bluuebunny/crossref_metadata_2025_split huggingface dataset:
RIG-I–Like Receptor LGP2 Is Required for Tumor Control by Radiotherapy
Authors: Zheng Wenxin , Ranoa Diana Rose E. , Huang Xiaona , Hou Yuzhu , Yang Kaiting , Poli Elizabeth C. , Beckett Michael A. , Fu Yang-Xin , Weichselbaum Ralph R. 
Published: October 2020

Abstract

Dendritic cells (DC) play an essential role in innate immunity and radiation-elicited immune responses. LGP2 is a RIG-I–like receptor involved in cytoplasmic RNA recognition and antiviral responses. Although LGP2 has also been linked to cell survival of both tumor cells and T cells, the role of LGP2 in mediating DC function and antitumor immunity elicited by radiotherapy remains unclear. Here, we report that tumor DCs are linked to the clinical outcome of patients with breast cancer who received radiotherapy, and the presence of DC correlates with gene expression of LGP2 in the tumor microenvironment. In preclinical models, host LGP2 was essential for optimal antitumor control by ionizing radiation (IR). The absence of LGP2 in DC dampened type I IFN production and the priming capacity of DC. In the absence of LGP2, MDA5-mediated activation of type I IFN signaling was abrogated. The MDA5/LGP2 agonist high molecular weight poly I:C improved the antitumor effect of IR. This study reveals a previously undefined role of LGP2 in host immunity and provides a new strategy to improve the efficacy of radiotherapy.

Significance:
These findings reveal an essential role of LGP2 in promoting antitumor immunity after radiotherapy and provide a new strategy to enhance radiotherapy.
Risk of Injuries around Diagnosis of Cervical Cancer and Its Precursor Lesions: A Nationwide Cohort Study in Sweden
Authors: Shen Qing , Lu Donghao , Andrae Bengt , Schelin Maria E.C. , Sjölander Arvid , Cao Yang , Sparén Pär , Fang Fang 
Published: October 2020

Abstract

Background:
Highly increased risk of injuries has been noted around the time of cancer diagnosis. Whether there is a similar increase in risk around the diagnosis of cervical cancer and its precursor lesions was unknown.

Methods:
We performed a cohort study including 3,016,307 Swedish women that participated in cervical screening during 2001 to 2012. We calculated the incidence rates (IR) of hospitalized iatrogenic or noniatrogenic injuries during the diagnostic workup, and the time interval from smear or punch biopsy until surgical treatment or 2 months after the last smear or biopsy, among women with invasive cervical cancer (ICC) or its precursor lesions. We calculated the IRs of injuries during the 2 months after a normal smear among the other women as reference. IR ratios (IRR) and 95% confidence intervals (CI) were calculated using Poisson regression.

Results:
Compared with other women, there was an increased rate of iatrogenic injuries during the diagnostic workup of women with ICC (IR, 0.58 per 1,000 person-months; IRR, 8.55; 95% CI, 3.69–19.80) as well as of women with cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ (IR, 0.09 per 1,000 person-months; IRR, 3.04; 95% CI, 1.73–5.34). We also found an increased rate of noniatrogenic injuries during the diagnostic workup of women with invasive cancer (IR, 0.65 per 1,000 person-months; IRR, 2.48; 95% CI, 1.30–4.47).

Conclusions:
Although rare, there was an increased risk of inpatient care for iatrogenic and noniatrogenic injuries during the diagnostic workup of women with ICC.

Impact:
Women experienced burden of medical complications and psychologic distress around diagnosis of a potential cervical cancer.
Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
Authors: Bruzek Amy K. , Ravi Karthik , Muruganand Ashwath , Wadden Jack , Babila Clarissa May , Cantor Evan , Tunkle Leo , Wierzbicki Kyle , Stallard Stefanie , Dickson Robert P. , Wolfe Ian , Mody Rajen , Schwartz Jonathan , Franson Andrea , Robertson Patricia L. , Muraszko Karin M. , Maher Cormac O. , Garton Hugh J.L. , Qin Tingtin , Koschmann Carl 
Published: October 2020

AbstractPurpose:Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.Experimental Design:We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.Results:Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.Conclusions:Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.
Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial
Authors: Xu Jianming , Shen Jie , Gu Shanzhi , Zhang Yun , Wu Lihua , Wu Jian , Shao Guoliang , Zhang Yanqiao , Xu Li , Yin Tao , Liu Jingfeng , Ren Zhenggang , Xiong Jianping , Mao Xianhai , Zhang Ling , Yang Jiayin , Li Lequn , Chen Xiaoming , Wang Zhiming , Gu Kangsheng , Chen Xi , Pan Zhanyu , Ma Kuansheng , Zhou Xinmin , Yu Zujiang , Li Enxiao , Yin Guowen , Zhang Xiao , Wang Shuni , Wang Quanren 
Published: October 2020

Abstract

Purpose:
We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).

Patients and Methods:
This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight &lt;50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1.

Results:
Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.

Conclusions:
Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.
See related commentary by Pinato et al., p. 908
Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET
Authors: Simonetta Federico , Alam Israt S. , Lohmeyer Juliane K. , Sahaf Bita , Good Zinaida , Chen Weiyu , Xiao Zunyu , Hirai Toshihito , Scheller Lukas , Engels Pujan , Vermesh Ophir , Robinson Elise , Haywood Tom , Sathirachinda Ataya , Baker Jeanette , Malipatlolla Meena B. , Schultz Liora M. , Spiegel Jay Y. , Lee Jason T. , Miklos David B. , Mackall Crystal L. , Gambhir Sanjiv S. , Negrin Robert S. 
Published: October 2020

Abstract

Purpose:
Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Noninvasive molecular imaging of CAR T cells by PET is a promising approach with the ability to provide spatial, temporal, and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T-cell molecular imaging. In this study, we assessed the ability of antibody-based PET (immunoPET) to noninvasively visualize CAR T cells.

Experimental Design:
After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer, which we have previously reported.

Results:
Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow–containing skeletal sites of CAR T-cell–treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T-cell persistence and function.

Conclusions:
This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T-cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.
See related commentary by Volpe et al., p. 911
Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition
Authors: Shorstova Tatiana , Su Jie , Zhao Tiejun , Dahabieh Michael , Leibovitch Matthew , De Sa Tavares Russo Mariana , Avizonis Daina , Rajkumar Shivshankari , Watson Ian R. , del Rincón Sonia V. , Miller Wilson H. , Foulkes William D. , Witcher Michael 
Published: October 2020

Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo. Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass spectrometry, coupled with knockdown of newly found targets such as thymidylate synthase, revealed that the repression of a panel of proteins involved in nucleotide synthesis underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell-cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian cancer subtypes.
Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers
Authors: Rashmi Ramachandran , Jayachandran Kay , Zhang Jin , Menon Vishnu , Muhammad Naoshad , Zahner Michael , Ruiz Fiona , Zhang Sisi , Cho Kevin , Wang Yuting , Huang Xiaojing , Huang Yi , McCormick Michael L. , Rogers Buck E. , Spitz Douglas R. , Patti Gary J. , Schwarz Julie K. 
Published: October 2020

Abstract
The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN−/− cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer
Authors: Dees Sundee , Ganesan Rajkumar , Singh Sanjaya , Grewal Iqbal S. 
Published: October 2020

Abstract
Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype that lacks estrogen receptor, progesterone receptor, and HER2 expression, does not respond to traditional endocrine and anti–HER2-targeted therapies. Current treatment options for patients with TNBC include a combination of surgery, radiotherapy, and/or systemic chemotherapy. FDA-approved therapies that target DNA damage repair mechanisms in TNBC, such as PARP inhibitors, only provide marginal clinical benefit. The immunogenic nature of TNBC has prompted researchers to harness the body's natural immune system to treat this aggressive breast cancer. Clinical precedent has been recently established with the FDA approval of two TNBC immunotherapies, including an antibody–drug conjugate and an anti-programmed death-ligand 1 monoclonal antibody. Chimeric antigen receptor (CAR)-T cell therapy, a type of adoptive cell therapy that combines the antigen specificity of an antibody with the effector functions of a T cell, has emerged as a promising immunotherapeutic strategy to improve the survival rates of patients with TNBC. Unlike the remarkable clinical success of CAR-T cell therapies in hematologic cancers with Kymriah and Yescarta, the development of CAR-T cell therapies for solid tumors has been much slower and is associated with unique challenges, including a hostile tumor microenvironment. The aim of the present review is to discuss novel approaches and inherent challenges pertaining to CAR-T cell therapy for the treatment of TNBC.
The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer
Authors: Borden Brittany A. , Baca Yasmine , Xiu Joanne , Tavora Fabio , Winer Ira , Weinberg Benjamin A. , Vanderwalde Ari M. , Darabi Sourat , Korn W. Michael , Mazar Andrew P. , Giles Francis J. , Crawford Lorin , Safran Howard , El-Deiry Wafik S. , Carneiro Benedito A. 
Published: October 2020

AbstractGlycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3β, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed &gt;100,000 tumors from two databases to analyze GSK-3β alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3β–mutated and wild-type tumors. GSK-3β was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3β–mutated tumors were observed for B cells (P = 0.018), monocytes (P = 0.002), dendritic cells (P = 0.005), neutrophils (P = 0.0003), and endothelial cells (P = 0.014). GSK-3β mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3β–mutated tumors compared with wild type in colorectal cancer (P = 0.03), endometrial cancer (P = 0.05), melanoma (P = 0.02), ovarian carcinoma (P = 0.0001), and uterine sarcoma (P = 0.002). Overall, GSK-3β molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3β mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3β mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.
Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft
Authors: Morton J. Jason , Alzofon Nathaniel , Keysar Stephen B. , Chimed Tugs-Saikhan , Reisinger Julie , Perrenoud Loni , Le Phuong N. , Nieto Cera , Gomez Karina , Miller Bettina , Yeager Randi , Gao Dexiang , Tan Aik-Choon , Somerset Hilary , Medina Theresa , Wang Xiao-Jing , Wang Jing H. , Robinson William , Roop Dennis R. , Gonzalez Rene , Jimeno Antonio 
Published: October 2020

Abstract

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines.

Implications:
Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.
Reperfusion Therapy Frequency and Outcomes in Mild Ischemic Stroke in the United States
Authors: Saber Hamidreza , Khatibi Kasra , Szeder Viktor , Tateshima Satoshi , Colby Geoffrey P. , Nour May , Jahan Reza , Duckwiler Gary , Liebeskind David S. , Saver Jeffrey L. 
Published: October 2020

Background and Purpose:
More than half of patients with acute ischemic stroke have minor neurological deficits; however, the frequency and outcomes of reperfusion therapy in regular practice has not been well-delineated.

Methods:
Analysis of US National Inpatient Sample of hospitalizations with acute ischemic stroke and mild deficits (National Institutes of Health Stroke Scale [NIHSS] score 0–5) from October 1, 2016, to December 31, 2017. Patient- and hospital-level characteristics associated with use and outcome of reperfusion therapies were analyzed. Primary outcomes included excellent discharge disposition (discharge to home without assistance); poor discharge disposition (discharge to facility or death); in-hospital mortality; and radiological intracranial hemorrhage.

Results:

Among 179 710 acute ischemic stroke admissions with recorded NIHSS during the 15-month study period, 103 765 (57.7%) had mild strokes (47.3% women; median age, 69 [interquartile range, 59–79] years; median NIHSS score of 2 [interquartile range, 1–4]). Considering reperfusion therapies among strokes with documented NIHSS, mild deficit hospitalizations accounted for 40.0% of IVT and 10.7% of mechanical thrombectomy procedures. Characteristics associated with IVT and with mechanical thrombectomy utilization were younger age, absence of diabetes, higher NIHSS score, larger/teaching hospital status, and Western US region. Excellent discharge outcome occurred in 48.2% of all mild strokes, and in multivariable analysis, was associated with younger age, male sex, White race, lower NIHSS score, absence of diabetes, heart failure, and kidney disease, and IVT use. IVT was associated with increased likelihood of excellent outcome (odds ratio, 1.90 [95% CI, 1.71–2.13],
P
<0.001) despite an increased risk of intracranial hemorrhage (odds ratio, 1.41 [95% CI, 1.09–1.83],
P
<0.001).

Conclusions:
In national US practice, more than one-half of acute ischemic stroke hospitalizations had mild deficits, accounting for 4 of every 10 IVT and 1 of every 10 mechanical thrombectomy treatments, and IVT use was associated with increased discharge to home despite increased intracranial hemorrhage.
Freedom, Compassion and Creativity
Authors: Searle Joshua T. 
Published: October 2020

Abstract
The response of the Church to the Revolution of Dignity (Революція гідності) in Ukraine in 2013–14 signalled a seismic shift in Christian public engagement with post-Soviet society. The implications and significance of the Revolution extended beyond the national boundaries of Ukraine. The revolutionary events became a symbol of hope for the church and society. Theologians and Christian leaders throughout the nations of the former Soviet Union began to reconsider the public witness of the church. This article uses the notion of public theology to explore how Ukrainian evangelical Christians can engage with matters of public significance in the aftermath of the Revolution of Dignity. I conclude with a proposal for the application of three principles (freedom, compassion and creativity) as appropriate points of departure for evangelical theological reflection on public issues in Eastern Europe and the former Soviet Union today.