tbuckley/cabot-search huggingface dataset:
Segmenting and tracking cell instances with cosine embeddings and recurrent hourglass networks
Authors: Christian Payer, Darko Štern, Marlies Feiner, Horst Bischof, Martin Urschler
Journal: Medical Image Analysis (2019)

Differently to semantic segmentation, instance segmentation assigns unique labels to each individual instance of the same object class. In this work, we propose a novel recurrent fully convolutional network architecture for tracking such instance segmentations over time, which is highly relevant, e.g., in biomedical applications involving cell growth and migration. Our network architecture incorporates convolutional gated recurrent units (ConvGRU) into a stacked hourglass network to utilize temporal information, e.g., from microscopy videos. Moreover, we train our network with a novel embedding loss based on cosine similarities, such that the network predicts unique embeddings for every instance throughout videos, even in the presence of dynamic structural changes due to mitosis of cells. To create the final tracked instance segmentations, the pixel-wise embeddings are clustered among subsequent video frames by using the mean shift algorithm. After showing the performance of the instance segmentation on a static in-house dataset of muscle fibers from H&E-stained microscopy images, we also evaluate our proposed recurrent stacked hourglass network regarding instance segmentation and tracking performance on six datasets from the ISBI celltracking challenge, where it delivers state-of-the-art results.
Abstract 2677: <i>MSIClass–</i>Identification and classification of microsatellite unstable using cell-free DNA from ultra-low-pass sequencing
Authors: Yosef E. Maruvka, Ruslana Frazer, Jonna Grimsby, Carrie Cibulskis, Viktor Adalsteinsson, Ryan Corcoran, Gad Getz
Journal: Cancer Research (2019)

Abstract The acquisition of mismatch repair deficiency is common in many tumor types. A unique subtype of mismatch repair deficient tumors, called tumors with microsatellite instability (MSI), has been recently approved for treatment with PD-1\PD-L1 blockade immunotherapy. Therefore, developing a quick, inexpensive, and easy-to-implement technique for classifying tumors as MSI is of utmost importance. Here, we describe such a method using next-generation sequencing data, and show that it can detect MSI from cell-free DNA (cfDNA), even when there is low fraction of tumor DNA in the cfDNA. We first analyzed the unique mutational features of MSI vs. microsatellite stable (MSS) tumors. Using our SignatureAnalyzer tool, we analyzed the signatures of the different insertions and deletions within microsatellite loci (MS-indels), and found that MSI tumors harbor elevated MS-indels of certain types, which we further validated using whole genome sequencing data from The Cancer Genome Atlas. We next used this information to develop a method (MSIClass) that analyzes the WGS data of a given sample by capturing the features unique to MSI tumors. This method assigns each sample a score based on aggregating information from all MS loci simultaneously; since MSIClass is a sample-based tool, it can call the MSI status of tumor samples that have no patient-matched normal sample. We further demonstrate that MSIClass requires minimal genomic information; indeed, sequencing coverage as low as 0.05x (current sequencing cost of ~$2/sample) is sufficient for accurate classification by MSIClass. Using in silico and in vitro DNA mixing we show that MSIClass can accurately identify MSI cases in very low purity cases, at 0.1% tumor DNA (using 0.5x sequencing coverage). We show that MSIClass, applied on cfDNA, could accurately classify 29 colon cases – 22 MSS and 7 MSI cases, 3 of which are early stage disease and with low tumor content. These results demonstrate that MSIClass is an inexpensive MSI test that can be applied in various cases: bulk sequencing where a matched normal is not available, cases of very low purity tumors, and even using cfDNA from blood in cases a biopsy is not available or possible. Finally, this methodology can be the basis for monitoring minimal residual disease, and potential be used for early detection of MSI tumors. Citation Format: Yosef E. Maruvka, Ruslana Frazer, Jonna Grimsby, Carrie Cibulskis, Viktor Adalsteinsson, Ryan Corcoran, Gad Getz. MSIClass–Identification and classification of microsatellite unstable using cell-free DNA from ultra-low-pass sequencing [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 2677.
Abstract 14869: Stromal Cell-derived Factor-1α is Associated With Future Renal Dysfunction in Patients With Coronary Artery Disease
Authors: Manabu Uematsu, Takamitsu Nakamura, Toru Yoshizaki, Chifumi Iizuka, Mika Futamata, Yosuke Watanabe, Juntaro Deyama, Kazuhiro Watanabe, Tsuyoshi Kobayashi, Daisuke Fujioka, Yukio Saito, Kazuto Nakamura, Kenichi Kawabata, Jun-ei Obata, Kiyotaka Kugiyama
Journal: Circulation (2017)

Introduction: We recently demonstrated that stromal cell-derived factor-1α (SDF-1α), a pro-inflammatory chemokine, is produced in infarcted myocardium and associated with left ventricular adverse r...
Abstract 3460: <i>MPRIP-ALK,</i>a novel ALK rearrangement that responds to ALK inhibitor in non-small-cell lung cancer
Authors: Wenfeng Fang, Jiadi Gan, Feng Lu, Yangyang Deng, Liang Chen, Yunpeng Yang, Li Zhang
Journal: Cancer Research (2019)

Abstract Oncogenic rearrangements of the anaplastic lymphoma receptor tyrosine kinase (ALK gene) have recently been described in 3% to 5% of lung adenocarcinomas. Kinds of fusion partners of ALK have been reported in non-small-cell lung cancer (NSCLC), with echinoderm microtubule-associated protein-like 4 (EML4)-ALKbeing the most prevalent one. Several tyrosine kinase inhibitors have been approved for treating patients with advanced-stage ALK-positive, NSCLC by Food and Drugs Administration (FDA). Comprehensive genomic profiling performed by means of next-generation sequencing assay demonstrated a novel myosin phosphatase-Rho-interacting protein gene (MPRIP)-ALK fusion in our case, in which a translocation involving chromosomes 2 and 9 has taken place. The rearrangement was verified by reverse transcription reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing. ALK immunohistochemistry demonstrated strong staining in patient’s tumor sample as extracted from formalin-fixed paraffin-embedded (FFPE) sections. We expressed MPRIP-ALK cDNA construct in non-cancer cell line Ba/F3 which showed IL-3-independent growth compared the growth stop of cells carrying empty vector, moreover, hyper-activation of the protein ALK, ERK, AKT were detected in Ba/F3 cells with MPRIP-ALK over-expressed. Furthermore, the colonies and activations of ALK downstream signaling pathways could be inhibited by crizotinib. The patient received standard chemotherapy on the first-line. She experienced progressive disease after 7 months, and commenced on crizotinib (250mg, twice per day) from March 2018. The patient showed significant improvement in cough, dorsalgia, and polypnea within one week. Partial response was gained after one month treatment and confirmed at the third month. She still remains on the crizotinib treatment without disease relapse up to now. In this study, we report a novel ALK rearrangement in a patient with NSCLC by RNA-seq. Our in vivo and in vitro studies have shown that the novel MPRIP-ALK fusion is a driver gene and can be targetable by crizotinib. Citation Format: Wenfeng Fang, Jiadi Gan, Feng Lu, Yangyang Deng, Liang Chen, Yunpeng Yang, Li Zhang. MPRIP-ALK,a novel ALK rearrangement that responds to ALK inhibitor in non-small-cell lung cancer [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 3460.
Abstract 2101: Targeting the root of cancer persister cells using an expressed barcode library
Authors: Yaara Oren, Pratiksha Thakore, Mike S. Cuoco, Heidie Frisco Cabanos, Aaron Hata, Joan S. Brugge, Aviv Regev
Journal: Cancer Research (2019)

Abstract Despite a favorable initial response, many cancer patients will experience recurrence of disease within months or years after diagnosis. Recurrence largely arises as a result of the growth of residual cancer cells that remain after treatment. The ability of a subset of cells to survive is attributed frequently to genetic heterogeneity, however recently it was shown that in multiple cancer types relapse can arise due to the presence of persister cells. Persisters are a subpopulation of transiently drug-tolerant cells that are able to survive therapy through reversible, non-mutational mechanisms. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are amongst the mechanisms hypothesized to underlie persister phenotype. However, given the lack of high-throughput methods to concurrently track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated the Watermelon library. The Watermelon library is a high-complexity expressed barcode library that enables simultaneous tracing of lineage as well as the transcriptional and proliferative state of each cell in the population during drug treatment. We have applied the watermelon system to study the mechanisms underlying the ability of a small population of cells to regain proliferative capacity under constant treatment with EGFR tyrosine kinase inhibitors. We combine time-lapse imaging with single-cell RNA sequencing to show that early drug-cyclers do not acquire a facilitating resistance mutation but rather transition to a new cell state. We find that this non-genetic drug-proliferative state is not restricted to a certain clonal lineage and can be reached by distinct transcriptional paths. We anticipate that this unique library, which can be applied to other systems, would facilitate a better understanding of the cellular and molecular pathways that affect non-inherited drug resistance. Citation Format: Yaara Oren, Pratiksha Thakore, Mike S. Cuoco, Heidie Frisco Cabanos, Aaron Hata, Joan S. Brugge, Aviv Regev. Targeting the root of cancer persister cells using an expressed barcode library [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 2101.
Excess Burden of Mental Illness and Hospitalization in Young-Onset Type 2 Diabetes
Authors: Thomas E. Finucane
Journal: Annals of Internal Medicine (2019)

Letters2 July 2019Excess Burden of Mental Illness and Hospitalization in Young-Onset Type 2 DiabetesThomas E. Finucane, MDThomas E. Finucane, MDJohns Hopkins Bayview Medical Center, Baltimore, Maryland (T.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L19-0242 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Ke and colleagues (1) observed that groups of patients with young-onset type 2 diabetes (T2D) had higher hospitalization rates across the lifespan than patients with usual-onset diabetes (defined as onset at age ≥40 years). They note, “the [young-onset T2D] group had worse control of modifiable risk factors, such as hemoglobin A1c level, [low-density lipoprotein cholesterol level], and [body mass index].” They propose that this association shows “the importance of early intervention to reduce the adverse effects of … cardiometabolic risk factors.”Using associations to make a causal inference is a common element in the effort to support ...Reference1. Ke C, Lau E, Shah BR, et al. Excess burden of mental illness and hospitalization in young-onset type 2 diabetes. A population-based cohort study. Ann Intern Med. 2019. [PMID: 30641547]. doi:10.7326/M18-1900 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Johns Hopkins Bayview Medical Center, Baltimore, Maryland (T.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L19-0242. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoExcess Burden of Mental Illness and Hospitalization in Young-Onset Type 2 Diabetes Calvin Ke , Eric Lau , Baiju R. Shah , Thérèse A. Stukel , Ronald C. Ma , Wing-Yee So , Alice P. Kong , Elaine Chow , Philip Clarke , William Goggins , Juliana C.N. Chan , and Andrea Luk Excess Burden of Mental Illness and Hospitalization in Young-Onset Type 2 Diabetes Calvin Ke , Baiju R. Shah , Thérèse A. Stukel , Juliana C.N. Chan , and Andrea Luk Metrics 2 July 2019Volume 171, Issue 1Page: 78KeywordsBody mass indexCholesterolDeath ratesDisclosureHemoglobinHospitalizationsLow density lipoproteinMedical risk factorsRandomized trialsType 2 diabetes ePublished: 2 July 2019 Issue Published: 2 July 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Publisher Correction: Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma
Authors: Antoni Ribas, Donald Lawrence, Victoria Atkinson, Sachin Agarwal, Wilson H. Miller, Matteo S. Carlino, Rosalie Fisher, Georgina V. Long, F. Stephen Hodi, Jennifer Tsoi, Catherine S. Grasso, Bijoyesh Mookerjee, Qing Zhao, Razi Ghori, Blanca Homet Moreno, Nageatte Ibrahim, Omid Hamid
Journal: Nature Medicine (2019)
Role of Glucosylceramide in Lung Endothelial Cell Fate and Emphysema
Authors: Kengo Koike, Evgeny V. Berdyshev, Andrew M. Mikosz, Irina A. Bronova, Anna S. Bronoff, John P. Jung, Erica L. Beatman, Kevin Ni, Danting Cao, April K. Scruggs, Karina A. Serban, Irina Petrache
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

The loss of pulmonary endothelial cells in emphysema is associated with increased lung ceramide. Ceramide perturbations may cause adaptive alterations in other bioactive sphingolipids, with pathogenic implications. We previously reported a negative correlation between emphysema and circulating glycosphingolipids (GSLs). Glucosylceramide (GlcCer), the initial GSL synthesized from ceramide by GCS (GlcCer synthase), is required for embryonic survival, but its role in the lung is unknown.
A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy.
Authors: Enriqueta Felip, Paal Brunsvig, Nuria Vinolas, Santiago Ponce Aix, Enric Carcereny Costa, Manuel Dómine Gomez, Jose Manuel Trigo Perez, Edurne Arriola, Rosario Garcia Campelo, James F. Spicer, Jonathan Robert Thompson, Ana Laura Ortega Granados, Robert J Holt, Katherine Lorens, James B. Lorens, Muhammad Shoaib, Abdul Siddiqui, Emmett V. Schmidt, Michael Jon Chisamore, Matthew Krebs
Journal: Journal of Clinical Oncology (2019)

9098 Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO naïve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with pre-defined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in &gt; 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.
Contribution of Coiled-Coil Assembly to Ca2+/Calmodulin-Dependent Inactivation of TRPC6 Channel and its Impacts on FSGS-Associated Phenotypes
Authors: Onur K. Polat, Masatoshi Uno, Terukazu Maruyama, Ha Nam Tran, Kayo Imamura, Chee Fah Wong, Reiko Sakaguchi, Mariko Ariyoshi, Kyohei Itsuki, Jun Ichikawa, Takashi Morii, Masahiro Shirakawa, Ryuji Inoue, Katsuhiko Asanuma, Jochen Reiser, Hidehito Tochio, Yasuo Mori, Masayuki X. Mori
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement TRPC6 is a receptor-activated nonselective cation channel. Naturally occurring mutations in this channel are associated with FSGS. FSGS-associated TRPC6 channel mutations appear to have a “gain-of-function” mechanism, but the exact mechanism remains unclear. The authors show that negative feedback regulation induced by cellular calcium levels, called Ca 2+ -dependent inactivation (CDI), is impaired in FSGS-associated TRPC6 channel mutations. Dysfunctional coiled-coil assembly in the mutated TRPC6 disrupts calmodulin bridging which is essential for CDI. The authors reveal how disruption in a Ca 2+ -dependent regulatory mechanism may play a role in FSGS. Background TRPC6 is a nonselective cation channel, and mutations of this gene are associated with FSGS. These mutations are associated with TRPC6 current amplitude amplification and/or delay of the channel inactivation (gain-of-function phenotype). However, the mechanism of the gain-of-function in TRPC6 activity has not yet been clearly solved. Methods We performed electrophysiologic, biochemical, and biophysical experiments to elucidate the molecular mechanism underlying calmodulin (CaM)-mediated Ca 2+ -dependent inactivation (CDI) of TRPC6. To address the pathophysiologic contribution of CDI, we assessed the actin filament organization in cultured mouse podocytes. Results Both lobes of CaM helped induce CDI. Moreover, CaM binding to the TRPC6 CaM-binding domain (CBD) was Ca 2+ -dependent and exhibited a 1:2 (CaM/CBD) stoichiometry. The TRPC6 coiled-coil assembly, which brought two CBDs into adequate proximity, was essential for CDI. Deletion of the coiled-coil slowed CDI of TRPC6, indicating that the coiled-coil assembly configures both lobes of CaM binding on two CBDs to induce normal CDI. The FSGS-associated TRPC6 mutations within the coiled-coil severely delayed CDI and often increased TRPC6 current amplitudes. In cultured mouse podocytes, FSGS-associated channels and CaM mutations led to sustained Ca 2+ elevations and a disorganized cytoskeleton. Conclusions The gain-of-function mechanism found in FSGS-causing mutations in TRPC6 can be explained by impairments of the CDI, caused by disruptions of TRPC’s coiled-coil assembly which is essential for CaM binding. The resulting excess Ca 2+ may contribute to structural damage in the podocytes.
Abstract 2439: A semi-supervised deconvolution method for quantifying the composition and activity of tumor-infiltrating cell types
Authors: Wennan Chang, Changlin Wan, Yifan Sun, Yan Han, Siyuan Qi, Xiongbin Lu, Sha Cao, Chi Zhang
Journal: Cancer Research (2019)

Abstract Tumor microenvironment (TME) plays a key role in tumorigenesis, disease progression and the acquirement of drug resistance. An accurate assessment of TME cellular compositions may not only shed light on how TME interacts with cancer cells, but also bring new insights for translational researchers in studying the non-responding mechanism of immunotherapy. Traditional deconvolution methods infer the relative proportions of predefined cell types based on a tissue omics data through either regression- or enrichment- based approaches. However, there are several challenges that remain unsolved in the current formulations, including (1) identifying the Immune/Stromal (I/S) cell types that truly exists in a TME, (2) identifying the marker genes for each cell type that are specifically expressed by one or a few I/S cell types in a TME, (3) co-linearity among to-be-assessed I/S proportions due to their co-infiltration. We have developed a novel semi-supervised deconvolution method namely ICTD (Inference of Cell types and Deconvolution), addressing the three challenges via (i) developing a Bi-Cross Validation (BCV) based matrix rank test to assess the significance level of the existence of cell types and signature genes, (ii) utilizing a constrained Non-negative Matrix Factorization (NMF) to eliminate the effect of co-linearity. We validated ICTD on bulk tumor datasets simulated using single-cell RNA-seq data. Our analysis suggested that ICTD has a largely improved prediction accuracy of TME compositions comparing to existing methods, and particularly, it is capable of identifying novel or sub-cell types. We applied our method to TCGA and other gene expression data of breast and prostate cancer. Subsets of CD8+ T cells with varied cytotoxicity levels and subtypes of fibroblast cells were identified. Moreover, integrated with an analysis of an independent single-cell and cell line gene expression dataset, we identified genes specifically expressed by cancer cells that are associated with decreased T cell cytotoxicity level. Citation Format: Wennan Chang, Changlin Wan, Yifan Sun, Yan Han, Siyuan Qi, Xiongbin Lu, Sha Cao, Chi Zhang. A semi-supervised deconvolution method for quantifying the composition and activity of tumor-infiltrating cell types [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 2439.