bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia
Authors: Oravecz-Wilson Katherine , Rossi Corinne , Zajac Cynthia , Sun Yaping , Li Lu , Decoville Thomas , Fujiwara Hideaki , Kim Stephanie , Peltier Daniel , Reddy Pavan 
Published: December 2020

Abstract

Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell–specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT.

Significance:
These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.
The FABRIC Cancer Portal: A Ranked Catalogue of Gene Selection in Tumors Over the Human Coding Genome
Authors: Kelman Guy , Brandes Nadav , Linial Michal 
Published: December 2020

Abstract

Contemporary catalogues of cancer driver genes rely primarily on high mutation rates as evidence for gene selection in tumors. Here, we present The Functional Alteration Bias Recovery In Coding-regions Cancer Portal, a comprehensive catalogue of gene selection in cancer based purely on the biochemical functional effects of mutations at the protein level. Gene selection in the portal is quantified by combining genomics data with rich proteomic annotations. Genes are ranked according to the strength of evidence for selection in tumor, based on rigorous and robust statistics. The portal covers the entire human coding genome (∼18,000 protein-coding genes) across 33 cancer types and pan-cancer. It includes a selected set of cross-references to the most relevant resources providing genomics, proteomics, and cancer-related information. We showcase the portal with known and overlooked cancer genes, demonstrating the utility of the portal via its simple visual interface, which allows users to pivot between gene-centric and cancer type views. The portal is available at fabric-cancer.huji.ac.il.

Significance:
A new cancer portal quantifies and presents gene selection in tumor over the entire human coding genome across 33 cancer types and pan-cancer.
Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium
Authors: Chen Chung-Hsin , Grollman Arthur P. , Huang Chao-Yuan , Shun Chia-Tung , Sidorenko Viktoriya S. , Hashimoto Keiji , Moriya Masaaki , Turesky Robert J. , Yun Byeong Hwa , Tsai Karen , Wu Stephanie , Chuang Po-Ya , Tang Chao-Hsiun , Yang Wen-Horng , Tzai Tzong-Shin , Tsai Yuh-Shyan , Dickman Kathleen G. , Pu Yeong-Shiau 
Published: December 2020

Abstract

Background:
Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC).

Methods:
Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A&gt;T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases.

Results:
In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in &gt;90% of these patients, indicating widespread AA exposure. A&gt;T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC.

Conclusions:
Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan.

Impact:
This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.
Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma
Authors: Zheng Lei , Ding Ding , Edil Barish H. , Judkins Carol , Durham Jennifer N. , Thomas Dwayne L. , Bever Katherine M. , Mo Guanglan , Solt Sara E. , Hoare Jessica A. , Bhattacharya Raka , Zhu Qingfeng , Osipov Arsen , Onner Beth , Purtell Katrina A. , Cai Hongyan , Parkinson Rose , Hacker-Prietz Amy , Herman Joseph M. , Le Dung T. , Azad Nilofer S. , De Jesus-Acosta Ana M.C. , Blair Alex B. , Kim Victoria , Soares Kevin C. , Manos Lindsey , Cameron John L. , Makary Martin A. , Weiss Matthew J. , Schulick Richard D. , He Jin , Wolfgang Christopher L. , Thompson Elizabeth D. , Anders Robert A. , Sugar Elizabeth , Jaffee Elizabeth M. , Laheru Daniel A. 
Published: December 2020

Abstract

Purpose:
Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX).

Patients and Methods:
Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS).

Results:
The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS &gt; 24 months to those with OS &lt; 15 months, longer OS was found to be associated with higher density of intratumoral TLA.

Conclusions:
It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.
A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers
Authors: Kawakami Masanori , Mustachio Lisa Maria , Chen Yulong , Chen Zibo , Liu Xiuxia , Wei Cheng-Hsin , Roszik Jason , Kittai Adam S. , Danilov Alexey V. , Zhang Xiaoshan , Fang Bingliang , Wang Jing , Heymach John V. , Tyutyunyk-Massey Liliya , Freemantle Sarah J. , Kurie Jonathan M. , Liu Xi , Dmitrovsky Ethan 
Published: December 2020

Abstract
Cyclin-dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically tractable antineoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Antineoplastic activity was studied in preclinical models. CYC065 treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon, and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active antineoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase and Src phosphorylation that regulate metastasis were each repressed by CYC065 treatment. Intriguingly, CYC065 treatment decreased lung cancer metastases in in vivo murine models. CYC065 treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemistry analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 antitumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065 treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.
Cabozantinib Unlocks Efficient In Vivo Targeted Delivery of Neutrophil-Loaded Nanoparticles into Murine Prostate Tumors
Authors: Chaudagar Kiranj Kishor , Landon-Brace Natalie , Solanki Aniruddh , Hieromnimon Hanna M. , Hegermiller Emma , Li Wen , Shao Yue , Joseph John , Wilkins Devan J. , Bynoe Kaela M. , Li Xiang-Ling , Clohessy John G. , Ullas Soumya , Karp Jeffrey M. , Patnaik Akash 
Published: December 2020

Abstract
A major barrier to the successful application of nanotechnology for cancer treatment is the suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pretreated with cabozantinib. Flow cytometric analysis revealed an approximately 4-fold increase of neutrophil-associated BSA-NPs and an approximately 32-fold increase in mean fluorescent dye uptake following 3 days of cabozantinib/BSA-NP administration, relative to BSA-NP alone. Strikingly, neutrophil depletion with Ly6G antibody abolished dye-loaded BSA-NP accumulation within tumors to baseline levels, demonstrating targeted neutrophil-mediated intratumoral NP delivery. Furthermore, we observed an approximately 13-fold decrease in accumulation of BSA-NPs in the liver, relative to uncoated NPs, post-cabozantinib treatment, suggesting that BSA coating of NPs can significantly enhance cabozantinib-induced, neutrophil-mediated targeted intratumoral drug delivery, while mitigating off-target toxicity. Collectively, we demonstrate a novel targeted nano-immunotherapeutic strategy for enhanced intratumoral delivery of BSA-NPs, with translational potential to significantly augment therapeutic indices of cancer medicines, thereby overcoming current pharmacologic barriers commonly encountered in preclinical/early-phase drug development.
Abstract PO-080: Increasing of emergency presentation on colorectal cancer patients during COVID-19 pandemic: A retrospective study on single-center academic hospital
Authors: Bagus Budhi Ida , Bagus Metria Ida , Ayu Setyawati Ida , Kade Mastini Ida Ayu 
Published: December 2020

Abstract
Background: Colorectal cancer was the most common cancer found in the GI tract; the two most common clinical emergency presentations were intestinal obstruction and perforation on the tumor site or proximally to the distal tumor. During the COVID-19 pandemic, we must face the new condition; we should modify the clinical outpatients’ schedule, which could address the other problem, that colorectal cancer patients refuse to continue treatment planning and that elective and well-prepared operations will be decreased.
Methods: We will report the clinical presentation of our colorectal cancer patients during the last 2 months from March until May 2020. All patients with emergency presentation of colorectal cancer will be included; any comorbidities will be recorded on this study. Patients with emergency colorectal cancer who could not fit for emergency operation will be excluded. Inpatient mortality and postoperative complications will be evaluated.
Results: During the 2-month period, we evaluated 26 cases of emergency colorectal cancer patients. Most of the patients came with total intestinal obstruction on the emergency presentation (22 cases); the others (4 cases) came with diffuse peritonitis due to colonic perforation. All patients were reported negative for COVID-19 on rapid test. Exploratory laparotomy was done in this emergency setting; 10 patients had sigmoid colon cancer, 15 patients had rectal cancer, and 6 patients had right colonic cancer. Intestinal perforation was found on rectal cancer patients. Tumor resection and primary anastomosis were done on 18 patients, and the others had stoma diversion. Inpatient mortality reported on 4 patients of perforation cases and had cardiopulmonary complication postoperatively.
Conclusion: During the COVID-19 pandemic, emergency presentation of colorectal patients increased, and intestinal perforation was the risk factor of inpatient mortality.
Citation Format: Budhi Ida Bagus, Metria Ida Bagus, Setyawati Ida Ayu, Mastini Ida Ayu Kade. Increasing of emergency presentation on colorectal cancer patients during COVID-19 pandemic: A retrospective study on single-center academic hospital [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-080.
Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women
Authors: Zhang Xiaotao , Hoffman Kristi L. , Wei Peng , Elhor Gbito Kplola Y. , Joseph Reji , Li Fangyu , Scheet Paul , Chang Shine , Petrosino Joseph F. , Daniel Carrie R. 
Published: December 2020

Abstract

Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20–75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted Pdifference &lt; 0.01) and distinct biological communities (Pdifference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded &gt;8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14–20.94) and 10.72 (3.30–34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value &lt; 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker.

Prevention Relevance:
Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.
Targeting of CD40 and PD-L1 Pathways Inhibits Progression of Oral Premalignant Lesions in a Carcinogen-induced Model of Oral Squamous Cell Carcinoma
Authors: Monteiro de Oliveira Novaes Jose A. , Hirz Taghreed , Guijarro Irene , Nilsson Monique , Pisegna Marlese A. , Poteete Alissa , Barsoumian Hampartsoum B. , Fradette Jared J. , Chen Limo N. , Gibbons Don L. , Tian Xiangjun , Wang Jing , Myers Jeffrey N. , McArthur Mark J. , Bell Diana , William William N. , Heymach John V. 
Published: December 2020

AbstractWe have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1–knockout (PD-L1ko) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1ko, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting.Prevention Relevance:PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis
Authors: Koh Jin-Sin , Hung Olivia Y. , Eshtehardi Parham , Kumar Arnav , Rabah Rani , Raad Mohamad , Kumar Sonali , Chaudhry Sundeep , Gupta Sonu , Hosseini Hossein , Brilakis Emmanouil , Corban Michel , Sabbak Nabil , Burnett Grady Murphy , Liu Chang , Mehta Puja K. , Quyyumi Arshed A. , Samady Habib 
Published: December 2020

Background:
Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease.

Methods:
In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed.

Results:

No significant differences in ΔSAQ angina frequency scores (
P
=0.53) or Duke Activity Status Index (
P
=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (
P
=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO
2
max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (
P
=0.02).

Conclusions:
Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02147067.