tbuckley/cabot-search huggingface dataset:
Abstract 172: Computational analysis of the NEK family of proteins reveals unique structural features and interactions with other cancer-related proteins
Authors: Andriele Silva, Shaneen Singh
Journal: Cancer Research (2021)

Abstract The human Never In Mitosis A-like kinase (NEK) protein family consists of serine/threonine kinases that are implicated in the assembly of the mitotic spindle, regulation of the disjunction of the centrosome, and the functioning of the primary cilium. Protein kinases that regulate the centrosome cycle are often abnormally controlled in tumor cells, as are NEK family members. NEK2 was first identified in pediatric solid tumors and also has elevated expression levels in breast, pancreatic and colorectal cancer. NEK1, NEK3, and NEK5 are highly expressed in thyroid tumors, NEK8 is overexpressed in primary human breast tumors, and NEK11's expression is upregulated in early-stage colorectal cancers. To effectively exploit NEKs as drug targets, it is critical to understand their structure-function relationships to help elucidate their mechanism of action. However, structural information for most NEKs and the range and breadth of their interactions with other proteins are still widely unknown. In this study, we use an integrated computational approach which includes the prediction of the 3D structure using homology modeling, threading, and ab initio techniques, the biophysical/biochemical characterization of the theoretical models, followed by in silico protein-protein predictions and docking analysis to present a comprehensive computational analysis of all eleven NEK proteins. Our results reveal unique structural features in some of NEK family members, such as the armadillo (ARM)-like fold in NEK10 and RCC1 repeats found in NEK8 and NEK9. In addition, we present detailed investigations of four predicted protein-protein interaction scenarios involving NEK1, NEK7, NEK8, and NEK9 using docking analysis. This analysis lends support to new, previously unreported interactions of these NEKs with other cancer-related proteins i.e., TNF alpha with NEK7, GEF2 with NEK9, LRRK2 with NEK1, and ARA9 with NEK8. The details of the residues involved in the interaction interfaces from our proposed interaction scenarios provide valuable data for designing rational experiments to validate these interactions. Overall, this study uncovers novel and intriguing information about the NEK protein family, unique protein-protein interaction predictions, and lays the groundwork for elucidating their molecular mechanism as well as for investigating their potential as therapeutic targets. Citation Format: Andriele Silva, Shaneen Singh. Computational analysis of the NEK family of proteins reveals unique structural features and interactions with other cancer-related proteins [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 172.
Abstract 1523: Cell Squeeze® delivery of antigen-encoding mRNA enables human PBMCs to drive antigen-specific CD8+ T cell responses for diverse clinical applications
Authors: Michael F. Maloney, Emrah Ilker Ozay, Christian Yee, Amy Merino, Paul R. Dunbar, Mubeen Mosaheb, Kelly Volk, Carolyne Smith, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead
Journal: Cancer Research (2021)

Abstract Antigen-specific CD8+ T cell priming is critical for mounting an effective immune response against altered self or foreign antigens that are found in most tumors and virally infected cells. T cell priming events require antigen presenting cells (APCs) to process and load antigenic peptides onto MHC molecules. One recently established method for providing APCs with foreign antigen is through delivery of mRNA. An advantage of using antigen-encoding mRNA, compared to protein or peptides, is the inherent protein amplification of mRNA translation; a single mRNA can be translated multiple times. In addition, when antigen-encoding mRNA is delivered directly to the cell, the antigens will have the appropriate post-translational modifications, potentially increasing the immunogenicity. Whereas typical mRNA vaccine platforms require modified nucleotides and lipid nanoparticle encapsulation, Cell Squeeze® technology allows for delivery of uncomplexed and unmodified mRNA directly into the cytosol. Here, we use ex vivo microfluidic Cell Squeeze® technology to deliver uncomplexed and unmodified mRNA encoding for disease related antigens into human peripheral blood mononuclear cells (PBMCs) to generate PBMC APCs. We demonstrate that squeezing PBMCs with mRNA results in effective delivery and translation of mRNA in major cell subsets including T cells, B cells, NK cells, and monocytes. Delivery of antigen-encoding mRNA to human PBMCs enables them to function as APCs, capable of presenting antigenic peptides on MHC molecules for activation of antigen-specific T cells. Specifically, we demonstrate squeezing antigen-encoding mRNA (e.g. HPV16 E7) into human PBMCs results in PBMC APCs that can elicit robust in vitro activation of antigen-specific CD8+ T cells. This approach to APC engineering demonstrates Cell Squeeze® technology's potential to leverage the modularity, cost-effectiveness, and streamlined manufacturing of multiple mRNAs to create cellular vaccines for treating various tumor and infectious disease targets. Citation Format: Michael F. Maloney, Emrah Ilker Ozay, Christian Yee, Amy Merino, Paul R. Dunbar, Mubeen Mosaheb, Kelly Volk, Carolyne Smith, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead. Cell Squeeze® delivery of antigen-encoding mRNA enables human PBMCs to drive antigen-specific CD8+ T cell responses for diverse clinical applications [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 1523.
中枢のSFRP5は肝臓のグルコースフラックスとVLDL-トリグリセリド分泌を調節する【JST・京大機械翻訳】
Authors: Li Yang, Tian Mingyuan, Yang Mengliu, Yang Gangyi, Chen Jianrong, Wang Han, Liu Dongfang, Wang Hongyan, Deng Wuquan, Zhu Zhiming, Zheng Hongting, Li Ling
Journal: Metabolism (2020)
Chronic, Scaly, Hypopigmented Macules on the Face
Authors: Rachel L. Flint, Caleb Hixson, Kristina Burke
Journal: JAMA Dermatology (2021)

A healthy Black woman in her 30s presented for evaluation of hypopigmented, intermittently pruritic patches. Patches were confined to her face and neck and occurred intermittently after her last pregnancy approximately 10 years ago. What is your diagnosis?
Abstract 461: Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development
Authors: Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen
Journal: Cancer Research (2021)

Abstract Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer and the fourth leading cause of cancer-related death worldwide. HCC incidence is highest most often in people with chronic liver diseases, yet the effect of cell composition on the progression of chronic liver diseases to HCC remains unknown. Using gene biomarkers of twenty cell-types identified from healthy liver scRNA-seq data, we estimated cell compositions of six chronic liver diseases and HCC based on their bulk RNA-seq samples. We observed a decrease in the enrichment of various health cells as the progression of liver diseases. Compared to a healthy state, liver fibrosis and HCC present higher enrichment of γδ2 T cells and lower enrichment of central venous liver sinusoidal endothelial cells (LSECs). High enrichment of γδ2 T cells was specifically observed in HCV and/or HBV positive HCC and advanced HCC. γδ2 T cell is one of the nine cell types that are associated with HCC prognosis. The analysis of multiple independent datasets confirmed that γδ2 T cells enrichment is more associated with poor prognosis in patients with lower Alpha-fetoprotein (AFP) level and HCV/HBV positive patients. Following pan-cancer analysis suggested enrichment of γδ2 T cells is associated with poor prognosis in kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and low grade gliomas. In addition, this type of cells is also enriched in the blood samples of various chronic liver diseases and HCC, indicating the potential of being diagnostic markers. In summary, the integrative bioinformatics analysis identified γδ2 T cells as a marker for HCC progression. Citation Format: Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen. Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development [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 461.
食道癌(EC)の限局的な化学放射線療法(CRT)後の局所制御不全における内視鏡サルベージ治療
Authors: Muto M, Hattori S, Yano T, Minashi K, Hamamoto Y, Mera K, Doi T, Ohtsu A, Yoshida S
Journal: Journal of Clinical Oncology (2005)
Abstract 1306: Primary NK cells and luciferase expressing reporter cell lines for use in developing ADCC assays for immuno-oncology drug screening
Authors: Haiyun Liu, Brian Della Fera, John Foulke, Luping Chen, Fang Tian
Journal: Cancer Research (2021)

Abstract Immuno-oncology is one of the fastest growing fields in oncology, and cancer immunotherapy in recent years represents a milestone in the treatment of cancer. Natural killer (NK) cells are potent innate effectors capable of targeting and killing virally infected and malignant cells. The use of monoclonal antibodies (mAbs) targeting tumor antigens triggers antibody-dependent cellular cytotoxicity (ADCC) by NK cells, which has shown prominent clinical efficacy in clearing tumors in cancer patients. Therefore, the development of tumor cell targeting mAbs and biologics dictate a clear need for human cell-based models to evaluate antibody efficacy. In this study, human PBMCs and purified NK cells from healthy donors are used to develop an ADCC assay. The NK cells purified from PBMCs are &amp;gt;90% CD45+ CD56+, express high levels of CD16, and NK activation markers such NKG2A, KIR2DL1, NKp44 upon activation. The activated NK cells exhibit both strong direct and antibody-dependent cytotoxicity. Genotyping for FcγRIIIa receptor F and V variant is also performed for cells isolated from different donors, which is the genetic polymorphism that affects ADCC response. In addition, we employ a portfolio of luciferase reporter tumor cell lines to evaluate NK cell direct killing and ADCC targeted killing. These include K562, Wil2S, BT474, A431, A375 parental, and CRISPR edited A375 KRAS mutant cell lines engineered to express luc2 reporter. The commonly targeted cell surface markers, such as CD20, Her2, and EGFR, are highly expressed within this panel of target tumor cell lines. We validate the ADCC assay system through testing the efficacy for some of the well-known mAb biologics such as anti-CD20, anti-HER2, and anti-EGFR. After co-culture of activated primary NK cells with luciferase reporter target cell lines and the addition of dilutions of ADCC and isotype control antibodies, we are able to show target cell specific and dose-dependent killing effects. The luciferase reporter provides great convenience in measuring target cell killing without having to use radioactive 51Cr release assay or pre-label the cells with calcein. This data demonstrates the utility of primary NK cells along with a portfolio of well characterized luciferase reporter tumor cell line to develop “custom” designed ADCC assays for studying NK cell immune response and screening for biological drugs for cancer immunotherapy. Citation Format: Haiyun Liu, Brian Della Fera, John Foulke, Luping Chen, Fang Tian. Primary NK cells and luciferase expressing reporter cell lines for use in developing ADCC assays for immuno-oncology drug screening [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 1306.
Intramyocardial delivery of human cardiac stem cell spheroids with enhanced cell engraftment ability and cardiomyogenic potential for myocardial infarct repair
Authors: Min Ah Han, Jeong Hwa Jeon, Ji Young Shin, Hee Jung Kim, Ji Soo Lee, Chae Won Seo, Ye Jin Yun, Mi Yun Yoon, Jong Tae Kim, Young Il Yang, Seung Jin Lee
Journal: Journal of Controlled Release (2021)
A predictive tool for clinically significant prostate cancer detection in men with prostate cancer suspicion
Authors: J. Morote, M. Triquell, A. Borque, L.M. Esteban, A. Celma, S. Roche, I. De Torres, R. Mast, M.E. Semidey, L. Regis, A. Santamaría, J.M. Abascal, C. Solà, P. Servián, D. Salvador, J. Planas, E. Trilla
Journal: European Urology (2021)
Abstract LB098: Vulnerability of <i>MTAP</i>-deleted nasopharyngeal carcinoma to MAT2A inhibition
Authors: Yuk Yu Chan, Jeff P. Bruce, Vivian W.Y. Lui, Grace T. Y. Chung, Sai-Wah Tsao, Ka-Fai To, Trevor J. Pugh, Kwok-Wai Lo
Journal: Cancer Research (2021)

Abstract Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer prevalent in Southern China and Southeast Asia. We have generated a comprehensive genomic profile of NPC using whole-genome sequencing (WGS) and established a catalogue of somatic alterations of this EBV-associated cancer. In addition to the significantly mutated genes reported in previous WES studies, our WGS study revealed recurrent structural variants (SVs) and copy number variants (CNVs) driving key oncogenic pathways, including cell cycle, NF-kappaB and TGF-beta signaling. While immediately druggable gene aberrations (e.g. PIK3CA mutations and FGFR3-TACC3 fusions) are found in only ~3-5% of NPC, a synthetic lethality-based target, homozygous deletion of MTAP defined by fine-mapping of CDKN2A/CDKN2B deletion breakpoints at chromosome 9p21.3 was frequently detected (34%). Notably, the study has also revealed mutual exclusivity among tumors with MTAP deletion and TP53 alterations (p=0.022). Loss of MTAP has further been validated in a cohort of advanced and recurrent tumors (16/50, 32%) by FISH analysis and immunohistochemistry staining. The high prevalence and clonal nature of MTAP deletion in NPC implicate synthetic lethal targeting of MTAP-deleted tumors as a potential precision treatment for NPC patients. Using a CRISPR-based MTAP-knockout cell line and MTAP-deleted patient derived xenograft (PDX), we revealed that MAT2A and PRMT5 inhibition selectively suppressed growth of MTAP-deleted NPC. Treatment with MAT2A inhibitor, FIADS-5, led to depleted PRMT5 activity and reduced symmetric arginine methylation (SAMe) in these in vitro and in vivo NPC models. In addition to selective growth inhibition, MAT2A inhibition also targeted various unique oncogenic properties in NPC. The FIADS-5 treatment was shown to induce TP53 and BAX expression, cellular differentiation and keratinization in these MTAP-deleted NPC. Our findings demonstrated the translational potential of targeting MTAP-deletion in this EBV-associated epithelial cancer. Citation Format: Yuk Yu Chan, Jeff P. Bruce, Vivian W.Y. Lui, Grace T. Y. Chung, Sai-Wah Tsao, Ka-Fai To, Trevor J. Pugh, Kwok-Wai Lo. Vulnerability of MTAP-deleted nasopharyngeal carcinoma to MAT2A inhibition [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 LB098.
Abstract 442: Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189
Authors: Shirish Gadgeel, Jhanelle Grey, Maria Teresa Rizzo, Patrick Peterson, Jongseok Kim, Delvys Rodríguez-Abreu
Journal: Cancer Research (2021)

Abstract Background: Pemetrexed (pem) and platinum (plat) plus pembrolizumab (pembro) showed clinical improvement in metastatic nonsquamous (NSQ) non-small-cell lung cancer (NSCLC). The aim of this analysis was to assess the clinical benefit of pem+plat+pembro in patients by tumor burden at baseline. Methods: The intention-to-treat population was analysed. Patients were randomized pem+plat+pembro (n=410) or pem+plat+placebo (n=206). The data cut-off date was May 20, 2019. OS, PFS, PFS-2, and ORR were evaluated by Kaplan-Meier and univariate Cox methods within subgroups identified by extent of distant metastasis (M1a vs. M1b), median number (≤3 vs. &amp;gt;3) of organ systems with lesions, and severity score of patient-reported symptoms (below median vs. above median) at baseline. These subgroup analyses were also replicated within PD-L1 TPS subgroups (&amp;lt;1%, 1-49%, ≥50%). Results: A consistent benefit in OS, PFS, PFS-2 and ORR was observed in the pem+plat+pembro treatment arm, compared to the pem+plat+placebo arm, irrespective of staging (M1a vs. M1b), number (≤ 3 vs. 3) of organ systems with lesions and severity of patient-reported symptoms (Table 1). Results by PD-L1 expression in the subgroups were generally consistent regardless of the level of expression. Conclusions: Pem+plat+pembro demonstrated consistent clinical benefit across all subgroups analysed regardless of baseline tumor burden. These results continue to support pem+plat+pembro as a standard of care in metastatic NSQ-NSCLC. TABLE 1.OS, PFS, PFS-2, and ORR in subgroups by tumor burden at baselineTreatment armsNaOSPFSPFS-2ORRHRHRHROdds ratioM1aPembro1230.540.480.572.66Placebo53M1bPembro2850.580.510.504.21Placebo152≤ 3b organ systems with lesionsPembro2350.490.410.436.00Placebo118&amp;gt; 3b organ systems with lesionsPembro1750.670.590.601.80Placebo88≤ medianc severity score of symptomsPembro1700.510.490.432.72Placebo82&amp;gt; medianc severity score of symptomsPembro1870.600.480.554.04Placebo97a.There were 3 patients with missing data for M1a and M1bb.Median number of organ systems with lesions was 3. Lesions include the primary tumorc.Median score = 122.2, based on six questions from the patient-reported LC-13 instrument Citation Format: Shirish Gadgeel, Jhanelle Grey, Maria Teresa Rizzo, Patrick Peterson, Jongseok Kim, Delvys Rodríguez-Abreu. Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189 [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 442.
Added value of randomized biopsy to mpMRI-targeted biopsy of the prostate: 5-year experience from a community-based urologic outpatient clinic
Authors: M. Chaloupka, P. Pfitzinger, R. Bischoff, L. Rath, A. Buchner, B. Schlenker, D-A. Clevert, C.G. Stief, M. Apfelbeck
Journal: European Urology (2021)
Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407
Authors: Steven F. Powell, Delvys Rodríguez-Abreu, Corey J. Langer, Ali Tafreshi, Luis Paz-Ares, Hans-Georg Kopp, Jeronimo Rodríguez-Cid, Dariusz M. Kowalski, Ying Cheng, Takayasu Kurata, Mark M. Awad, Jinaxin Lin, Bin Zhao, M. Catherine Pietanza, Bilal Piperdi, Marina C. Garassino
Journal: Journal of Thoracic Oncology (2021)

IntroductionThis exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone.MethodsWe pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain.ResultsA total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without.ConclusionsWith or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.
Efficacy and safety of marginal grafts from Expanded Criteria Donor (ECD) and Donation after Circulatory Death (DCD) in elderly recipients
Authors: A. Dominguez, M. Ruiz Hernández, V. Gómez Dos Santos, J.A. López Plaza, C. Sánchez Guerrero, F.J. Burgos Revilla
Journal: European Urology (2021)