PRMT5 WT metastases, gemcitabine-treated PRMT5 KO metastases exhibited an 89% reduction in liver tumor burden (17.2 vs. 152.8, p=<0.001). Conclusions: PRMT5 genetic depletion significantly reduces pancreatic cancer growth in murine models of orthotopic growth and liver metastasis. Additionally, PRMT5 depletion improves gemcitabine response in these models. PRMT5 is a possible therapeutic target in pancreatic cancer treatment that necessitates further investigation.

Citation Format: William J. Kane, Sara J. Adair, Sarbajeet Nagdas, Denis Liu, Xiaolong Wei, Mazhar Adli, Todd W. Bauer. PRMT5 inhibition sensitizes pancreatic cancer to gemcitabine in orthotopic and metastatic murine models [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-007.
Abstract PO-038: Activation of Kras and loss of Pten induces pancreatic ductal adenocarcinoma from pancreatic acinar cells in mice
Authors: Hunt Wesley J. , Dubois Claire L. , Samani Atefeh , Taghizadeh Farnaz , Schaeffer David F. , Sander Maike , Kopp Janel L.
Published: November 2020

Cellular origin has an impact on tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). We have previously demonstrated the effects of Pten loss and/or Kras activation in adult pancreatic ductal cells and their involvement in PDAC tumorigenesis. However, mature acinar cells have not been studied in this genetic context before. We used adult Ptf1aCreER;KrasG12D mice with homozygous (Ptenf/f (KPf/f)) or heterozygous (Ptenf/+ (KPf/+)) loss of Pten to specifically express KrasG12D and reduce Pten in the acinar cell lineage to examine this phenotype. We found that KPf/f mice reach humane endpoint much faster than KPf/+ or KP+/+ mice do, suggesting Pten limits tumor development and progression. Upon morphological examination, we found that most tumors develop as moderately or well differentiated or a mixture of both with cystic lesions and gastric-type glands dominating tumor architecture. Morphologically, no differences were found between KPf/f and KPf/+ mice. Tumors have large areas of Alcian Blue and PAS positivity that vary between tumors but not between genotypes. We characterized the tumors by immunohistochemistry (IHC) and found that they are Mucin 1 positive and Mucin 2 negative, regardless of their genotype. Additionally, we stained them for Mucin 5AC, Keratin 20, and Claudin 18 and found variable patterns of positivity amongst tumors regardless of genotype. In summary, our data shows that loss of Pten in acinar cells in context of Kras activation can promote PDAC. In contrast, our previous data demonstrates that loss of Pten alone can predispose ductal, but not acinar cells to tumorigenesis, and activation of Kras further synergizes with Pten reduction. These data suggest that ductal cells are more sensitive than acinar cells to Pten perturbation.

Citation Format: Wesley J. Hunt, Claire L. Dubois, Atefeh Samani, Farnaz Taghizadeh, David F. Schaeffer, Maike Sander, Janel L. Kopp. Activation of Kras and loss of Pten induces pancreatic ductal adenocarcinoma from pancreatic acinar cells in mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-038.
Abstract PO-039: Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors
Authors: Kasikci Ezgi , Aydemir Esra , Bayrak Omer Faruk , Sahin Fikrettin
Published: November 2020

Purpose: The main purpose of this study is to demonstrate the effects of epithelial to mesenchymal transition activating transcription factor silencing (EMT-ATF silencing) on migration, invasion, drug resistance and tumor forming abilities of various pancreatic cancer cell lines. Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated. Methods: EMT activating transcription factors “Snail, Slug and Twist” were silenced by short hairpins on Panc-1, MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines. The changes in migration, invasion, laminin attachment, cancer stem-like cell properties and tumor forming abilities were investigated. Chemo sensitivity assays and small molecule inhibitors of EMT were applied to the metastatic pancreatic cancer cell line AsPC-1. Results: EMT-ATF silencing reduce EMT and stem cell-like characteristics of pancreatic cancer cell lines. Following EMT-ATF silencing amongst the four PC cell lines, AsPC-1 showed the best response and was chosen for further chemo resistance and combinational therapy applications. EMT downregulated AsPC-1 cells showed less resistance to selected chemotherapeutics compared to the control group. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing. Conclusion: Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance.

Citation Format: Ezgi Kasikci, Esra Aydemir, Omer Faruk Bayrak, Fikrettin Sahin. Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-039.
Abstract PO-052: Determining the role of Apolipoprotein E in pancreatic cancer immune suppression
Authors: Kemp Samantha B. , Steele Nina G. , Lima Fatima , Espinoza Carlos , Zhang Yaqing , Nwosu Zeribe , Carpenter Eileen S. , Hoffman Meggie , Pacheco Amanda , Velez-Delgado Ashley , The Stephanie , Crawford Howard C. , Pasca di Magliano Marina
Published: November 2020

Pancreatic cancer (PDA) is a lethal malignancy with a 5-year survival rate of about 10%. The poor prognosis is, in part, due to patients most often presenting with already metastatic disease. PDA is characterized by an abundant, fibroinflammatory stroma, that contains abundant cancer-associated fibroblasts and infiltrating immune cells. Myeloid cells such as tumor-associated macrophages (TAMs) are abundant within the stroma and a key driver of immunosuppression. We and others have identified elevated expression of Apolipoprotein E (ApoE) in a subset of TAMs. Further, using single cell sequencing of human tumor samples as well as mouse tumors, we determined that ApoE expression is elevated in tumor macrophages compared to macrophages in the normal pancreas. ApoE has been well studied in various biological processes, but its role in pancreatic cancer has not been determined. In this study, we sought to determine whether ApoE had a functional role within the pancreatic cancer microenvironment. Based on observations in other systems, we hypothesized that it might be a mediator of immune suppression in pancreatic cancer. We thus implanted mouse pancreatic cancer cell lines in syngeneic wild type C57/BL6 mice or in ApoE-/- mice. We did not observe a change in tumor growth in ApoE-/- mice compared to control. However, histological and Mass Cytometry (CyTOF) analysis revealed changes in the tumor microenvironment in ApoE-/- mice. Tumors from ApoE-/- mice had fewer aSMA+ fibroblasts, and subsequently less collagen deposition. In addition, CyTOF analysis revealed an increase in CD8+ T cell and CD4+ T cell infiltration, along with a decrease in regulatory T cells. Tumors harvested from ApoE-/- mice had lower levels of both Tgfb1 and Cxcl1. Further analysis in vitro, revealed ApoE secreted from tumor-associated macrophages regulates tumor-cell derived Tgfb1 and Cxcl1. Cxcl1 in turns inhibits T cell infiltration in tumors. We are currently conducting mechanistic studies to determine the mediators of the cytokine-regulatory effects of ApoE in cancer cells. Further, we are exploring whether ApoE loss sensitizes tumors in vivo to immunoregulatory agents.

Citation Format: Samantha B. Kemp, Nina G. Steele, Fatima Lima, Carlos Espinoza, Yaqing Zhang, Zeribe Nwosu, Eileen S. Carpenter, Meggie Hoffman, Amanda Pacheco, Ashley Velez-Delgado, Stephanie The, Howard C. Crawford, Marina Pasca di Magliano. Determining the role of Apolipoprotein E in pancreatic cancer immune suppression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-052.
Abstract PO-061: The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis
Authors: Velez-Bonet Ericka , Kaul Sabrina , Pontious Corbin , Hong Marcus , Dubai Kelly , Cruz-Monserrate Zobeida
Published: November 2020

Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 10% due to a lack of early detection and effective treatments. Aspartic protease Cathepsin E (CTSE) expression is increased early in PDAC, but its role in tumorigenesis is unknown. We hypothesize that high CTSE expression promotes proliferation, invasion, inhibition of apoptosis, and the secretion of cancer-associated cytokines in PDAC. Methods: Human PDAC cell lines (Mpanc96, Panc-1, and Miapaca2) were engineered to express high levels of CTSE. Cell proliferation, invasion, and apoptosis were analyzed and compared to control cell lines expressing low levels of CTSE. Cells were treated with aspartic protease inhibitors (Pepstatin A and Ritonavir) and monitored for proliferation (24 - 72 hours) and invasion (48 hours). Apoptosis was measured using propidium iodide and analyzed via flow cytometry. Conditioned media from cells was collected (72 hours) after treatment to assess differential secretion of cancer-associated cytokines using a cytokine array. Results: Proliferation was not affected by the overexpression of CTSE; however, inhibition of CTSE slowed proliferation in the Panc-1 and MiaPaca2, but not Mpanc96 cells. CTSE inhibitors promoted invasion of Mpanc96 and Panc-1, but not Miapaca2 cells, regardless of CTSE levels. Apoptosis was not significantly different between the cell lines treated with the aspartic protease inhibitors compared to controls. Increased expression of CTSE induced the secretion of various cytokines such as epithelial neutrophil-activating protein 78 (ENA-78), a chemokine expressed in inflammatory pancreatic disorders. Treatment with the inhibitor Pepstatin A decreased ENA-78 secretion. Conclusions: CTSE levels does not appear to affect proliferation or apoptosis; however, inhibition of CTSE increased cell invasion and resulted in altered cytokine secretion. Further studies examining how CTSE influences invasiveness, and cytokine secretion may create new opportunities for developing effective therapies for PDAC.

Citation Format: Ericka Velez-Bonet, Sabrina Kaul, Corbin Pontious, Marcus Hong, Kelly Dubai, Zobeida Cruz-Monserrate. The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-061.
Abstract PO-063: Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis
Authors: Zhang Yaqing , Donahue Katelyn L. , Yan Wei , Nwosu Zeribe C. , Brown Kristee L. , Yang Sion , Crawford Howard C. , Lyssiotis Costas A. , Frankel Timothy L. , Bednar Filip , Pasca di Magliano Marina
Published: November 2020

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibrotic stroma, which includes vascular elements, infiltrating immune cells, extracellular matrix and a large number of fibroblasts. The tumor microenvironment as a whole has been believed to be immunosuppressive. However, how different cell populations within the stroma contribute to the establishment of the immunosuppression is not fully understood. We sought to investigate the crosstalk between cancer cells, fibroblasts and immune cells within pancreatic cancer with the goal to identify novel targets for PDA treatment. Targeting regulatory T cell (Treg), which acts to suppress immune responses, is considered as one potential approach to relieve the immunosuppression of pancreatic cancer. However, we previously showed that Treg depletion in a genetically engineered mouse model of pancreatic cancer (KC;Foxp3DTR) failed to relieve immunosuppression and led to accelerated tumor progression. We discovered that Treg depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Conversely, Treg depletion resulted in differentiation of inflammatory fibroblast subsets with an increase in chemokines Ccl3, Ccl6, and Ccl8. To fully understand the contribution of Tregs to pancreatic carcinogenesis, we performed single-cell RNA-sequencing (scRNA-seq) with Pancreatic intraepithelial neoplasia (PanIN) from KC mouse and Treg depleted PanIN lesions from KC;Foxp3DTR mouse. scRNA-seq allows us to address cell type identification and heterogeneity of cell responses by unsupervised clustering, which uncovered dramatic differences in several stromal cell populations including fibroblast, CD4 T cell and macrophage subsets between the KC and KC;Foxp3DTR pancreata. We have expanded list of genes that are regulated in tumor associated fibroblasts upon Treg depletion through scRNA-seq. For example, Il33 was one of down-regulated genes in fibroblasts upon Treg depletion. We also obtained potential ligands/receptors interactions between tumor cells, fibroblasts and immune cells through interactome analysis. Our data describe an unexpected crosstalk between Tregs and fibroblasts and point to new mechanisms regulating fibroblast differentiation in pancreatic cancer.

Citation Format: Yaqing Zhang, Katelyn L. Donahue, Wei Yan, Zeribe C. Nwosu, Kristee L. Brown, Sion Yang, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-063.
Abstract PR-005: Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy
Authors: Siolas Despina , Vucic Emily , Kurz Emma , Hajdu Cristina , Bar-Sagi Dafna
Published: November 2020

Intratumoral genetic alterations can cause remodeling of local immune cell populations through distinct cellular mechanisms. After oncogenic KRAS, TP53 is the gene most frequently mutated in pancreatic ductal adenocarcinoma (PDAC). These mutations in TP53 are neomorphic and confer phenotypes distinct from those due to homozygous TP53 deletion. We sought to evaluate the non-cell-autonomous role of mutant p53 protein in the immune microenvironment by studying KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) engineered using CRISPR/Cas gene editing to express the Trp53R172H gain-of-function mutation. We found distinct immune profiles associated with orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy.

Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-005.
A Case Report of Prurigo Nodularis-Like Lesions in a Patient with Lepromatous Leprosy
Authors: Nawalerspanya Siwanon , Sangmala Siripan , Aiempanakit Kumpol
Published: November 2020

Leprosy or Hansen’s disease is a chronic granulomatous infection that primarily affects the peripheral nerves and, consequently, the skin. Clinical manifestations vary from hypopigmentation to erythematous plaques, and it can present with leonine facies. We report a case of a patient with an uncommon clinical presentation of prurigo nodularis-like lesions without loss of sensation, for which two biopsy specimens demonstrated different histological subtypes. The first was the classic histology of lepromatous leprosy, whereas the other specimen revealed an atypical histoid leprosy variant pattern. This case report describes a patient with an atypical presentation of leprosy.
Effects of Colchicine on NSAID-Induced Severe Small Intestinal Damage: A Pilot Study
Authors: Otani Koji , Watanabe Toshio , Higashimori Akira , Nadatani Yuji , Nagami Yasuaki , Taira Koichi , Inui Kentaro , Fujiwara Yasuhiro
Published: November 2020

Background: We previously reported that nonsteroidal anti-inflammatory drugs (NSAIDs) induced small intestinal damage through nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent interleukin-1β secretion in mice. Our further study demonstrated that colchicine, a therapeutic agent for gout, significantly suppressed NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation in mice. However, clinical efficacy of colchicine for NSAID-induced small intestinal damage has not been established. Objectives: We examined the clinical efficacy of colchicine in patients with NSAID-induced severe small intestinal damage as an animal-to-human translational research. Methods: This is a single-center, single-arm, prospective pilot study. From February 2017 to March 2019, we performed video capsule endoscopy (VCE) to screen 10 patients who took NSAIDs continuously for more than 3 months, and 7 of those with severe small intestinal damage were enrolled. Participants were treated with oral colchicine 0.5 mg twice daily for 8 weeks and thereafter followed up with blood tests and VCE. Results: After 8 weeks of colchicine treatment, complete healing was achieved in 4 patients (57.1%), and the median number of small erosions decreased significantly from 7.0 (range, 5.0–10.5) to 0.0 (range, 0.0–2.3) (p = 0.031). One patient withdrew due to diarrhea, and 5 patients revealed slightly elevated liver enzymes during the study. No other adverse events including changes in blood tests and clinical symptoms were observed. Conclusions: Colchicine treatment achieved a high rate of complete healing in patients with NSAID-induced severe small intestinal damage.
Clinical Characteristics and Treatment Outcomes of Patients with Eosinophilic Esophagitis and Eosinophilic Gastroenteritis
Authors: Okimoto Eiko , Ishimura Norihisa , Ishihara Shunji
Published: November 2020

Background: Eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), part of the spectrum of eosinophilic gastrointestinal disorders (EGID), share pathogenic similarities. We examined differences regarding clinical characteristics and treatment outcomes between EoE and EGE cases. Methods: Two-hundred fifteen EGID patients, including 181 with EoE and 34 with EGE, diagnosed at Shimane University Hospital between February 2011 and March 2019 were enrolled. Information regarding clinical parameters and treatment outcomes was reviewed. Results: EoE showed significant male predominance (82.3%) as compared with EGE (50.0%) (p < 0.001). Furthermore, patients with EoE were significantly older and had a higher body mass index (24.8 ± 4.0 vs. 22.2 ± 4.3, p < 0.05). Over 90% of the EoE patients were initially given proton pump inhibitor (PPI) treatment, of whom 73.2% showed clinical and histological remission. Vonoprazan, a more potent acid inhibitor than PPI, was effective in two-thirds of the nonresponsive EoE patients initially treated with a PPI. In contrast, oral glucocorticoid administration was mainly given to patients with EGE (58.8%). Of 13 EGE patients treated with a food-elimination diet, responsible foods were successfully identified in 9, with 7 controlled in a state of remission without glucocorticoid therapy. Conclusions: We found different clinical characteristics and treatment strategies in the present EoE and EGE cases. Most of the EoE patients responded to and were maintained by acid suppressive therapy, using PPI or vonoprazan. For EGE patients, glucocorticoid administration was mainly used though food-elimination diet therapy also showed beneficial effects.
Association between Patients’ Knowledge and Adherence to Anticoagulants, and Its Effect on Coagulation Control
Authors: Ahmed Hazem , Saddouh Enas Ahmed , Abugrin Mohamed Elhadi , Ali Alya Muftah Mohammed , Elgdhafi Elham Omran , Khaled Ala , Tarek Ahmed , Elhadi Muhammed
Published: November 2020

Background: Warfarin requires strict monitoring by measuring prothrombin time (PT), international normalized ratio (INR), and time in therapeutic range (TTR). Several factors can lead to poor PT/INR control including vitamin K status, medication adherence, knowledge, and quality of life. The present study aims to assess patient adherence to warfarin treatment and its correlation with INR control. Methods: A cross-sectional study was conducted between October 2017 and January 2018 at Tripoli University Hospital. Data were collected by structured questionnaires which included; demographic and clinical characteristics, the Oral Anticoagulation Knowledge (OAK) test, and the Morisky Medication Adherence Scale (MMAS-8). Results: The final analysis included 88 out of 140 patients (73.33%). There were significant differences in age range, gender, marital status, and education level between the 2 groups (poor knowledge and adequate knowledge) (p < 0.05). There was a significant positive correlation between OAK test score and TTR. Overall, 76.2% of patients were adherent to warfarin (MMAS score ≥6) and 20.45% of patients were of high adherence (MMAS score of 8). The median score was 6 (IQR 6–7). A statistically significant, strong positive correlation between adherence to medication and TTR as an indicator of INR control was found (rs[86] = 0.472, p < 0.0001). Conclusion: The study addressed and identified several areas for future improvement of patient outcomes. The implementation of new approaches to enhance patient knowledge and adherence is warranted, and measures to provide treatment for all patients that require it are needed, to improve outcomes and decrease adverse drug effects.
Long-Term Evaluation of the Vagal Denervation by Cardioneuroablation Using Holter and Heart Rate Variability
Authors: Pachon-M Jose Carlos , Pachon-M Enrique I. , Pachon Carlos Thiene C. , Santillana-P Tomas G. , Lobo Tasso J. , Pachon-M Juan Carlos , Zerpa-A Juan Carlos , Cunha-P Maria Z. , Higuti Christian , Ortencio Felipe Augusto , Amarante Ricardo C. , Silva Ricardo F. , Osorio Thiago G.
Published: November 2020

Background:

Several disorders present reflex or persistent increase in vagal tone that may cause refractory symptoms even in a normal heart patient. Cardioneuroablation, the vagal denervation by radiofrequency ablation of the neuromyocardial interface, was developed to treat these conditions without pacemaker implantation. A theoretical limitation could be the reinnervation, that naturally grows in the first year, that could recover the vagal hyperactivity. This study aims to verify the vagal denervation degree in the chronic phase after cardioneuroablation. Additionally, it intends to investigate the arrhythmias behavior after cardioneuroablation.

Methods:

Prospective longitudinal study with intrapatient comparison of 83 very symptomatic cases without significant cardiopathy, submitted to cardioneuroablation, 49 (59%) male, 47.3±17 years old, having vagal paroxysmal atrial fibrillation 58 (70%) or neurocardiogenic syncope 25 (30%), New York Heart Association class<II and absence of significant comorbidities. Cardioneuroablation was performed in both atria by interatrial septum puncture, with irrigated conventional catheter and electroanatomic reconstruction. Ablation targeted the neuromiocardial interface by fragmentation mapping (AF-Nests) using the velocity fractionation software, conventional recording, and anatomic localization of the ganglionated plexi. Heart rate variability (time and frequency domain) and arrhythmias were compared by 24h-Holter, before, and 1 year and 2 years after cardioneuroablation. In a 40 month follow-up, 80% of patients were asymptomatic.

Results:

Time- and frequency-domain heart rate variability demonstrated significant decrease in all autonomic parameters, showing an important parasympathetic and sympathetic activity reduction at 2-year post-cardioneuroablation (
P
<0.001). There was no difference in heart rate variability between the 1-year and 2-year post-cardioneuroablation (
P
>0.05) suggesting that the reinnervation has halted. There was also an important reduction in all bradyarrhythmias and tachyarrhythmias pre-cardioneuroablation versus post-cardioneuroablation (
P
<0.01).

Conclusions:

There is an important and significant vagal and sympathetic denervation after 2 years of cardioneuroablation with a significant reduction in bradyarrhythmia and tachyarrhythmia in the whole group. There were no complications.