bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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 &lt;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

Abstract

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 &lt; 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 &lt; 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

Abstract

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

Abstract

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 (&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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=&lt;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=&lt;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

Abstract
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.