tbuckley/cabot-search huggingface dataset:
Abstract 2807: Variations in glycolytic activity of HCC subtypes as monitored by in vivo h 13C MRI
Authors: Qianhui Dou, Aaron K. Grant, Cody Callahan, Muneeb Ahmed, Leo L. Tsai
Journal: Cancer Research (2021)

Abstract Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer-related death worldwide. Despite therapeutic advancements, a significant proportion of patients progress, highlighting the need to improve diagnostic approaches to monitor therapy. Radiofrequency ablation (RFA), an accepted locoregional therapy for early HCC, can stimulate more aggressive tumor biology within under-treated or distant tumors. Increased glycolytic activity is a hallmark feature of cancer, but variations in metabolism and its link to tumor aggression can impact the sensitivity of HCC to therapies affecting these pathways. Tumor metabolic phenotypes can be characterized by hyperpolarized 13C MRI (h13C MRI), which can also be used to assess treatment response. In this study, we used orthotopic rat HCC models with two different cell lines N1S1 and MCA-RH7777, and analyzed their mRNA expression of glycolysis-related genes and in vivo glycolytic activity with h13C MRI. We then partially-treated tumors with radiofrequency ablation (RFA) and used h13C MRI to measure in vivo tumor metabolism before and 3 days after RFA to compare them to histologic and phenotypical measures of disease progression. N1S1 tumors grew only as single lesions, while MCA-RH7777 rapidly produced intra-hepatic and distal metastases. Glycolysis-related genes including HK2, HK3, PFKFB3, and MCT4 were highly expressed in N1S1, but not in MCA-RH7777, while GPT1 was highly expressed in MCA-RH7777 but not in N1S1. In vivo h13C MRI demonstrated significantly increased 13C lactate flux in N1S1 tumor compared to the background normal liver, while 13C lactate flux in MCA-RH7777 rat model did not, consistent with mRNA expression patterns. Tumor 13C lactate flux was significantly increased and 13C alanine flux was significantly decreased following partial RFA treatment to N1S1 tumors when compared to untreated tumors, which was associated with an increase in tumor Ki67 expression. However, no change was seen on h13C MRI between the RFA and control arms in MCA-RH7777 tumors, even though growth and total tumor burden progressed significantly more following RFA. In contrast to N1S1, there was also no difference between 13C lactate flux and 13C alanine flux within MCA-RH7777 tumors and the neighboring normal hepatic parenchyma, suggesting that glycolytic activity in these tumors did not drive RFA-stimulated progression. Targeting of glycolytic pathways as a potential therapy for HCC may therefore be limited to certain subtypes, and h13C MRI may be used to select for sensitivity. Citation Format: Qianhui Dou, Aaron K. Grant, Cody Callahan, Muneeb Ahmed, Leo L. Tsai. Variations in glycolytic activity of HCC subtypes as monitored by in vivo h 13C MRI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2807.
Case 20-2021: A 69-Year-Old Man with Ataxia
Authors: Vikram Khurana, Claudio M. de Gusmao, McKinley Glover, Jeffrey Helgager
Journal: New England Journal of Medicine (2021)

A 69-year-old man with a family history of celiac disease was evaluated at this hospital for progressive ataxia of 9 years' duration. He had impaired proprioception, vestibulopathy, and cerebellar dysfunction. MRI of the head showed mild diffuse parenchymal volume loss and prominent cerebellar volume loss. A diagnosis was made.
フレキシブルエレクトロニクスは神経科学研究をどのように進めるか?【JST・京大機械翻訳】
Authors: Chen Yihang, J Rommelfanger Nicholas, I Mahdi Ali, Wu Xiang, T Keene Scott, Obaid Abdulmalik, Salleo Alberto, Wang Huiliang, Hong Guosong
Journal: Biomaterials (2021)
Prostate Mapping: The Madrid protocol (Transperineal prostate biopsies combining Micro-ultrasound and mpMRI fusion biopsy) concordance with robotic radical prostatectomy specimens
Authors: M.E. Rodríguez Socarrás, J. Gomez Rivas, D. Carrion, L. Llanes Gonzalez, J. Reinoso Elbers, J. Fernandez Del Alamo, V. Cuadros Rivera, E. Garcia Cruz, P. Juarez Del Dago, F. Gomez Sancha
Journal: European Urology (2021)
Can the Health Care System Manage Increased Workloads From Expanded Access to Cancer Treatment?
Authors: Fabian McCartney Johnston, Thomas J. Smith
Journal: JAMA Network Open (2021)

Zachary A. K. Frosch, MD; Nicholas Illenberger, MS; Nandita Mitra, PhD; Daniel J. Boffa, MD; Matthew A. Facktor, MD; Heidi Nelson, MD; Bryan E. Palis, MA; Justin E. Bekelman, MD; Lawrence N. Shulman, MD; Samuel U. Takvorian, MD, MS
Patient-derived xenografts and organoids model therapy response in prostate cancer
Authors: S. Karkampouna, F. La Manna, A. Benjak, M. Kiener, M. De Menna, E. Zoni, J. Grosjean, I. Klima, A. Garofoli, M. Bolis, A. Vallerga, J. Theurillat, M.R. De Filippo, V. Genitsch, D. Keller, T.H. Booij, C.U. Stirnimann, K. Eng, A. Sboner, C.K.Y. Ng, S. Piscuoglio, P.C. Gray, M.A. Rubin, G.N. Thalmann, J. Kruithof-De
Journal: European Urology (2021)
Abstract 2702: Prostate stromal transcriptome as biomarker of aggressive prostate cancer
Authors: Yinglu Zhou, Chaoran Ma, Giuseppe Nicoló Fanelli, Lavinia Stefanizzi, Elizaveta Gazeeva, Lorelei A. Mucci, Massimo Loda, Svitlana Tyekucheva, Kathryn L. Penney
Journal: Cancer Research (2021)

Abstract Background: Prostate cancer has a heterogeneous prognosis. Discovery of molecular biomarkers that improve identification of potentially lethal prostate cancer could enhance the ability to determine which patients would benefit most from immediate treatment. Most prognostic biomarkers have focused on those in prostate tumors. However, it is increasingly recognized that the tumor microenvironment contributes to cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with clinically significant, high-grade prostate cancer. Methods: We performed RNA-sequencing (Illumina TruSeq RNA Exome library preparation) of macrodissected stromal samples (adjacent to and distant from tumor) from 363 radical prostatectomy specimens from Health Professionals Follow-up Study and Physicians' Health Study participants. We performed a differential expression analysis comparing the gene expression and pathways of stroma adjacent to and distant from tumor. We also performed a cluster analysis and computed a single sample gene set enrichment analysis (ssGSEA) score to assess the association of our previously reported 25 stromal signature genes (Tyekucheva et al. 2017) to determine the association with Gleason score. Results: Eighty-eight genes as well as eight Gene Ontology pathways and fourteen Canonical pathways were differentially expressed (FDR&amp;lt;0.05) between tumor adjacent to and distant from tumor. Pathways included cell-substrate adhesion, muscle development, and cardiomyopathy. 30% of men had high-grade (Gleason score 8-10) tumors. We observed higher expression of the individual signature genes in the cluster enriched for high Gleason score tumors, and a higher stromal signature ssGSEA score was associated with high Gleason score (p=0.04). Conclusions: Pathways differentially expressed between stroma adjacent to and distant from tumor suggest known differences in cell types by location or a potential field effect. We observed that the direction of the association of the stromal signature with Gleason score agreed with our previous report. We are currently analyzing the full expression dataset to identify additional stromal genes associated with Gleason score and lethal prostate cancer, and performing multi-plex immunohistochemistry to assess stromal cell-type heterogeneity in regions of tumor and normal prostate across tissue microarrays. Citation Format: Yinglu Zhou, Chaoran Ma, Giuseppe Nicoló Fanelli, Lavinia Stefanizzi, Elizaveta Gazeeva, Lorelei A. Mucci, Massimo Loda, Svitlana Tyekucheva, Kathryn L. Penney. Prostate stromal transcriptome as biomarker of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2702.
Abstract 544: Urine as a non-invasive alternative to blood for germline and somatic mutation detection in hepatocellular carcinoma
Authors: Amy Kim, Selena Lin, Yixiao Cui, Terence Gade, Fwu-Shan Shieh, Max Chao, John Shieh, Surbhi Jain, Jonathan Cheng, James Hamilton, Hie-Won L. Hann, Dmitry Goryunov, Ying-Hsiu Su
Journal: Cancer Research (2021)

Abstract BACKGROUND: Cell-free DNA (cfDNA) from blood has become a promising analyte for cancer diagnostics. However, because blood contains high concentrations of proteins and enzyme inhibitors, plasma cfDNA quality can be variable. Urinary cfDNA has been shown to contain mutations associated with non-genitourologic cancers including hepatocellular carcinoma (HCC). In this study, we evaluate urine as a noninvasive alternative to blood-based liquid biopsy for both germline and ctDNA genotyping in HCC. METHOD: Using qPCR, whole-genome sequencing (WGS), and targeted NGS, DNA isolated from blood or urine of patients with HCC was evaluated and analyzed for overall genome coverage, HCC hotspot coverage, and germline or somatic mutation concordance. Targeted NGS of plasma and urine cfDNA was also performed for detection of somatic variants. RESULTS: Similar to plasma cfDNA, urine cfDNA showed a major mononucleosomal species of 165-170 bp, with dinucleosomal species also discernable in most healthy individuals and patients with HCC. Overall genome coverage breadth was similar between urine and plasma cfDNA, with higher fraction of covered cancer-associated mutation hotspots in urine cfDNA. Quantitative PCR analyses of HCC-associated mutations (TP53, CTNNB1, and hTERT) in 102 patients with HCC, revealed 78% overall concordance between plasma and urine. Targeted NGS of HCC-associated gene regions in additional 15 patients showed an 97% overall position-level concordance between plasma and urine cfDNA. Furthermore, urine outperformed plasma in both the sensitivity and specificity of detection of CTNNB1 and hTERT mutations. CONCLUSION urine DNA can potentially be used as a completely noninvasive diagnostic biomarker for HCC. Citation Format: Amy Kim, Selena Lin, Yixiao Cui, Terence Gade, Fwu-Shan Shieh, Max Chao, John Shieh, Surbhi Jain, Jonathan Cheng, James Hamilton, Hie-Won L. Hann, Dmitry Goryunov, Ying-Hsiu Su. Urine as a non-invasive alternative to blood for germline and somatic mutation detection in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 544.
Disparities in Screening and Treatment of Cardiovascular Diseases in Patients With Mental Disorders Across the World: Systematic Review and Meta-Analysis of 47 Observational Studies
Authors: Marco Solmi, Jess Fiedorowicz, Laura Poddighe, Marco Delogu, Alessandro Miola, Anne Høye, Ina H. Heiberg, Brendon Stubbs, Lee Smith, Henrik Larsson, Rubina Attar, René E. Nielsen, Samuele Cortese, Jae Il Shin, Paolo Fusar-Poli, Joseph Firth, Lakshmi N. Yatham, Andre F. Carvalho, David J. Castle, Mary V. Seeman, Christoph U. Correll
Journal: American Journal of Psychiatry (2021)

This study used meta-analysis to assess disparities in cardiovascular disease (CVD) screening and treatment in people with mental disorders, a group that has elevated CVD incidence and mortality.The authors searched PubMed and PsycInfo through July 31, 2020, and conducted a random-effect meta-analysis of observational studies comparing CVD screening and treatment in people with and without mental disorders. The primary outcome was odds ratios for CVD screening and treatment. Sensitivity analyses on screening and treatment separately and on specific procedures, subgroup analyses by country, and by controlling for confounding by indication, as well as meta-regressions, were also run, and publication bias and quality were assessed.Forty-seven studies (N=24,400,452 patients, of whom 1,283,602 had mental disorders) from North America (k=26), Europe (k=16), Asia (k=4), and Australia (k=1) were meta-analyzed. Lower rates of screening or treatment in patients with mental disorders emerged for any CVD (k=47, odds ratio=0.773, 95% CI=0.742, 0.804), coronary artery disease (k=34, odds ratio=0.734, 95% CI=0.690, 0.781), cerebrovascular disease (k=8, odds ratio=0.810, 95% CI=0.779, 0.842), and other mixed CVDs (k=11, odds ratio=0.839, 95% CI=0.761, 0.924). Significant disparities emerged for any screening, any intervention, catheterization or revascularization in coronary artery disease, intravenous thrombolysis for stroke, and treatment with any and with specific medications for CVD across all mental disorders (except for CVD medications in mood disorders). Disparities were largest for schizophrenia, and they differed across countries. Median study quality was high (Newcastle-Ottawa Scale score, 8); higher-quality studies found larger disparities, and publication bias did not affect results.People with mental disorders, and those with schizophrenia in particular, receive less screening and lower-quality treatment for CVD. It is of paramount importance to address underprescribing of CVD medications and underutilization of diagnostic and therapeutic procedures across all mental disorders.
Abstract 1707: Increasing immune cell infiltration in hepatocellular carcinoma tumors using a novel GPC3-targeting aptamer conjugate
Authors: Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Kristin Thompson, Shuhao Zhu
Journal: Cancer Research (2021)

Abstract Glypican 3 (GPC3) is a cell membrane-bound heparin sulfate proteoglycan, expressed at the cell surface of many cancer types. It has emerged as a leading target for hepatocellular carcinoma treatment due to its overexpression in aberrant liver cells and low expression in healthy adult tissues. One of the major challenges in treating hepatocellular carcinoma with current immunotherapies is turning cold tumors into immunogenic ones. Unmethylated CpG oligodeoxynucleotides (ODNs) are known immune stimulators, however their use in combination therapy for cancer treatment is limited due to the requirement of intra tumoral injections to prevent systemic toxicity. Here, we describe a unique GPC3-specific aptamer, able to target GPC3-expressing cancer cells in vivo as a means to deliver the immunostimulatory CpG 7909. Systemic administration through intra peritoneal (i.p.) injection of the GPC3 aptamer-CpG conjugate (GRX51) decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-50% depending on treatment schedule, while also increasing immune cell infiltration. Final tumor volumes of GRX51-treated animals are consistent with tumor volumes of animals treated with the standard of care compound, sorafenib tosylate. Due to its GPC3-targeting capacity, systemic dosing of GRX51 (15 mg/kg) is less toxic than systemic administration with equimolar amounts of CpG 7909 alone (5 mg/kg), with a comparable effect on tumor shrinkage. While both GRX51 and CpG 7909 induce immune cell recruitment, GRX51 treated mice had a final immune:tumor cell ratio of 2.45 ± 0.56, while CpG 7909-treated animals had a ratio of 1.51 ± 0.95 relative to the vehicle control after a 7-day on/7-day off daily dosing schedule. Using the Hep3B xenograft in CD34+ humanized mice, we also showed GRX51 primes tumors for combination treatments with FDA approved checkpoint inhibitors. Mice were treated with GRX51 (7.5 mg/kg daily i.p. dose, 11 days), the PD-1R inhibitor pembrolizumab (10 mg/kg once every 3 days i.p., 11 days), or a combination of the two drugs. The GRX51 treatment alone outperformed pembrolizumab alone, reducing tumor size by 33% and 18% respectively. Notably, the combination of GRX51 with pembrolizumab reduced tumor size by 63%. Together, our data show that GRX51 is a novel GPC3-targeting molecule capable of reducing tumor size and priming GPC3-positive tumors for combination immunotherapy, without inducing major systemic toxicity with i.p. injection. Citation Format: Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Kristin Thompson, Shuhao Zhu. Increasing immune cell infiltration in hepatocellular carcinoma tumors using a novel GPC3-targeting aptamer conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1707.
Abstract 3047: Spatial heterogeneity in diffuse intrinsic pontine gliomas treated with a PDGFR inhibitor
Authors: Sasi Arunachalam, Samuel W. Brady, Xiaotu Ma, Karol Szlachta, Heather Mulder, John Easton, Christopher L. Tinkle, Cynthia Wetmore, Suzanne J. Baker, Jinghui Zhang
Journal: Cancer Research (2021)

Abstract Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors that arise in the pons. To understand the spatial heterogeneity in DIPG, we performed ultra-deep sequencing and copy number profiling of 44 multi-region autopsy samples from 10 DIPG patients after phase I treatment with the PDGFR inhibitor crenolanib. Our study recapitulated the previously reported temporal order of driver mutation acquisition starting with histone H3 K27M followed by cell cycle (TP53 and PPM1D) or growth factor pathways (AVCR1, or PIK3R1), with mutations affecting PI3K and MAPK pathways being late, subclonal events. Further, we observed that aneuploidy was likely an early event as copy number heterogeneity was minimal in most patients. Compared to previous DIPG studies, we observed an enrichment in subclonal mutations and convergent evolution of PI3K alterations. This enrichment may have been due to selection for crenolanib resistance, or to the prior treatment history of the patients within the cohort. We also detailed intra-patient clonal composition among tumor samples and identified founder clones that were dominant in only a single location, which we considered to be non-migratory “occupier” clones, in four patients. By contrast, in six other cases, we observed clones that frequently invaded other sites. Interestingly, in one case with TP53 convergent evolution, aneuploidy clone carrying TP53 R273H mutation invades all other sequenced tumor sites whereas another clone with TP53 R248W does not. These results indicate the importance of understanding spatial heterogeneity within DIPG patients, which is crucial to the identification of effective treatments. Citation Format: Sasi Arunachalam, Samuel W. Brady, Xiaotu Ma, Karol Szlachta, Heather Mulder, John Easton, Christopher L. Tinkle, Cynthia Wetmore, Suzanne J. Baker, Jinghui Zhang. Spatial heterogeneity in diffuse intrinsic pontine gliomas treated with a PDGFR inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3047.
Abstract LB158: Implications of Targeting Novel Pathways in Exhausted T Cells for Immuno-Oncology Therapeutic Intervention
Authors: Rhoanne McPherson, Francis Acklam, Joanne Hay, Mark Barbour, Courtney Grant, Preeti Singh, Adriana Gambardella, Justyna Rzepecka, Stephen Anderton, Hayley Gooding
Journal: Cancer Research (2021)

Abstract The induction of CD8+ T cell exhaustion, driven by the tumor microenvironment, is thought to be a major mechanism by which tumors can escape immune surveillance and are able to persist and progress. T cell exhaustion is typically characterized by the expression of co-inhibitory markers such as PD-1, LAG-3 and TIM-3 and a reduced capacity for pro-inflammatory cytokine production. Whilst treatment with therapeutics targeted at checkpoint inhibitors, such as Nivolumab (anti-PD-1), have shown great promise in the treatment of a subset of individuals and tumor types, resistance to these approaches is prevalent. As such, novel approaches are required in order to provide alternative options for the rescue of T cell exhaustion and cancer treatment. Here we describe the characteristics of an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumor microenvironment and where exhaustion can be partially rescued by treatment with anti-PD-1. Furthermore, we demonstrate the effect of treatment with an inhibitor of a novel target identified in exhausted T cells on T cell function; both through analysis of pro-inflammatory cytokine production and the ability to kill tumor cells. These assays and approaches enable investigation into the ability of compounds to influence reversal of T cell exhaustion where anti-PD-1 treatment does not fully reverse the exhausted phenotype and offers the ability to test combination therapy approaches. Citation Format: Rhoanne McPherson, Francis Acklam, Joanne Hay, Mark Barbour, Courtney Grant, Preeti Singh, Adriana Gambardella, Justyna Rzepecka, Stephen Anderton, Hayley Gooding. Implications of Targeting Novel Pathways in Exhausted T Cells for Immuno-Oncology Therapeutic Intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB158.
Metformin elicits dual therapeutic effects on renal inflammatory and oxidative injury in calcium oxalate nephrocalcinosis
Authors: C. Duan, H. Liu, T. Ye, X. Yang, P. Lv, X. Yao, B. Li, K. Tang, Z. Chen, X. Song, T. Wang, Y. Deng, G. Zeng, J. Liu, J. Xing, Z. Ye, H. Xu
Journal: European Urology (2021)