scholarly journals Immune-Depleted Tumor Microenvironment Signature Is Associated with BTK Inhibitor Resistance in Mantle Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1321-1321
Author(s):  
Preetesh Jain ◽  
Krystle Nomie ◽  
Vitaly Segodin ◽  
Evgeniy Egorov ◽  
Yixin Yao ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Stock Options ◽  
Research Funding ◽  
Immune Cell ◽  
Cancer Center ◽  
Rna Seq ◽  
Sequencing Data ◽  
Mutation Profile ◽  
Mantle Cell ◽  
Privately Held

Abstract Background - The tumor microenvironment (TME) plays a vital role in the growth and survival of mantle cell lymphoma (MCL) cells. However, characterization of the TME transcriptomic profile in MCL, its prognostic impact and response to Bruton's tyrosine kinase inhibitors (BTKi) is unknown. Unlike other lymphomas, the TME in MCL patients has not been fully characterized at the transcriptomic and genomic levels. To further understand the relevance of tumor-immune landscape in tissue microenvironments in the context of BTKi, we performed multi-omic profiling of the TME in tissues from MCL patients. Methods - Tissue biopsies were collected from MCL patients treated with BTKi. The study was conducted under an Institutional Review Board-approved protocol at The University of Texas MD Anderson Cancer Center. A total of 42 patients treated with BTKi were included. Among evaluable patients, DNA and RNA extraction was performed from fresh biopsies from lymph nodes and non-nodal tissues (including bone marrow). Whole exome (WES) and bulk RNA sequencing (RNA-seq) were performed to assess the somatic mutation profile, copy number abnormalities and gene expression profile to identify TME gene clusters. RNA sequencing data from an independent cohort of MCL patients from Scott et al (n = 122) was analyzed. Joint WES and RNA-seq, mutation calling, expression analysis, and cell type deconvolution from the transcriptome were performed using the BostonGene automated pipeline. Overall survival was calculated after starting BTKi therapy. Results - We obtained 42 MCL tissue samples (28 lymph nodes, 13 various tissues and one bone marrow) from patients treated with BTKi. Samples were obtained at/after starting treatment with BTKi at clinical progression. Unsupervised clustering based on the activities of the proposed transcriptomic signatures identified four distinct MCL subtypes based on tumor-immune cell gene signatures. We identified the four distinct MCL microenvironment signatures - normal lymph node like (N; n = 27), immune cell-enriched or "Hot" (IE; n = 46), mesenchymal (M; n = 44) and immune depleted/deserted or 'cold' (D; n = 51). The tumor proliferation rate signature and PI3K pathways were significantly overexpressed in immune-depleted (D) TME group. Evaluable patients were further classified based on response to BTKi as sensitive (n = 17), primary resistant (n = 11) or acquired resistant (n = 11). The TME was further dichotomized into immune cell rich and immune desert categories based on commonly involved immune cells and pathways. BTKi resistant MCL primarily exhibited immune depleted TME subtype. To explore the somatic mutation profile in relation to TME clusters, we performed a multiomic analysis combining WES data with RNA sequencing data and depicted according to the four TME clusters. Somatic mutations in TP53, NSD2, NOTCH1, KMT2D, SMARCA4, which were previously reported in ibrutinib-resistant MCL and/or in refractory high-risk MCL patients, were predominant in the immune-depleted TME cluster (D). Conclusions - Overall, we defined BTKi sensitivity and resistance by immune-hot and immune-cold TME portraits, respectively. The immune-depleted TME subtype (D) was characterized by dominant proliferation gene signature, overexpressed PI3K pathway, BTKi resistance and poor outcomes in MCL patients. Disclosures Jain: Lilly: Consultancy; kite: Consultancy. Nomie: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Segodin: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Egorov: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Vega: CRISPR Therapeutics and Geron: Research Funding; i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding. Svekolkin: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Frenkel: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Attaulakhanov: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Sanofi: Research Funding; Amgen: Research Funding; EMD: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Denovo: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Epizyme, Inc.: Consultancy; Morphosys: Research Funding; Genmab: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy; Kite: Research Funding; Guardant: Research Funding; SeaGen: Consultancy; Cellectis: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; Spectrum: Consultancy; Acerta: Research Funding; 4D: Research Funding; Pharmacyclics: Research Funding. Wang: BGICS: Honoraria; Newbridge Pharmaceuticals: Honoraria; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mumbai Hematology Group: Honoraria; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Loxo Oncology: Consultancy, Research Funding; Moffit Cancer Center: Honoraria; Lilly: Research Funding; Bayer Healthcare: Consultancy; OMI: Honoraria; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Clinical Care Options: Honoraria; Dava Oncology: Honoraria; CStone: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding.

scholarly journals IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Pravesh Gupta ◽  
Minghao Dang ◽  
Krishna Bojja ◽  
Tuan Tran M ◽  
Huma Shehwana ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Wild Type ◽  
Sequencing Data ◽  
Human Gliomas ◽  
Cell Clusters ◽  
Recurrent Gliomas ◽  
Antigen Presenting

Abstract The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

scholarly journals The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Xuefei Liu ◽  
Ziwei Luo ◽  
Xuechen Ren ◽  
Zhihang Chen ◽  
Xiaoqiong Bao ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Malignant Cells ◽  
Sequencing Data ◽  
Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

scholarly journals Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4997-4997
Author(s):  
Surbhi Shah ◽  
Shuchi Gulati ◽  
Ang Li ◽  
Julie Fu ◽  
Vaibhav Kumar ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Tumor Board ◽  
Bleeding Complications ◽  
Advisory Committees ◽  
Icu Admission ◽  
Patients With Cancer ◽  
Privately Held

Abstract Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Two-Stage Poisson Model for Testing RNA-Seq Data

2011 ◽  
Vol 10 (1) ◽  
Author(s):  
Paul L. Auer ◽  
Rebecca W Doerge
Keyword(s):  
Rna Sequencing ◽  
Statistical Approach ◽  
Poisson Model ◽  
Real Data ◽  
Rna Seq ◽  
Sequencing Data ◽  
Sequencing Technology ◽  
Two Stage ◽  
Individual Gene ◽  
Unique Nature

RNA sequencing technology is providing data of unprecedented throughput, resolution, and accuracy. Although there are many different computational tools for processing these data, there are a limited number of statistical methods for analyzing them, and even fewer that acknowledge the unique nature of individual gene transcription. We introduce a simple and powerful statistical approach, based on a two-stage Poisson model, for modeling RNA sequencing data and testing for biologically important changes in gene expression. The advantages of this approach are demonstrated through simulations and real data applications.

scholarly journals SimFuse: A Novel Fusion Simulator for RNA Sequencing (RNA-Seq) Data

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Yuxiang Tan ◽  
Yann Tambouret ◽  
Stefano Monti
Keyword(s):  
Sample Size ◽  
Rna Sequencing ◽  
High Throughput Sequencing ◽  
Performance Metrics ◽  
Simulated Data ◽  
Real Data ◽  
Rna Seq ◽  
Sequencing Data ◽  
Detection Algorithms ◽  
Fusion Detection

The performance evaluation of fusion detection algorithms from high-throughput sequencing data crucially relies on the availability of data with known positive and negative cases of gene rearrangements. The use of simulated data circumvents some shortcomings of real data by generation of an unlimited number of true and false positive events, and the consequent robust estimation of accuracy measures, such as precision and recall. Although a few simulated fusion datasets from RNA Sequencing (RNA-Seq) are available, they are of limited sample size. This makes it difficult to systematically evaluate the performance of RNA-Seq based fusion-detection algorithms. Here, we present SimFuse to address this problem. SimFuse utilizes real sequencing data as the fusions’ background to closely approximate the distribution of reads from a real sequencing library and uses a reference genome as the template from which to simulate fusions’ supporting reads. To assess the supporting read-specific performance, SimFuse generates multiple datasets with various numbers of fusion supporting reads. Compared to an extant simulated dataset, SimFuse gives users control over the supporting read features and the sample size of the simulated library, based on which the performance metrics needed for the validation and comparison of alternative fusion-detection algorithms can be rigorously estimated.

scholarly journals SSCC: a novel computational framework for rapid and accurate clustering large single cell RNA-seq data

2018 ◽  
Author(s):  
Xianwen Ren ◽  
Liangtao Zheng ◽  
Zemin Zhang
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Large Scale ◽  
Random Projection ◽  
Rna Seq ◽  
Sequencing Data ◽  
Computational Framework ◽  
Human Blood Cells ◽  
Single Cell Rna Sequencing ◽  
Data Volume

ABSTRACTClustering is a prevalent analytical means to analyze single cell RNA sequencing data but the rapidly expanding data volume can make this process computational challenging. New methods for both accurate and efficient clustering are of pressing needs. Here we proposed a new clustering framework based on random projection and feature construction for large scale single-cell RNA sequencing data, which greatly improves clustering accuracy, robustness and computational efficacy for various state-of-the-art algorithms benchmarked on multiple real datasets. On a dataset with 68,578 human blood cells, our method reached 20% improvements for clustering accuracy and 50-fold acceleration but only consumed 66% memory usage compared to the widely-used software package SC3. Compared to k-means, the accuracy improvement can reach 3-fold depending on the concrete dataset. An R implementation of the framework is available from https://github.com/Japrin/sscClust.

scholarly journals Heterogeneity of Minimal/Measurable Residual Disease (MRD) Practices in Adult B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in the United States

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4478-4478
Author(s):  
Juliana E. Hidalgo-Lopez ◽  
Gail J. Roboz ◽  
Brent Wood ◽  
Michael Borowitz ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
United States ◽  
Bone Marrow ◽  
Best Practices ◽  
Stock Options ◽  
Research Funding ◽  
The United States ◽  
Bone Marrow Sample ◽  
Sample Collection ◽  
Nccn Guidelines ◽  
Privately Held

Abstract Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These factors may impact the quality and reliability of MRD assessment. Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway. Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment. Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients. Figure 1 Figure 1. Disclosures Hidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.

scholarly journals Prevalence of Acute and Chronic Migraine Among Patients with Von Willebrand Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4245-4245
Author(s):  
Corey Macgregor ◽  
Travis Helm ◽  
Frank Cerasoli ◽  
Judith A. Boice ◽  
Robert F. Sidonio
Keyword(s):  
General Population ◽  
Chronic Migraine ◽  
Stock Options ◽  
Research Funding ◽  
Total Sample ◽  
Von Willebrand Disease ◽  
The Past ◽  
Age Of Diagnosis ◽  
Von Willebrand ◽  
Privately Held

Abstract Background: The prevalence of migraine in the general population is approximately 18% in females and 6% in males (Lipton, et. al. Headache 2001;41:646). Among migraineurs, 7-8% experience chronic migraines (CM) (Adams AM, et. al. Cephalalgia 2015;35:563). Von Willebrand factor (VWF), secreted from endothelial cells, is reported to be elevated in migraineurs and in particular during the course of migraine, although its role is unclear (Cesar, et. al. Acta Neurol Scand 1995;91:412; Tietjen, et. al. Neurology 2001;57:334; Tietjen, et. al. Cephalalgia 2018;38:511). Patients with Von Willebrand Disease (VWD) have low levels of or a defective form of VWF, which has led some to hypothesize a lower prevalence of migraine in the VWD population. Conversely, a retrospective case control study found that migraine in VWD patients (n=197) was 6 times more prevalent when compared with age- and sex-match healthy controls (n=197) (18% vs. 3%, respectively)(Hassan, et. al. Intl Journal of Hem, Blood Diseases and Disorders 2014;2:23-5). The current investigation was performed to further explore the relationship between migraine and VWD. Methods: A cross-sectional study was conducted in March 2021 using the InCrowd digital survey tool in which patients with self-reported diagnosis of VWD were invited to participate. The study included 75 VWD patients ≥18 years of age. Survey questions detailed VWD sub-type, gender, clinical diagnosis of migraine, medical specialty diagnosing migraine, migraine treatments, and age of diagnosis. The Lipton Identify Chronic Migraine (ID-CM) tool was used within the survey to identify patients who had experienced chronic migraine(Lipton, et al. Cephalalgia. 2016;36:203). Criteria for designation of chronic migraine from the ID-CM was either the combination of Frequency of Migraine and Symptoms or the combination of Use of Medication and Activity Avoidance. Results: The gender distribution of the 75 participants was 83% female and 17% male. The sub-type of VWD diagnosed was: Type 1 (57%), Type 2 (28%), Type 3 (15%). Fifty-seven percent (57%) of all VWD patients reported being diagnosed with migraine. Rates did not vary significantly by VWD sub-type. Diagnosed migraine was only slightly more common in females (60%, n=62) compared with males (46%, n=7). Average age of diagnosis was 22 years with a median of 17 years (n=43). Two clear clusters defined the age of diagnosis with migraine. The first was between ages 10 and 20 (n=24, 56% of total sample reporting age) and the second was approximately age 30 [28-32] (n=8, 19% of total sample reporting age). Migraine diagnosis was established by primary care physicians (44%), neurologists (44%) hematologists (9%), and headache specialists (2%). Only 4% of surveyed patients met the ID-CM criteria for chronic migraine, yet 71% of patients met the criteria for migraine symptoms. Chronic migraine diagnosis using the ID-CM tool requires a combination of headache frequency (at least half of the past 30 or 90 days), multiple migraine symptoms (present >rarely in the past 30 days), medication use for headache as well as interference with activities (≥10 of the past 30 days) and a headache that either interfered with plans or caused worry for making plans (>rarely in the past 30 days). Frequency of migraine was mentioned by 11% of patients and symptoms by 71%, medication use by 31%, activity limitation by 15%, and changing plans by 25%. Conclusions: This survey illustrates that migraine is significantly more common in people with VWD than in the general population, regardless of VWD sub-type. However, the age-associated incidence pattern follows a similar bimodal distribution as observed in the general population(Victor, et al. Cephalalgia. 2010;30:1065). Notably, the prevalence of diagnosed migraine in VWD males approaches the prevalence in VWD females and exceeds that of females in the general population (Lipton RB, et. al. Headache 2001;41:646). These results suggest a distinct etiology of VWD that makes affected patients more susceptible to migraine. Notably, migraine treatment options may be more limited for these patients, given that traditional NSAIDs are commonly used for fast-acting migraine relief, but their antiplatelet effects and potential for gastrointestinal bleeding make them undesirable in VWD. Further investigation of both the etiology and treatment for VWD migraine is warranted. Disclosures Macgregor: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Helm: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cerasoli: RX Medical Dynamics LLC: Consultancy, Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boice: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sidonio: Novo Nordisk: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Biomarin: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

scholarly journals Pre-Clinical Characterization of a Novel Fusion Protein (AT-03), with Pan-Amyloid Binding and Removal

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1207-1207
Author(s):  
Christophe Sirac ◽  
Arnaud Jaccard ◽  
Roussine Codo ◽  
Sebastien Bender ◽  
Gemma Martinez-Rivas ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Stock Options ◽  
Research Funding ◽  
Specific Binding ◽  
The Body ◽  
Al Amyloidosis ◽  
Patent Holder ◽  
Single Chain ◽  
Amyloid Deposits ◽  
Privately Held

Abstract Background: Amyloidosis is characterized by extracellular deposition of protein fibrils that can involve any organ or tissue in the body. It is a severe, progressive and often lethal disorder. There are approximately seventeen different systemic amyloid diseases, each associated with the deposition of a specific precursor protein. Toxic amyloid deposits result in significant organ dysfunction and increased morbidity and mortality. Reduction and removal of tissue amyloid deposits could restore organ function, improve quality of life and increase life expectancy for patients. We have developed and characterized a fusion protein consisting of serum amyloid protein (SAP) linked to a single chain human IgG1 Fc domain, designated AT-03. SAP is a pentameric serum protein that is ubiquitously associated with amyloid deposits. The high affinity and specificity for amyloid resulted in the use of radio-iodinated SAP as an imaging agent for the non-invasive detection of systemic amyloid. The SAP domain of the fusion protein targets the amyloid deposits delivering Fc domains to stimulate amyloid removal via macrophage mediated phagocytosis. Methods: Binding of AT-03 to ATTR and AL fibrils and extracts was assessed by ELISA. Ex vivo phagocytosis of amyloid substrates was studied using activated human THP-1 cells. The biodistribution of AT-03 in murine models of AA, AApoA2 and AL amyloidosis was evaluated immunohistochemically or by SPECT imaging and microautoradiography. Clearance of AA amyloidosis in response to AT-03 therapy was accessed in a mouse model using histological scoring of amyloid burden. Results: AT-03 bound amyloid AL and ATTR substrates with sub nanomolar EC50 values. Systemic administration of AT-03 resulted in specific binding to diverse forms of amyloid in the heart, kidney, liver and/or spleen in multiple animal models. Opsonization of amyloid deposits with AT-03 in vitro resulted in a dose dependent phagocytosis by activated THP-1 cells. A single IV dose of AT-03 resulted in significant reduction of splenic AA amyloid within 14 days post-injection. Conclusions: We have developed a novel fusion protein with sub nanomolar pan amyloid reactivity that specifically binds diverse forms of amyloid in multiple organs and tissues in vivo and can effectuate amyloid removal. The data indicates that AT-03 may serve as a novel therapeutic for the removal of systemic amyloid deposits of diverse types. AT-03 is currently being developed for clinical evaluation. Disclosures Sirac: Attralus, Inc: Patents & Royalties, Research Funding. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy. Bell: Attralus Inc: Current Employment. Guthrie: Attralus Inc: Current Employment. Selvarajah: Attralus Inc: Current Employment. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder. Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding.

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