bluuebunny/crossref_metadata_2025_split huggingface dataset:
Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration
Authors: Sultan Hussein , Wu Juan , Fesenkova Valentyna I , Fan Aaron E , Addis Diane , Salazar Andres M , Celis Esteban 
Published: September 2020

BackgroundImmunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.MethodsWe used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.ResultsA specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.ConclusionsThese findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.
Effects of feeding blend-pelleted co-products on nutrient intake, digestibility, and production performance of high producing dairy cows
Authors: Ismael Aya , Guevara-Oquendo Victor Hugo , Refat Basim , Feng Xin , Yu Peiqiang 
Published: September 2020

The objectives of this study were to examine the effects of feeding newly developed blend-pelleted carinata meal (BPPCR) and blend-pelleted canola meal (BPPCN) on nutrient intake, digestibility, and production performance of high producing dairy cows. In this study, nine mid-lactating Holstein cows (body weight, 679 ± 124 kg; days in milk, 96 ± 22) were used in a triplicated 3 × 3 Latin square study. Within each square, each cow was randomly assigned to one of three treatments: control (typical barley-based diet in Western Canada), BPPCR (soybean and canola meal in the control diet replaced by BPPCR), and BPPCN (soybean and canola meal in the control diet replaced by BPPCN). Each period lasted for 21 d, with the first 14 d as an adaptation period. The total collection of feces and urine were conducted on six cows from two Latin squares. The results showed that there were no treatment effects on milk yield, milk composition, and nutrient intake and digestibility (P > 0.10). The nitrogen balance among the three treatment groups was not different either. In conclusion, replacing soybean meal and canola meal with blend-pelleted co-products did not affect the nutrient intake, digestibility, and production performance in high producing dairy cows.
Inactivation of Salmonella Enteritidis on cherry tomatoes by ultrasound, lactic acid, detergent, and silver nanoparticles
Authors: de São José Jackline Freitas Brilhante , Ramos Afonso Mota , Vanetti Maria Cristina Dantas , de Andrade Nélio José 
Published: September 2020

Ultrasound (US) combined with chemical agents could represent an effective method for decontaminating fruits and vegetables. This study aimed to evaluate the use of US (40 kHz for 5 min) alone or with 1% lactic acid (LA), 1% commercial detergent (DET), or 6 mg/L silver nanoparticles (AgNP, average diameter 100 nm) as an alternative treatment to 200 mg/L sodium dichloroisocyanurate for inactivating Salmonella enterica serovar Enteritidis present on cherry tomatoes. The interfacial tension between sanitizing solutions and bacterial adhesion was investigated. Sanitizers in solutions with DET and AgNP had lower surface tension. All treatments, except that with DET, reduced Salmonella Enteritidis by more than one logarithmic cycle. There was no significant difference between the mean values of log colony-forming units (CFU)/g reduction in all treatments. Transmission electron microscopy revealed the loss of the Salmonella Enteritidis capsule following treatment with US and with US + LA. Salmonella Enteritidis counts (2.29 log CFU/g) in cherry tomatoes were markedly reduced to safe levels by treatment with the combination of AgNP and US + LA (2.37 log CFU/g).
PET Reporter Gene Imaging and Ganciclovir-Mediated Ablation of Chimeric Antigen Receptor T Cells in Solid Tumors
Authors: Murty Surya , Labanieh Louai , Murty Tara , Gowrishankar Gayatri , Haywood Tom , Alam Israt S. , Beinat Corinne , Robinson Elise , Aalipour Amin , Klysz Dorota D. , Cochran Jennifer R. , Majzner Robbie G. , Mackall Crystal L. , Gambhir Sanjiv S. 
Published: September 2020

Abstract

Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. In addition, the potential adverse effects of CAR T cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a PET reporter gene for imaging of T-cell trafficking in patients with brain tumor. The HSV1-TK enzyme can act as a suicide gene of transduced cells through treatment with the prodrug ganciclovir. Here we report the molecular engineering, imaging, and ganciclovir-mediated destruction of B7H3 CAR T cells incorporating a mutated version of the HSV1-tk gene (sr39tk) with improved enzymatic activity for ganciclovir. The sr39tk gene did not affect B7H3 CAR T-cell functionality and in vitro and in vivo studies in osteosarcoma models showed no significant effect on B7H3 CAR T-cell antitumor activity. PET/CT imaging with 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG) of B7H3-sr39tk CAR T cells in an orthotopic model of osteosarcoma revealed tumor homing and systemic immune expansion. Bioluminescence and PET imaging of B7H3-sr39tk CAR T cells confirmed complete tumor ablation with intraperitoneal ganciclovir administration. This imaging and suicide ablation system can provide insight into CAR T-cell migration and proliferation during clinical trials while serving as a suicide switch to limit potential toxicities.

Significance:
This study showcases the only genetically engineered system capable of serving the dual role both as an effective PET imaging reporter and as a suicide switch for CAR T cells.
Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment
Authors: Subramani Elavarasan , Radoul Marina , Najac Chloe , Batsios Georgios , Molloy Abigail R. , Hong Donghyun , Gillespie Anne Marie , Santos Romelyn Delos , Viswanath Pavithra , Costello Joseph F. , Pieper Russell O. , Ronen Sabrina M. 
Published: September 2020

Abstract

Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)–based metabolic changes for detection of response to temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1–13C]glucose and [3–13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following temozolomide treatment. In line with these results, hyperpolarized [5–13C]glutamate produced from [2–13C]pyruvate and hyperpolarized [1–13C]glutamate produced from [1–13C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma.

Significance:
These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.
Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC)
Authors: Musher Benjamin L. , Melson Joshua E. , Amato Gianni , Chan David , Hill Marisa , Khan Iftekhar , Kochuparambil Samith T. , Lyons Susan E. , Orsini James , Pedersen Susanne K. , Robb Bruce , Saltzman Joel , Silinsky Jennifer , Gaur Snigdha , Tuck Melissa K. , LaPointe Lawrence C. , Young Graeme P. 
Published: September 2020

Abstract

Background:
Most recurrences of early-stage colorectal cancer detected with current surveillance measures are widespread and incurable. Circulating tumor DNA (ctDNA) may facilitate earlier diagnosis of recurrent colorectal cancer and improve cancer-related outcomes.

Methods:
Plasma from patients undergoing standard surveillance after definitive treatment for stage II/III colorectal cancer was assayed with COLVERA and carcinoembryonic antigen (CEA) at a single time point. Results were correlated with radiographic imaging. Assay performance, including sensitivity and specificity for recurrence, were compared. Impact of potentially confounding variables was also explored.

Results:
322 patients were included in the final analysis, and 27 recurrences were documented over a median follow-up period of 15 months. Sensitivity for recurrence was 63% [confidence interval (CI), 42.4–80.6] and 48% (CI, 28.7–68.1) for COLVERA and CEA (≥5 ng/mL), respectively (P = 0.046), while specificity was 91.5% (CI, 87.7–94.4) and 96.3% (CI, 93.4–98.1), respectively (P = 0.016). Smoking and age were independent predictors of CEA but not COLVERA positivity.

Conclusions:
COLVERA was more sensitive but less specific than CEA in detecting recurrent colorectal cancer. Short median follow-up may have been responsible for apparent false positives in COLVERA. Studies with serial sampling and longer follow-up are needed to assess whether earlier detection of colorectal cancer recurrence translates into clinical benefit.

Impact:
This prospective study showed that COLVERA (a two-gene ctDNA assay) was more sensitive for detection of recurrence in a cohort of patients undergoing surveillance after definitive therapy for stages II and III colorectal cancer.
Strategizing Screening for Melanoma in an Era of Novel Treatments: A Model-Based Approach
Authors: Gogebakan Kemal Caglar , Berry Elizabeth G. , Geller Alan C. , Sonmez Kemal , Leachman Sancy A. , Etzioni Ruth 
Published: September 2020

Abstract

Background:
Benefit–harm tradeoffs of melanoma screening depend on disease risk and treatment efficacy. We developed a model to project outcomes of screening for melanoma in populations with different risks under historic and novel systemic treatments.

Methods:
Computer simulation model of a screening program with specified impact on overall and advanced-stage incidence. Inputs included meta-analyses of treatment trials, cancer registry data, and a melanoma risk prediction study

Results:
Assuming 50% reduction in advanced stage under screening, the model projected 59 and 38 lives saved per 100,000 men under historic and novel treatments, respectively. With 10% increase in stage I, the model projects 2.9 and 4.7 overdiagnosed cases per life saved and number needed to be screened (NNS) equal to 1695 and 2632 under historical and novel treatments. When screening was performed only for the 20% of individuals with highest predicted risk, 34 and 22 lives per 100,000 were saved under historic and novel treatments. Similar results were obtained for women, but lives saved were lower.

Conclusions:
Melanoma early detection programs must shift a substantial fraction of cases from advanced to localized stage to be sustainable. Advances in systemic therapies for melanoma might noticeably reduce benefits of screening, but restricting screening to individuals at highest risk will likely reduce intervention efforts and harms while preserving &gt;50% of the benefit of nontargeted screening.

Impact:
Our accessible modeling framework will help to guide population melanoma screening programs in an era of novel treatments for advanced disease.
Replication and Genetic Risk Score Analysis for Pancreatic Cancer in a Diverse Multiethnic Population
Authors: Bogumil David , Conti David V. , Sheng Xin , Xia Lucy , Shu Xiao-ou , Pandol Stephen J. , Blot William J. , Zheng Wei , Le Marchand Loïc , Haiman Christopher A. , Setiawan Veronica Wendy 
Published: September 2020

Abstract

Background:
Genome-wide association studies (GWAS) have identified several SNPs associated with pancreatic cancer. No studies yet have attempted to replicate these SNPs in US minority populations. We aimed to replicate the associations of 31 GWAS-identified SNPs with pancreatic cancer and build and test a polygenic risk score (PRS) for pancreatic cancer in an ethnically diverse population.

Methods:
We evaluated 31 risk variants in the Multiethnic Cohort and the Southern Community Cohort Study. We included 691 pancreatic ductal adenocarcinoma (PDAC) cases and 13,778 controls from African-American, Japanese-American, Latino, Native Hawaiian, and white participants. We tested the association between each SNP and PDAC, established a PRS using the 31 SNPs, and tested the association between the score and PDAC risk.

Results:
Eleven of the 31 SNPs were replicated in the multiethnic sample. The PRS was associated with PDAC risk [OR top vs. middle quintile = 2.25 (95% confidence interval, 1.73–2.92)]. Notably, the PRS was associated with PDAC risk in all ethnic groups except Native Hawaiian (OR per risk allele ranged from 1.33 in Native Hawaiians to 1.91 in African Americans; P heterogeneity = 0.12).

Conclusions:
This is the first study to replicate 11 of the 31 GWAS-identified risk variants for pancreatic cancer in multiethnic populations, including African Americans, Japanese Americans, and Latinos. Our results also suggest a potential utility of PRS with GWAS-identified risk variants for the identification of individuals at increased risk for PDAC across multiple ethnic groups.

Impact:
PRS can potentially be used to stratify pancreatic cancer risk across multiple ethnic groups.
Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy
Authors: Sun Jingwei , Lu Qiao , Sanmamed Miguel F. , Wang Jun 
Published: September 2020

AbstractImmunomodulatory agents blocking the PD-1/PD-L1 pathway have shown a new way to treat cancer. The explanation underlying the success of these agents may be the selective expression of PD-L1 with dominant immune-suppressive activities in the tumor microenvironment (TME), supporting a more favorable tumor response-to-toxicity ratio. However, despite the big success of these drugs, most patients with cancer show primary or acquired resistance, calling for the identification of new immune modulators in the TME. Using a genome-scale T-cell activity array in combination with bioinformatic analysis of human cancer databases, we identified Siglec-15 as a critical immune suppressor with broad upregulation on various cancer types and a potential target for cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint inhibitory ligands. It shows prominent expression on macrophages and cancer cells and a mutually exclusive expression with PD-L1, suggesting that it may be a critical immune evasion mechanism in PD-L1–negative patients. Interestingly, Siglec-15 has also been identified as a key regulator for osteoclast differentiation and may have potential implications in bone disorders not limited to osteoporosis. Here, we provide an overview of Siglec-15 biology, its role in cancer immune regulation, the preliminary and encouraging clinical data related to the first-in-class Siglec-15 targeting mAb, as well as many unsolved questions in this pathway. As a new player in the cancer immunotherapeutic arena, Siglec-15 may represent a novel class of immune inhibitors with tumor-associated expression and divergent mechanisms of action to PD-L1, with potential implications in anti-PD-1/PD-L1–resistant patients.
Delving into Early-onset Pancreatic Ductal Adenocarcinoma: How Does Age Fit In?
Authors: Tsang Erica S. , Topham James T. , Karasinska Joanna M. , Lee Michael K.C. , Williamson Laura M. , Mendis Shehara , Denroche Robert E. , Jang Gun Ho , Kalloger Steve E. , Moore Richard A. , Mungall Andrew J. , Bathe Oliver F. , Tang Patricia A. , Notta Faiyaz , Wilson Julie M. , Laskin Janessa , O'Kane Grainne M. , Knox Jennifer J. , Goodwin Rachel A. , Loree Jonathan M. , Jones Steven J.M. , Marra Marco A. , Gallinger Steven , Schaeffer David F. , Renouf Daniel J. 
Published: September 2020

AbstractPurpose:With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood.Experimental Design:We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; n = 117), intermediate (age of onset 55–70 years; n = 264), and average (age of onset ≥70 years; n = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups.Results:EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in CDKN2A (P = 0.0017), and were more likely to achieve biallelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset (P = 1.5e-4). Transcription factor forkhead box protein C2 (FOXC2) was significantly upregulated in EOPC tumors (P = 0.032). Genes significantly correlated with FOXC2 in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included VIM (P = 1.8e-8), CDH11 (P = 6.5e-5), and CDH2 (P = 2.4e-2).Conclusions:Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represents novel molecular characteristics of EOPC.See related commentary by Lou, p. 8
Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance)
Authors: Innocenti Federico , Sibley Alexander B. , Patil Sushant A. , Etheridge Amy S. , Jiang Chen , Ou Fang-Shu , Howell Stefanie D. , Plummer Sarah J. , Casey Graham , Bertagnolli Monica M. , McLeod Howard L. , Auman James T. , Blanke Charles D. , Furukawa Yoichi , Venook Alan P. , Kubo Michiaki , Lenz Heinz-Josef , Parker Joel S. , Ratain Mark J. , Owzar Kouros 
Published: September 2020

Abstract

Purpose:
Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.

Experimental Design:
Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models.

Results:
The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10−6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10−6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G&gt;A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced.

Conclusions:
This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.
Protein Glycosylation: “New-yet-Old” Target for Immunotherapy
Authors: Bhat Jaydeep , Kabelitz Dieter 
Published: September 2020

Abstract
The use of checkpoint monotherapy in treating cancer has limited success. Post-translational modifications (PTM) of proteins such as glycosylation might have clinical implications due to distinct modifications found in diseases and its regulatory role in the immunometabolic gene expression. Such novel mechanistic targets hold great promise for combined immunotherapy.
See related article by Shi et al., p. 5990