tbuckley/cabot-search huggingface dataset:
A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.
Authors: Jacob Stephen Thomas, Diane Habib, Diana L. Hanna, Irene Kang, Syma Iqbal, Jorge J. Nieva, Denice Tsao-Wei, Francisco Acosta, Ming Hsieh, Yilong Zhang, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2021)

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m 2 and 125mg/m 2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m 2 . Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m 2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m 2 . All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in &gt; 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t 1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m 2 . PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.
Saci-IO TNBC: Randomized phase II trial of sacituzumab govitecan (SG) +/- pembrolizumab in PD-L1– metastatic triple-negative breast cancer (mTNBC).
Authors: Ana Christina Garrido-Castro, Tanya Elizabeth Keenan, Tianyu Li, Paulina Lange, Catherine Callahan, Jennifer Guerriero, Nabihah Tayob, Leilani Anderson, Clinton Yam, Brooke R. Daniel, Lisa A. Carey, Rita Nanda, Eric P. Winer, Elizabeth A. Mittendorf, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2021)

TPS1106 Background: Immune checkpoint inhibitors (ICIs) have not yet benefited most patients with breast cancer. In mTNBC, ICIs combined with chemotherapy have improved survival only in PD-L1+ mTNBC. The optimal ICI combination agent to overcome primary resistance in PD-L1– mTNBC is unknown. One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.6 months in mTNBC with ≥2 prior lines of chemotherapy. 1 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity. 2 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models. 3 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors, 4 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors. Methods: This is a multi-center 1:1 randomized phase II trial to investigate whether the addition of pembrolizumab (200 mg IV every 3 weeks) to SG (10 mg/kg IV days 1+8 every 21 days) improves PFS compared to SG alone in mTNBC that is PD-L1– by standard of care testing with 22C3 CPS &lt; 10 or SP142 immune cells &lt; 1% (NCT04468061). Key eligibility criteria include no prior systemic therapy for mTNBC and evaluable disease. Previously treated brain metastases are permitted. Exclusion criteria include prior treatment with SG, irinotecan, and PD-1/L1 inhibitors. Based on a sample size of 110 patients per arm, the trial has 80% power to detect a 3-month difference in median PFS from 5.5 months in the SG-alone cohort to 8.5 months in the SG + pembrolizumab cohort with a one-sided alpha of 0.1. Participants undergo mandatory baseline and on-treatment research biopsies if their disease is safely accessible. Tumor biopsies will be evaluated for Trop-2, immune cells, inhibitory checkpoints, transcriptomic signatures, and genomic alterations. Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed. The trial is currently open and enrolling patients. References: 1) Bardia A et al. Ann Oncol 31, S1142-S1215 (2020). 2) Cardillo TM et al. Bioconjug Chem 26, 919-931 (2015). 3) Iwai T et al. Oncotarget 9, 31411-31421 (2018). 4) Hibino S et al. Cancer Res 78, 3027-3040 (2018). Clinical trial information: NCT04468061 .
Characterization of the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC): Prognostic value and therapeutic implications of an M0-macrophage enriched subtype.
Authors: Mark Farha, Randy Vince, Srinivas Nallandhighal, Judith Stangl-Kremser, Steven Goldenthal, Daniel Triner, Todd Matthew Morgan, Ganesh S. Palapattu, Aaron M. Udager, Simpa Samuel Salami
Journal: Journal of Clinical Oncology (2021)

4572 Background: Metastatic clear cell renal cell carcinoma (ccRCC) has a 5-year survival of 12%, but the number of approved immune checkpoint blockade (ICB) agents is growing, necessitating the need to better identify responders. The composition and role of the tumor immune microenvironment (TIME) has yet to be comprehensively characterized in ccRCC. Here, we leveraged a genomic data driven approach to characterize TIME subtypes in ccRCC. Methods: Whole transcriptome data from patients with local and metastatic disease in the Cancer Genome Atlas KIRC (TCGA-KIRC) project was utilized (n = 537). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free (PFS) and overall (OS) survival of each cluster was analyzed, and Gene Set Enrichment analysis was performed among clusters. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB in the TCGA-KIRC clusters. Results: There was a distinct M0 hi cluster identified which demonstrated a higher proportion of patients with stage III/IV disease, decreased PFS and OS (Table). Additionally, the M0 hi cluster was characterized by lower PD-L1 expression (ANOVA, p = 0.0045) and an enrichment of epithelial to mesenchymal transition (EMT) hallmark genes [Enrichment Score = 0.64, p = 0.001]. The M0 hi cluster also showed a higher degree of T-Cell Exclusion (ANOVA, p = 2.2x10 -16 ), predominance of Cancer Associated Fibroblasts (CAFs; ANOVA, p = 2.2x10 -16 ) and Myeloid Derived Suppressor Cells (MDSCs; ANOVA, p = 4.1x10 -10 ). The M0 hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (Table). Conclusions: Comprehensive characterization of the TCGA-KIRC cohort led to identification of a distinct cluster of ccRCC defined molecularly by decreased PD-L1 and increased EMT gene expression and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and an exclusion of T Cells. Patients within this cluster exhibited aggressive disease and poor predicted response to ICB. These findings warrant further validation to identify appropriate therapeutic approaches for this ccRCC subgroup.[Table: see text]
Chromosome-level genome assembly of a regenerable maize inbred line A188
Authors: Guifang Lin, Cheng He, Jun Zheng, Dal-Hoe Koo, Ha Le, Huakun Zheng, Tej Man Tamang, Jinguang Lin, Yan Liu, Mingxia Zhao, Yangfan Hao, Frank McFraland, Bo Wang, Yang Qin, Haibao Tang, Donald R. McCarty, Hairong Wei, Myeong-Je Cho, Sunghun Park, Heidi Kaeppler, Shawn M. Kaeppler, Yunjun Liu, Nathan Springer, Patrick S. Schnable, Guoying Wang, Frank F. White, Sanzhen Liu
Journal: Genome biology (2021)

Abstract Background The maize inbred line A188 is an attractive model for elucidation of gene function and improvement due to its high embryogenic capacity and many contrasting traits to the first maize reference genome, B73, and other elite lines. The lack of a genome assembly of A188 limits its use as a model for functional studies. Results Here, we present a chromosome-level genome assembly of A188 using long reads and optical maps. Comparison of A188 with B73 using both whole-genome alignments and read depths from sequencing reads identify approximately 1.1 Gb of syntenic sequences as well as extensive structural variation, including a 1.8-Mb duplication containing the Gametophyte factor1 locus for unilateral cross-incompatibility, and six inversions of 0.7 Mb or greater. Increased copy number of carotenoid cleavage dioxygenase 1 ( ccd1 ) in A188 is associated with elevated expression during seed development. High ccd1 expression in seeds together with low expression of yellow endosperm 1 ( y1 ) reduces carotenoid accumulation, accounting for the white seed phenotype of A188. Furthermore, transcriptome and epigenome analyses reveal enhanced expression of defense pathways and altered DNA methylation patterns of the embryonic callus. Conclusions The A188 genome assembly provides a high-resolution sequence for a complex genome species and a foundational resource for analyses of genome variation and gene function in maize. The genome, in comparison to B73, contains extensive intra-species structural variations and other genetic differences. Expression and network analyses identify discrete profiles for embryonic callus and other tissues.
The comparative effectiveness of direct oral anti-coagulants and low molecular weight heparins for prevention of recurrent venous thromboembolism in cancer: The CANVAS pragmatic randomized trial.
Authors: Deborah Schrag, Hajime Uno, Rachel Pam Greenerger Rosovsky, Cynthia Rutherford, Kristen Marie Sanfilippo, John L. Villano, Monic R Drescher, Nagesh H. Jayaram, Chris E. Holmes, Lawrence Eric Feldman, Ottavia Zattra, Christine Cronin, Ethan M. Basch, Anna Weiss, Jean M. Connors
Journal: Journal of Clinical Oncology (2021)

12020 Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWH for preventing recurrent VTE but have higher risk of bleeding. However, the balance of benefits and burdens remains uncertain. Objective: The CANVAS pragmatic trial compared recurrent VTE, bleeding and death in cancer patients following an initial VTE treated with either DOAC or LMWH therapy. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial, with randomized and preference cohorts. Between 12/16 and 4/20, 671 participants were randomized and followed for 6-months. Between 12/16 and 12/17, 140 participants declined randomization, chose their preferred anticoagulant and were followed for 6-months. The preference cohort was closed when predetermined stopping criteria were met. Final follow-up was 11/30/20. Randomized patients were assigned 1:1 to receive either a DOAC or a LMWH. If assigned to LMWH, transitions to warfarin were allowed. Physicians and patients could choose among any DOAC or LMWH. Doses were suggested based on FDA-approved labeling but not mandated. Patients from 67 practices in the US with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of symptomatic or radiographically detected VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified-into to treat popululation, (all subjects who received study drug). The 1° outcome was recurrent VTE. The aim was to establish noninferiority of anticoagulation with a DOAC as defined by the upper limit of the 2-sided 90% CI for the difference in the event rate at 6 months of &lt; 3%. Secondary outcomes included death and bleeding. Hypothesis testing included only the randomized cohort but propensity score adjusted results for the preference and combined cohorts are also shown. Results: The non-inferiority criteria for recurrent VTE was met. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in a noninferior risk of recurrent VTE with no differences in rates of bleeding or death in randomized patients. Clinical trial information: NCT02744092. [Table: see text]
Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.
Authors: Gang Hua, Xiaoxi Chen, Ruoying Yu, Hua Bao, Xue Wu, Yang Shao
Journal: Journal of Clinical Oncology (2021)

3011 Background: Sequential treatment with first-, second-generation ALK TKI followed by third-generation TKI (lorlatinib) have been widely applied to ALK-positive lung cancer. However, acquired resistance is often driven by secondary ALK mutations, which are needed to be further explored. Circulating tumor DNA, a non-invasive approach, can detect tumor-derived DNA from multiple metastatic sites and has become a promising strategy for assessing the genetic evolution of tumors and analyzing TKI resistance. Methods: Post-progression plasma specimens were collected and sequenced with a targeted gene panel from a total of 116 patients underwent ALK TKI treatment with from February 2014 to April 2020. The ALK TKIs administrated in this cohort included crizotinib (first-generation), ceritinib (second-generation), alectinib (second-generation), brigatinib (second-generation), ensartinib (second-generation) and lorlatinib (third-generation). Results: In this ALK-positive lung adenocarcinoma cohort, 49.1% were female and the rest were male with a median age of 52 (range 20 to 79). More than half of patients received more than one line of ALK TKI treatment. The most frequent ALK fusion type is EML4-ALK including EML4-ALK v1(E13; A20, 37/116, 31.9%) and EML4-ALKv3(E6a/b; A20, 49/116, 42.2%). TP53 (29.1%, 41/141) was the most frequently mutated gene other than ALK. Frequently identified secondary mutations in patients progressing on ALK inhibitors were ALK mutations L1196M and G1202R. ALK G1202R was more common in patient with v3 fusion than in v1 (25.8% vs 0%; P&lt;.001) while ALK L1196M was more common in v1 than in v3 (20.8% vs 3.2%; P=.005). Meanwhile, G1202R was identified at higher ratio in patients progressed on second-generation ALK TKI than first- and third-generation ALK TKI (11.3% vs 0% and 9.1%) whereas L1196M was more found in patients progressed on first-generation ALK TKI (9.1% vs 1.9% and 4.5%). Other identified secondary mutations were ALK F1174C/V/L, E1210K/Q, D1269A, D1203N and L1122M/V. Compound ALK mutations (≥2 concurrent ALK mutations) were more common in patients relapsed on third-generation ALK TKI lorlatinib (36.4%) compared to first- (12.1%) and second-generation (20.8%) ALK TKIs. Using serial plasma specimens, clone evolution analysis showed that five patients developed compound ALK mutations after sequential ALK TKI treatments and two novel ALK compound lorlatinib-resistant mutations D1203N+I1171N and F1174C+G1202R were identified. Conclusions: Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance.
Mutated MYD88 Homozygosity Is Increased in Previously Treated Patients with Waldenstrom's Macroglobulinemia, and Associates with CXCR4 Mutation Status and Ibrutinib Exposure
Authors: Nickolas Tsakmaklis, Lian Xu, Robert Manning, Guang Yang, Xia Liu, Jiaji Chen, Maria Demos, Amanda Kofides, Gloria Chan, Maria Luisa Guerrera, Christopher Patterson, Jorge J. Castillo, Steven P Treon, Zachary Hunter
Journal: Blood (2017)
Annals Graphic Medicine - Last Human Contact in COVID-19
Authors: Pooja Gandhi, Arnav Agarwal
Journal: Annals of Internal Medicine (2021)

Web Exclusives8 June 2021Annals Graphic Medicine - Last Human Contact in COVID-19FREEPooja Gandhi, MSpPathSt and Arnav Agarwal, MDPooja Gandhi, MSpPathStToronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada (P.G.)Search for more papers by this author and Arnav Agarwal, MDUniversity of Toronto, Toronto, Ontario, Canada (A.A.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0090 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Author, Article, and Disclosure InformationAuthors: Pooja Gandhi, MSpPathSt; Arnav Agarwal, MDAffiliations: Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada (P.G.)University of Toronto, Toronto, Ontario, Canada (A.A.)Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G20-0090.Author/Illustrator Information: Pooja Gandhi, MSpPathSt, is a registered speech-language pathologist working at University Health Network (Toronto, Ontario) and Joseph Brant Hospital (Burlington, Ontario), and is a PhD candidate at University of Toronto (Toronto, Ontario) (e-mail, pooja.gandhi@uhn.ca). Arnav Agarwal, MD, is a resident physician in internal medicine at University of Toronto (Toronto, Ontario), and an incoming clinical fellow in general internal medicine at McMaster University (Hamilton, Ontario) (e-mail, arnav.agarwal@mail.utoronto.ca).This article was published at Annals.org on 8 June 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics June 2021Volume 174, Issue 6 Page: W58-W59 ePublished: 8 June 2021 Issue Published: June 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development
Authors: Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato
Journal: Journal of Clinical Investigation (2021)

Cancer cells reprogram lipid metabolism during their malignant progression, but limited information is currently available on the involvement of alterations in fatty acid synthesis in cancer development. We herein demonstrate that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid synthesis, plays a critical role in regulating the growth and differentiation of leukemia-initiating cells. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPA, a transcription factor regulating myeloid differentiation, for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). We identified ACC1 as a target of the Trib1-COP1 complex and found that an ACC1 mutant resistant to degradation because of the lack of a Trib1-binding site attenuated complex-driven leukemogenesis. Stable ACC1 protein expression suppressed the growth-promoting activity and increased ROS levels with the consumption of NADPH in a primary bone marrow culture, and delayed the onset of AML with increases in mature myeloid cells in mouse models. ACC1 promoted the terminal differentiation of Trib1-COP1-expressing cells and eradicated leukemia-initiating cells in the early phase of leukemic progression. These results indicate that ACC1 is a natural inhibitor of AML development. The upregulated expression of the ACC1 protein has potential as an effective strategy for cancer therapy.
Contact-dependent inhibition of HIV-1 replication in ex vivo human tonsil cultures by polymorphonuclear neutrophils
Authors: Tatjana Reif, Gerhard Dyckhoff, Ralph Hohenberger, Carl-Christian Kolbe, Henning Gruell, Florian Klein, Eicke Latz, Bettina Stolp, Oliver T. Fackler
Journal: Cell Reports Medicine (2021)

Polymorphonuclear neutrophils (PMNs), the most abundant white blood cells, are recruited rapidly to sites of infection to exert potent anti-microbial activity. Information regarding their role in infection with human immunodeficiency virus (HIV) is limited. Here we report that addition of PMNs to HIV-infected cultures of human tonsil tissue or peripheral blood mononuclear cells causes immediate and long-lasting suppression of HIV-1 spread and virus-induced depletion of CD4 T cells. This inhibition of HIV-1 spread strictly requires PMN contact with infected cells and is not mediated by soluble factors. 2-Photon (2PM) imaging visualized contacts of PMNs with HIV-1-infected CD4 T cells in tonsil tissue that do not result in lysis or uptake of infected cells. The anti-HIV activity of PMNs also does not involve degranulation, formation of neutrophil extracellular traps, or integrin-dependent cell communication. These results reveal that PMNs efficiently blunt HIV-1 replication in primary target cells and tissue by an unconventional mechanism.