tbuckley/cabot-search huggingface dataset:
Development and validation of a novel disease risk model for patients with AML receiving allogeneic hematopoietic cell transplantation.
Authors: Piyanuch Kongtim, Omar Hasan, Jorge Miguel Ramos Perez, Ankur Varma, Julianne Chen, Gabriela Rondon, Samer Srour, Qaiser Bashir, Muzaffar H. Qazilbash, Rohtesh Mehta, Elizabeth J. Shpall, Amin Majid Alousi, Issa F. Khouri, Partow Kebriaei, Uday R. Popat, Richard E. Champlin, Stefan O. Ciurea
Journal: Journal of Clinical Oncology (2019)

7016 Background: Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in AML patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific Disease Risk Group (AML-DRG) and revise our previously developed Hematopoietic Cell Transplant - Composite Risk (HCT-CR) model by incorporating molecular data and MRD status before transplant to predict post-transplant outcomes of patients with AML. Methods: The study included 1414 consecutively treated adult AML patients, who received first AHCT between 1/2005-8/2018 at our institution. Patients were randomly assigned into a training (N = 944) and validation set (N = 470). To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox’s regression analysis (MVA) in a training dataset was converted into scores.The AML-DRG was the sum of scores from all significant covariates, while the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. Results: Based on results of MVA, the following scores were assigned to each AML-related variable; 1 point to secondary AML; 1 point to the 2017 ELN adverse risk; 2 points to CR with MRD positive/unknown; and 4 points to active disease at transplant. These were used to generate the AML-DRG (low-risk score 0-2; intermediate-risk score 3-4; and high-risk score &gt; 4) with significantly different OS with HR of 2.02 (P &lt; 0.001), and 3.85 (P &lt; 0.001) for intermediate and high risk group compared with low risk group. By adding 1 point for patients &gt; / = 60 years or HCT-CI &gt; 3 to the AML-DRG, we created 4 risk groups of AML-HCT-CR (low-risk: score 0-2; intermediate-risk: score 3; high-risk: score 4 and very high-risk: score ≥5) with distinct survival outcomes. The AML-DRG and AML-HCT-CR model had C-index of 0.672 and 0.715, respectively which were better compared with DRI, ELN2017 and cytogenetic risk model. Conclusions: Prognostic models incorporating molecular data and MRD status before transplant allow better stratification and improved survival estimates of AML patients post-transplant.
Abstract 47: Analyzing immune cell infiltration of cancer spheroids in a 3D cell culture platform
Authors: Sei Hien Lim, Chee Mun Kuan, Marco Campisi, Valeria Chiono, Andrea Pavesi
Journal: Cancer Research (2019)

Abstract The adoption of in vitro 3D cell culture models as a bridge between conventional 2D cell culture models and the complex in vivo animal models has been increasing. A carefully designed 3D model can run biological assays with animal model-like complexities but with the simplicity and affordability of traditional cell culture. For example, traditional 2D and transwell assays of immune cell infiltration efficiency are unrealistic, as cell migration is gravity-driven. AIM 3D cell culture chips offer a more realistic immune cell infiltration model by compartmentalizing immune cells and cancer spheroids in parallel channels. The chips consist of a 3D hydrogel channel and two flanking media channels. Cancer spheroids are cultured within the hydrogel channel while immune cells are seeded in one of the media channels. The seeded immune cells are required to actively invade and seek out target cancer cells in 3D hydrogel in AIM chips before they can infiltrate the cancer spheroids. This is a process similar to immune cell infiltration in vivo. By utilizing high content confocal imaging, fluorescent-labeled immune cells that migrate into the 3D hydrogel can be visualized and quantified. This assay, in combination with adoptive T cell therapy or immune checkpoint blockade, can determine the roles of tumor infiltrated lymphocytes in immunotherapy through quantifying the live: dead ratio of cancer spheroids in the chips. This is particularly useful as a quality control tool for cellular adoptive immunotherapy where the infiltration efficiency and tumoricidal activity of engineered immune cells can be accessed in vitro. In summary, AIM 3D cell culture chips create a more physiologically relevant 3D microenvironment for visualizing immune cell infiltration of cancer spheroids. Citation Format: Sei Hien Lim, Chee Mun Kuan, Marco Campisi, Valeria Chiono, Andrea Pavesi. Analyzing immune cell infiltration of cancer spheroids in a 3D cell culture platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 47.
Abstract 2816: SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME
Authors: Hyo Young Kim, Hee-Jung Kim, Jae Hoon Jung, So Young Jo, Ju Hee Kim, Wansang Cho, Mingi Kim, Junhyeong Yim, Seung Bum Park
Journal: Cancer Research (2019)

Abstract Although stage I melanoma is highly curable, the prognosis of late stage melanoma is poor and treatment options are limited to immune checkpoint modulators (ICMs). In this study, we synthesized a novel small molecule, SB1703, and identified high-mobility group box (HMGB) proteins as the direct binding target proteins. SB1703 inhibited melanoma growth in B16F10 syngeneic mouse model. To elucidate the tumor growth inhibitory mechanism, we determined the changes in myeloid-derived suppressor cell (MDSC) number during drug treatment. MDSCs expand in disease states such as cancer and have immune suppressive functions. Serum HMGB1 and interleukin (IL)-6 levels were increased in vehicle administered mice and decreased in SB1703 administered mice. We examined the possibility of combinatorial treatment with SB1703 and ICMs. SB1703 showed synergistic effect with ICMs. In conclusion, SB1703 exhibited therapeutic effects against melanoma in both single and combination treatments with ICMs, which might be due to modulation of myeloid cells such as MDSCs Citation Format: Hyo Young Kim, Hee-Jung Kim, Jae Hoon Jung, So Young Jo, Ju Hee Kim, Wansang Cho, Mingi Kim, Junhyeong Yim, Seung Bum Park. SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2816.
Abstract 4992: The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis
Authors: Xu Yang, Dongxu Wang, Jianzhen Lin, Jianping Xiong, Junyu Long, Yi Bai, Jin Bian, Hanchun Huang, Xiaobo Yang, Yilei Mao, Xinting Sang, Haitao Zhao
Journal: Cancer Research (2019)

Abstract Introduction: Immune-related adverse events (irAEs) were mostly induced by immune checkpoint blockade (ICB) and were associated with the immune response. Whether irAEs are associated with clinical benefits during ICB treatment in cancer patients remains unclear. This systematic review and meta-analysis aimed to investigate the relationship between irAEs and clinical efficacy. Methods: We systemically searched and selected irAEs and clinical outcome data from cancer patients treated with ICB in the PubMed, Embase, and Cochrane Central Trial databases up to July 26, 2018. Keywords used for the search included PD-1, PD-L1, CTLA-4, immune checkpoint and immune-related adverse events. The relationships between the occurrence of irAEs and the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed using relative risk (RR) or hazard ratio (HR) values and 95% confidence intervals (CIs) in random-effect models. Results: Nineteen eligible observational articles were included in this systematic review and fourteen studies including 3022 participants (1264 with irAEs and 1758 with non-irAE) were included in our meta-analysis. The occurrence of irAEs was significantly associated with higher ORR (RR = 2.36, 95% CI: 1.85-3.02; P &amp;lt; 0.001), better PFS (HR = 0.48, 95% CI: 0.26-0.70; P &amp;lt; 0.001), and longer OS (HR = 0.42; 95% CI = 0.18-0.67; P = 0.001) than those in the non-irAE group. Subgroup analysis showed that the effect size of ORR in anti-PD-1 therapy (RR = 2.68, 95% CI, 2.21-3.26) was inferior to that of the anti-CTLA-4 therapy (RR = 1.91, 95% CI, 0.44-8.32). The meta-regression models also found that ICB type (anti-CTLA-4 or anti-PD-1) were associated with significant heterogeneity (P = 0.005). Conclusion: In conclusion, irAEs indicate greater ORR, PFS and OS than non-irAEs in ICB treatment, and the relationship in anti-PD-1 therapy was stronger than in anti-CTLA-4 therapy. With appropriate management of irAEs, the clinical predictor, continued treatment may be possible to maximize its potential ICB benefits. Note: This abstract was not presented at the meeting. Citation Format: Xu Yang, Dongxu Wang, Jianzhen Lin, Jianping Xiong, Junyu Long, Yi Bai, Jin Bian, Hanchun Huang, Xiaobo Yang, Yilei Mao, Xinting Sang, Haitao Zhao. The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4992.
Abstract 19103: Prognosis and Prognostic Factors of Elderly Patients With Chronic Heart Failure: A Report From the CHART 2 Study
Authors: Masayuki Sato, Yasuhiko Sakata, Takuya Oikawa, Ruri Abe, Shintaro Kasahara, Hajime Aoyanagi, Masanobu Miura, Kotaro Nochioka, Takashi Shiroto, Jun Takahashi, Satoshi Miyata, Hiroaki Shimokawa
Journal: Circulation (2017)

Background: Chronic heart failure (CHF) in elderly patients has become an emerging healthcare issue in the current super-aging society. Thus, it is important to elucidate differences in prognosis a...
My Doctor Told Me I Have Fatty Liver—What Do I Need to Know?
Authors: Elizabeth S. Aby, Jihane N. Benhammou, James H. Tabibian
Journal: JAMA Internal Medicine (2019)

Dimitrios A. Koutoukidis, PhD; Nerys M. Astbury, PhD; Kate E. Tudor, PhD; Elizabeth Morris, BMBCh; John A. Henry, BA; Michaela Noreik, PhD; Susan A. Jebb, PhD; Paul Aveyard, PhD
Abstract LB-184: The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review
Authors: Daniel J. Lin, James C. Ng, Lei Huang, Max Robinson, James O'Hara, Janet A. Wilson, Andrew L. Mellor
Journal: Cancer Research (2019)

Abstract Background: Novel cancer immunotherapy includes application of immune checkpoint inhibitors to the treatment of solid tumors. The body’s own immune system is thereby harnessed to tip the balance in favor of antitumor activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumor microenvironment (TME) via tryptophan metabolism. Programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are immune checkpoints involved in T-cell inhibition and immunosuppression. Another immune checkpoint, IDO1, breaks down tryptophan into its metabolites which results in immunosuppression in the TME. Aim: To assess the evidence on IDO in head and neck squamous cell carcinoma (HNSCC). Methods: Medline, EMBASE using Ovid, Scopus, Web of Science, Cochrane Library databases, and ClinicalTrials.gov were searched from inception until present day. Results: We included 32 studies. Of those, 5 involved cell lines, 7 assessed tumor immunohistochemistry, 6 measured IDO gene transcription, and 14 reported on clinical trials. The human cell lines studied commonly were SCC4, SCC15, and SCC25 in which IDO expression and activation by the Stimulator of Interferon Genes (STING) pathway played a central role. Retrospective immunohistochemistry studies of lower lip, oral cavity, tongue, tonsil, and larynx found that relatively high IDO expression correlated with worse survival. Gene transcription studies showed increased IDO in tumors that expressed PD-L1 and harbored human papillomavirus (HPV). Phase I/II clinical trials showed 1) objective responses (34%) and disease control rates (62%) for IDO1 inhibitor in combination with a PD-1 inhibitor, 2) consistent safety profile in combination versus monotherapy, and 3) IDO gene expression as a predictive biomarker for response to PD-L1 therapy. Conclusions: IDO is integral to TME immunity in HNSCC particularly in HPV positive tumors, modulating existing therapies and application in combinatorial immunotherapy. Retrospective studies have shown the presence of IDO in the TME and suggest a link to prognosis and prediction of HNSCC treatment outcome. However, the exact mechanism of IDO-driven immune modulation in the HNSCC TME remains unclear. We now require prospective longitudinal studies to track IDO activity and expression throughout HNSCC treatment, thence optimise IDO-based immunotherapy. Citation Format: Daniel J. Lin, James C. Ng, Lei Huang, Max Robinson, James O'Hara, Janet A. Wilson, Andrew L. Mellor. The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-184.
Abstract 4666: p21CIP1 promotes mammary cancer initiating cells via activation of Wnt/TCF1/CyclinD1 signaling
Authors: Rachel B. Hazan
Journal: Cancer Research (2019)

Abstract Cancer stem cells (CSCs) generate and sustain tumors due to tumor initiating potential, resulting in recurrence or metastasis. We showed previously that knockout of the cell cycle inhibitor, p21CIP1, in the PyMT mammary tumor model, inhibits metastasis; however the exact mechanism remained unknown. Here, we show a pivotal role for p21 in potentiating a cancer stem cell-like phenotype. p21 knockout in PyMT mammary tumor cells suppressed tumorsphere formation, ALDH1 expression, and tumor initiating potential, that were in turn rescued by p21 overexpression. Consistent with these effects, p21 loss caused mesenchymal to epithelial transition that was accompanied by downregulation of Slug, Sox9, basal keratins and upregulation of luminal keratins and Claudin-3. Furthermore, p21 knockout suppressed Wnt/β-catenin signaling which was due to TCF1 downregulation. In turn, TCF1 knockdown in PyMT cells, attenuated Wnt signaling and tumorsphere formation. Interestingly, p21 rescue in p21 knockout cells, caused dramatic upregulation of Cyclin D1, consistent with known inhibition of Cyclin D1 nuclear export by p21. These data suggest that p21 promotes a cancer stem like phenotype via Wnt-TCF1 signaling along with direct upregulation of Cyclin D1 by p21. Citation Format: Rachel B. Hazan. p21CIP1 promotes mammary cancer initiating cells via activation of Wnt/TCF1/CyclinD1 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4666.
Abstract 1741: Identification of microsatellite instability in hematologic malignant cell lines
Authors: Priyanjali Bhattacharya, Naveed Anjum Chikan, Arati Sharma, Dhimant Desai, Charyguly Annageldiyev, Pinaki Patel, Trupti N. Patel
Journal: Cancer Research (2019)

Abstract Defective DNA repair machinery which is a consequence of chromosomal or molecular alterations is associated with variety of diseases including solid tumors. Cytogenetic analysis is an important tool in diagnosis and treatment of hematologic malignancies. Our aim is to understand the role of microsatellite instability in initiation and progression of blood cancers. Here we hypothesize that leukemogenic cells may carry defective repair mechanisms that contribute to other genomic instabilities. In order to explore the possible role of microsatellite instability (MSI) in leukemia and lymphoma, eight different DNA repair genes involved in mismatch repair (MMR) and direct reversal of damage (DRD) were analyzed in K562 (CML), Molt-4 (T-ALL) and Daudi (Burkitt’s lymphoma) cell lines. Fragment analysis was carried out using novel primers considering repeat motifs enriched with (A)n, (CA)n and (AT)n for instability. Almost all the cell lines showed moderate to high level of microsatellite instability and exhibited a shift in selected repeat regions indicating possible loss (66.7%) (MSH2, MSH4, MSH6, MLH1, MLH3, PMS1) or gain (25%) (MSH3, MGMT) of nucleotide repeats as compared to normal DNA. The K562, Philadelphia negative CML cell line appeared to be microsatellite stable (MSS) for genes MSH2 and MLH1. Treatment induced microsatellite instability is known in leukemic patient cells as also seen in Molt-4 cells. Our present and previous observations suggest that MSI is a non-random event in leukemia/lymphoma which needs confirmatory future studies in newly diagnosed untreated patient samples. Considering the fact that both MSI and MSS represents two distinct molecular pathways of carcinogenesis, assessment of MSI, if added as distinct diagnostic criteria, can possibly refine early detection and help in identifying novel targets in management of hematologic malignancies. Citation Format: Priyanjali Bhattacharya, Naveed Anjum Chikan, Arati Sharma, Dhimant Desai, Charyguly Annageldiyev, Pinaki Patel, Trupti N. Patel. Identification of microsatellite instability in hematologic malignant cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1741.
Abstract 3532: Tumor mutational burden (TMB) assessment and variant detection using an ultra-high multiplexed 20,000 amplicons NGS panel via a rapid 4 hour workflow
Authors: Kathryn E. Pendleton, Yang L. Liu, Lifeng Lin, Lucie S. Lee, Jeffery Liu, Guoying Liu, Zhitong Liu
Journal: Cancer Research (2019)

Abstract Tumor mutational burden (TMB) is currently of high interest in the field of immuno-oncology due to its correlation with patient response to checkpoint inhibitor chemotherapy. Traditionally, TMB is calculated using whole exome sequencing; however, targeted sequencing approaches provide better coverage of the genetic regions of interest at lower costs. While hybrid-capture based target enrichment methods are well-established, the 2-5 day workflows are time consuming and require specialized equipment and highly trained operators. Here we present an ultrafast, 4-hour method for preparing target enriched NGS libraries for assessing TMB that would streamline and lower the cost of immuno-oncology studies. This multiplex-PCR-based technology provides a highly efficient, accurate and robust method for unbiased enrichment of tens of thousands of target regions while minimizing non-specific primer-primer interactions and GC bias and maximizing coverage uniformity. We demonstrate this using a highly-multiplexed prototype NGS panel that contains ~20,000 amplicons and covers 355 genes for assessment of TMB. Sequencing-ready NGS libraries were prepared using the Paragon Genomics CleanPlex® target enrichment technology. The 3-step workflow combines target enrichment and NGS library preparation. The protocol includes an ultra-high multiplex PCR step to amplify regions of interest with target-specific primers, a background cleaning step to remove non-specific PCR products, and a final PCR to add Illumina sequencing adapter and sample indexes. Libraries were made using 20ng of genomic DNA and sequenced on an Illumina NextSeq® platform. Sequencing metrics such as on-target rates were calculated, and variants were identified using Paragon Genomics’ variant calling algorithm. Using the CleanPlex technology, this prototype TMB panel exhibits &amp;gt;95% uniformity at 0.2X mean, limited GC bias, and &amp;gt;94% detection rate for mutants with 5% allele frequencies. The CleanPlex background cleaning step was essential for removing the undesirable byproducts of the multiplexed reaction step. CleanPlex technology demonstrates that it is capable of creating high quality amplicon libraries with high uniformity, low GC bias, and sensitive variant calling even in ultra-multiplexed libraries with ~20,000 amplicons with a workflow under 4-hours. Citation Format: Kathryn E. Pendleton, Yang L. Liu, Lifeng Lin, Lucie S. Lee, Jeffery Liu, Guoying Liu, Zhitong Liu. Tumor mutational burden (TMB) assessment and variant detection using an ultra-high multiplexed 20,000 amplicons NGS panel via a rapid 4 hour workflow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3532.
Cross‐sectional screening study for <i>Leishmania</i> <scp>DNA</scp> and antibodies in biologic‐treated patients with psoriasis living in an area endemic for leishmaniasis
Authors: P.S. Kurizky, C.M. Gomes, M.V. Cesetti, G.A. Martins, N.A.T. Regattieri, F.F. Marianelli, L. Sevilha Santos, V. Medeiros Silva, N.A. Paula, M.A.C. Frade, E.F. Silva, L.M.H. Mota
Journal: British Journal of Dermatology (2019)
2018 年英国皮肤科医师协会关于儿童和青少年史蒂文斯‐约翰逊综合征/中毒性表皮坏死松解症治疗指南
Authors: T. McPherson, L.S. Exton, S. Biswas, D. Creamer, P. Dziewulski, L. Newell, K.L. Tabor, G.N. Wali, G. Walker, R. Walker, S. Walker, A.E. Young, M.F. Mohd Mustapa, R. Murphy
Journal: British Journal of Dermatology (2019)

斯蒂文斯‐约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 是一种紧迫的、严重的免疫反应,它们可能会引起口腔、眼睛和生殖器部位的皮肤脱落和严重溃疡。在英国,每年每 1 百万 18 岁以下的人群中就有 5‐6 人受到这种疾病的影响。它的死亡率(导致死亡的)为 5‐10%,而幸存者中的复发率高达 18%。 英国皮肤科医师协会领导了一组相关专家,在制定帮助儿童和年轻人诊断和管理 SJS/TEN 的指南的过程中,对这些证据进行了研究。就像许多罕见的情况一样,很少有对比两种治疗方法的高质量的试验。大多数证据来自医学文献(即医学期刊)中报道的患者实例。 本研究揭示了儿童和成人在 SJS/TEN 的病因和转归方面的一些重要差异。感染在儿童和年轻人中是一个更常见的原因,而药物治疗可能是所有年龄段的原因。儿童死于 SJS/TEN 的可能性比成人小。预防长期并发症至关重要。 早期阶段的管理应确保识别病因,停止可能是病因的任何可能的药物治疗,并考虑感染作为触发因素。改善转归的最佳证据是在适当的临床环境中提供的良好支持性护理。这需要入住有皮肤脱落管理经验的适当专科病房,以及一个能够处理所有潜在临床并发症的医院专家团队。 更长期的治疗包括支持患者及其家属解决那些影响眼睛、皮肤、肺部和心理的并发症。 该指南强调,关于管理这种潜在破坏性反应的最佳方法仍有许多未知之处,并指出需要更好的常规数据收集、诊断和标准化治疗,以及一种多学科(涉及不同类型的医疗保健服务工作者)的管理方法。