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Publications Tag

Indica Labs / Posts tagged "Publications"

CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice

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HALO Link Publications, Infectious Disease
March 17, 2021

Daniel Stone,et al, Molecular Therapy Methods & Clinical Development, 2021
Hepatitis B leads to over 850,000 deaths annually due to complications from chronic infection including cirrhosis and hepatocellular carcinoma. While antiviral drugs successfully reduce viral loads in patients, a cure does not yet exist. This study out of the Jerome laboratory at the Fred Hutchinson Cancer Research Center performed in vivo gene editing utilizing a mouse model for chronic HBV infections and demonstrated a proof-of-concept of safe and effective...

Monomeric/dimeric forms of Fgf15/FGF19 show differential activity in hepatocyte proliferation and metabolic function

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HALO Link Publications, Metabolism
March 17, 2021

Courtney M. Williams et al, The FASEB Journal, 2021
Williams and colleagues at Regeneron Pharmaceuticals perform structure/function relationship studies on Fgf15 and FGF19 using site-directed mutagenesis and downstream functional assays in order to understand their distinct functions in a common pathway. Both molecules are therapeutic targets due to involvement in hepatocellular carcinoma and bile acid production. This publication identifies a single cysteine residue is identified that controls dimerization and hepatocyte proliferation. Understanding these molecular pathways may inform future...

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Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma

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HALO Publications, Immuno-oncology
March 16, 2021

Jason Yongsheng Chan,et al, The Journal of Clinical Investigation, 2020
To molecularly characterize the rare and aggressive tumors known as angiosarcomas, Chan et al utilized a combination of transcriptomic immuno-oncology profiling with multiplex immunohistochemistry and immunofluorescence. HALO image analysis software was used for the quantification of PD-L1, CD68, CD8, FOXP3, CD15, and ERG. From these studies, three phenotypes of patients were identified according to etiology, anatomical origin, signaling pathways, and the tumor inflammation signature. These distinct biological phenotypes...

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Neuron Publication Cover

PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding

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Neuroscience, Publications
March 16, 2021

Alexander Jaisl, et al, Neuron, 2020
To advance the molecular understanding of obesity, Jais and colleagues set out to identify neuronal populations in mice that respond to being fed a calorie dense, highly palatable food. They identified prepronociceptin (PNOC)-expressing neurons in the hypothalamus that are activated upon acute high fat diet feeding and promote overconsumption. In this publication, HALO image analysis software was used for quantification of transgene expression in mouse neuronal tissue. Future studies on PNOC-expressing neurons...

An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer

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HALO Publications, Immuno-oncology
March 16, 2021

Dr. Paula Voabil and colleagues used a patient derived tumor fragment platform to investigate immune responses immediately following PD-1 blockade. The Tissue Classifier Add-on and the Multiplex IHC module of HALO® were used in this publication to quantify immune biomarkers in the tumor and stroma, contributing to their conclusion that the ability of tumors to respond to PD-1 blockage correlates with the ability of intratumoral immune cells to be reactivated by the blockade....

Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

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Immuno-oncology, Publications
March 16, 2021

Myriam Chalabi, et al, Nature Medicine, 2020
Immunotherapy is known to be effective in late-stage, mismatch repair (MMR) deficient colorectal cancers but not in MMR proficient cancer. This study reports the early results from the NICHE clinical trial that is evaluating treatment of early stage, nonmetastatic preoperative colon cancer with a CTLA-4 inhibitor and a PD-1 inhibitor. Chalabi and colleagues report that the treatment was well tolerated and that a major pathological response was seen in 19/20 patients with...

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Transmission of tauopathy strains is independent of their isoform composition

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Neuroscience, Publications
March 16, 2021

Zhuohao He, et al, Nature Communications, 2020
The accumulation of aggregated tao proteins in neurons is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease. A challenge in the study of tauopathies has been the lack of an appropriate model system. He and colleagues demonstrate here a new mouse model for human tauopathies where the expression of tao isoforms is similar to that in human adult brains. The Area Quantification Module of HALO played a key role in the analysis...

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Mechanical regulation of glycolysis via cytoskeleton architecture

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HALO Publications, Oncology
March 16, 2021

Jin Suk Park,et al, Nature, 2020
Park and colleagues explored the question of how regulation of glycolysis responds to structural changes in tissue architecture and chose lung cells and tissue for their studies due to the regular mechanical stress experienced during respiration. In vitro studies demonstrated downregulation of glycolysis following a change in substrate via the degradation of the platelet isoform of the phosphofructokinase (PFKP) enzyme. In vitro studies also showed that oncogenic transformation changed the ability of PFKP...

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Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis

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Immunology, Publications
March 16, 2021

Julien Carvelli, et al, Nature, 2020
Researchers aiming to block excessive lung inflammation in COVID-19 patients found upregulated immune checkpoint biomarkers in patients with a range of COVID-19 symptoms (from paucisymptomatic to acute respiratory distress syndrome). In addition, Carvelli et al found increased expression of C5a, an inflammatory mediator, in serum and the C5aR1 receptor on myeloid cells in COVID-19 patients, which are known to initiate inflammatory responses by recruiting neutrophils and monocytes to lungs. An in vitro neutrophil...

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Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

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HALO Publications, Immuno-oncology
March 16, 2021

Jules Russick, et al, Journal for ImmunoTherapy of Cancer, 2020
Natural killer (NK) cells are known to have cytotoxic effector functions in tumor immunosurveillance. More recently, evidence of a second potentially inhibitory or regulatory role have emerged. Here, Russick et al compared expression patterns of NK cells inside tumors to nontumoral NK cells to understand their inhibitory functions in the context of the non-small cell lung carcinoma (NSCLC) tumor microenvironment (TME). These studies identified a novel and specific...

Kaiso (ZBTB33) subcellular partitioning functionally links LC3A/B, the tumor microenvironment, and breast cancer survival

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HALO Publications, Oncology
March 16, 2021

Sandeep K Singhal, et al, Communications Biology, 2021
Singhal and colleagues apply quantitative automated image analysis to investigate the role of a transcriptional regulator, Kaiso, in a diverse cohort of breast cancer tumors. Specifically, they utilized the Highplex FL Module with the Tissue Microarray Module of HALO to characterize the tumor microenvironment in breast cancer TMA cores, including pan-cytokeratin, PD-L1, CD8, and CD68. They found that cytoplasmic Kaiso is associated with an immune-suppressed tumor microenvironment and found novel connections between Kaiso...

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Intratumoral interleukin-12 mRNA therapy promotes TH1 transformation of the tumor microenvironment

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Immuno-oncology, Publications
March 16, 2021

Susannah L Hewitt, et al, Clinical Cancer Research, 2020
In patients with advanced stage lung disease, it is beneficial to evaluate candidacy for immunotherapy without invasive biopsy testing. Lou et al performed a concordance study to evaluate formalin fixed cell blocks compared to lung tumor resections using a PD-L1 22C3 IHC pharmDx™ assay and found strong concordance between pathologists and HALO image analysis software. Future research will focus on clinical validation by assessing the clinical benefit from immunotherapy following PD-L1 immunohistochemistry...

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Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein

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HALO Publications
March 16, 2021

Chris McKinnon, et al, Acta Neuropathologica Communications, 2020
In this study, McKinnon et al identify overexpression of α-synuclein leading to catalytic impairment of the 26S proteosome in defined regions of rat brains. Brain tissue was fixed following α-synuclein overexpression for immunofluorescence studies of dopaminergic neurons which were quantified by the HALO image analysis platform. Future research will focus on characterizing the relationship between proteasome impairment and neurodegeneration....

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Implementation of PD-L1 22C3 IHC pharmDxTM in Cell Block Preparations of Lung Cancer: Concordance with Surgical Resections and Technical Validation of CytoLyt® Prefixation

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Oncology, Publications
March 16, 2021

Si Kei Lou, et al, Acta Cytologica, 2020
In patients with advanced stage lung disease, it is beneficial to evaluate candidacy for immunotherapy without invasive biopsy testing. Lou et al performed a concordance study to evaluate formalin fixed cell blocks compared to lung tumor resections using a PD-L1 22C3 IHC pharmDx™ assay and found strong concordance between pathologists and HALO image analysis software. Future research will focus on clinical validation by assessing the clinical benefit from immunotherapy following PD-L1 immunohistochemistry on...

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Deep Learning-Based Annotation Transfer between Molecular Imaging Modalities: An Automated Workflow for Multimodal Data Integration

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HALO AI Publications
March 15, 2021

Alan M. Race, et al, Analytical Chemistry, 2021
With increasing demand to correlate data across multiple imaging modalities, Race and colleagues demonstrate a mechanism by which annotations can be generated on images from one imaging modality and transferred to a second image modality for data integration (and optionally, back again). Further, they perform this workflow on mass spectrometry images of a pancreatic cancer mouse model and hematoxylin and eosin-stained sections. HALO and HALO AI image analysis software was used to develop...

Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

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HALO AI Publications
March 15, 2021

Juliana de Almeida-Faira, et al, Diabetologia, 2021
In this study, researchers set out to understand how miR-126-3, a microRNA found at increased levels in offspring of maternally obese mice, functioned in adipocyte metabolism. de Almeida-Faria and colleagues used proteomic approaches to identify a novel ER protein that is a direct target of miR-126-3 called Lunapark. HALO and HALO AI were used to train a DenseNet algorithm to selectively identify crown-like structures in H&E-stained fat tissue. Further, de Almeida-Faria and colleagues demonstrate...

Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer

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HALO AI Publications
March 15, 2021

Liang Guo, et al, Clinical Science, 2020
Prior to this publication it was known that dysfunctional PD-1hi CD8+ T cells infiltrated tumors, although it was unknown if this phenotype played a role in triple-negative breast cancer (TNBC). Guo et al set out to explore this phenotype in triple-negative breast cancer and using HALO and HALO AI demonstrated using both quantitative multiplexed immunohistochemistry and multispectral fluorescence imaging that PD-1hi CD8+ T cells were found in TNBC patient tissue biopsy core analysis but...

Comparing Deep Learning and Immunohistochemistry in Determining the Site of Origin for Well-Differentiated Neuroendocrine Tumors

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HALO AI Publications
March 15, 2021

Jordan Redemann, et al, Journal of Pathology Informatics, 2020
Metastatic neuroendocrine tumors behave differently according to site of origin and it is important clinically to identify the primary site in order to identify an appropriate therapy. The site of origin in neuroendocrine tumors are challenging to identify based on H&E alone and can require an immunohistochemistry (IHC) panel. Redemann and colleagues evaluated the performance of HALO AI, a deep-learning convolutional neural network (CNN) on site of origin identification from a set...

Independent Prognostic Value of Intratumoral Heterogeneity and Immune Response Features by Automated Digital Immunohistochemistry Analysis in Early Hormone Receptor-Positive Breast Carcinoma

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HALO AI Publications
March 15, 2021

Dovile Zilenaite, et al, Frontiers in Oncology, 2020
This study by Zilenaite and colleagues evaluated the prognostic value of digital image analysis using HALO on analysis of hormone receptor positive breast cancer IHC biomarkers including ER, PR, HER2, and Ki67 combined with information on tumor heterogeneity and immune response. HALO AI was used for tissue classification to differentiate tumor, stroma, and background (necrosis, artifacts, glass). For quantitative analysis of breast cancer biomarker expression and localization, the Multiplex IHC module of HALO...

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Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

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HALO AI Publications
March 15, 2021

Antje Neeb, et al, European Urology, 2021
Researchers set out to evaluate the role of the ATM kinase in metastatic castration-resistant prostate cancer (mCRPC) with the long-term goal of improving molecular stratification in patients. HALO and HALO AI were used in the analysis of 800 ATM immunohistochemistry samples. Neeb et al detected ATM loss by IHC in 11% of their patient cohort which was associated with increased genomic instability but was not associated with a worse outcome. An in vitro model...

Identification of immune checkpoints in COVID-19

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Spotlight on Covid-19 Research Publications
February 26, 2021

Researchers aiming to block excessive lung inflammation in COVID-19 patients found upregulated immune checkpoint biomarkers in patients with a range of COVID-19 symptoms (from paucisymptomatic to acute respiratory distress syndrome). In addition, Carvelli et al found increased expression of C5a, an inflammatory mediator, in serum and the C5aR1 receptor on myeloid cells in COVID-19 patients, which are known to initiate inflammatory responses by recruiting naeutrophils and monocytes to lungs. An In vitro neutrophil migration assay quantified with the CytoNuclear FL...

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Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

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Spotlight on Covid-19 Research Publications
October 15, 2020

Hoang, T.N., Pino, M., Boddapati, A.K. et al.. Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. This article is a preprint and has not been certified by peer review, doi: https://doi.org/10.1101/2020.09.16.300277 Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib...

ARDS and Cytokine Storm in SARS-CoV-2 Infected Caribbean Vervets

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Spotlight on Covid-19 Research Publications
October 15, 2020

Blair, R.V., Vaccari, M., Doyle-Meyers, L.A.. et al. ARDS and Cytokine Storm in SARS-CoV-2 Infected Caribbean Vervets. This article is a preprint and has not been certified by peer review. doi: https://doi.org/10.1101/2020.06.18.157933 SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Up to now, SARS-CoV-2 has infected more than five million and led to more than 300,000 deaths worldwide. Among those persons with serious COVID-19...

Acute Respiratory Distress and Cytokine Storm in Aged, SARS-CoV-2 Infected African Green Monkeys, but not in Rhesus Macaques

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Spotlight on Covid-19 Research Publications
October 15, 2020

Blair, R.V., Vaccari, M., Doyle-Meyers, L.A.. et al. Acute Respiratory Distress and Cytokine Storm in Aged, SARS-CoV-2 Infected African Green Monkeys, but not in Rhesus Macaques. This article is a preprint and has not been certified by peer review.  doi: https://doi.org/10.1101/2020.06.18.157933. SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a...

Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-Human Primates

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Spotlight on Covid-19 Research Publications
October 15, 2020

Rutkai, I., Mayer, M.G., Hellmers, L.M., et al. Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-Human Primates. This article is a preprint and has not been certified by peer review. DOI: 10.21203/rs.3.rs-59871/v1 Neurological manifestations are a significant complication of coronavirus infection disease-19 (COVID-19). Understanding how COVID-19 contributes to neurological disease is needed for appropriate treatment of infected patients, as well as in initiating relevant follow-up care after recovery. Investigation of autopsied brain tissue has been key to advancing our understanding...

Lung Expression of Human ACE2 Sensitizes the Mouse to SARS-CoV-2 Infection

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Spotlight on Covid-19 Research Publications
October 15, 2020

Han, K., Blair, R.V., Iwanaga ,N., et al. Lung Expression of Human ACE2 Sensitizes the Mouse to SARS-CoV-2 Infection. Am J Respir Cell Mol Biol. 2020 Sep 29. Preclinical mouse models that recapitulate some characteristics of COVID-19 will facilitate focused study of pathogenesis and virus-host responses. Human angiotensin converting enzyme (hACE2) serves as an entry receptor for SARS-CoV-2 to infect people via binding to spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6)...

Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

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HALO Publications, Infectious Disease, Spotlight on Covid-19 Research Publications
October 15, 2020

Lisa H Tostanoski, et al, Nature Medicine, 2020
In this study led by researchers at Harvard Medical School, they report the first demonstration of prevention of severe clinical disease in a hamster model of SARS-CoV-2 that were provided with a single immunization of the adenovirus serotype 26 (Ad26) vaccine. The Ad26 vaccine utilizes a stabilized spike protein of the SARS-CoV-2 and in the United States this vaccine is commonly known as the Johnson and Johnson vaccine. This study,...

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Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates

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Spotlight on Covid-19 Research Publications
October 15, 2020

Fahlberg, M.D., Blair, R.V., Doyle-Meyers, L.A. et al. Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates.  This article is a preprint and has not been certified by peer review. doi: https://doi.org/10.1101/2020.07.21.213777.  We investigated the immune events following SARS-COV-2 infection, from the acute inflammatory state up to four weeks post infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. The acute phase was characterized by a rapid migration of CD16+ monocytes from the blood and concomitant increase...

ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas

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Spotlight on Covid-19 Research Publications
October 15, 2020

Kusmartseva, I., Wu, W., Syed, F. et al. ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas. This article is a preprint and has not been certified by peer review.  doi: https://doi.org/10.1101/2020.08.31.270736 Diabetes is associated with increased mortality from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of the key molecule for SARS-CoV-2 infection of cells, angiotensin-converting enzyme-2 (ACE2). Specifically, we analyzed five public scRNAseq pancreas...

Two distinct immunopathological profiles in autopsy lungs of COVID-19

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HALO AI Publications, Spotlight on Covid-19 Research Publications
October 15, 2020

Ronny Nienhold, et al, Nature Communications, 2020
An international consortium of researchers characterized lung tissue from patients with COVID-19 using transcriptomic, histologic, and cellular analyses. Nienhold and colleagues report two phenotypes associated with lethal COVID-19 disease. One showed high levels of interferon stimulated genes in the lungs as well as limited lung damage and high levels of cytokines and viral loads. The second phenotype included severe lung damage with low levels of interferon stimulated genes, low viral loads, and high levels...

Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment

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HALO AI Publications
September 9, 2020

Uma Shanmugasundaram, et al, JCI Insight, 2020
Shanmugasundaram and colleagues used a nonhuman primate model to study T-cell responses associated with latent tuberculosis infection (LTBI). LTBI patients are asymptomatic and are thought to have contained the M. tuberculosis bacteria within granulomatous lesions in the lung. This research group wanted to characterize the immune responses associated with LTBI in order to understand how to prevent the progression to active tuberculosis (TB). In this JCI Insight publication, researchers report that rhesus macaques with...

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 infection in the lung epithelium

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Spotlight on Covid-19 Research Publications
September 9, 2020

Bryce A. Schuler, A. Christian Habermann, Erin J. Plosa, Chase J. Taylor, Christopher Jetter, Meghan E. Kapp, John T. Benjamin, Peter Gulleman, David S. Nichols, Lior Z. Braunstein, Alice Hackett, View ORCID ProfileMichael Koval, Susan H. Guttentag, Timothy S. Blackwell, Vanderbilt COVID-19 Consortium Cohort, Steven A. Webber, Nicholas E. Banovich, View ORCID ProfileJonathan A. Kropski, Jennifer M. S. Sucre, HCA Lung Biological Network bioRxiv | Posted August 03, 2020 | This article is a preprint and has not been certified by...

Artificial Intelligence-Based Quantification of Epithelial Proliferation in Mammary Glands of Rats and Oviducts of Göttingen Minipigs

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HALO AI Publications
September 9, 2020

Henning Hvid, Mikala Skydsgaard, Nikolai K. Jensen, Birgitte M. Viuff, Henrik E. Jensen, Martin B. Oleksiewicz, Peter H. Kvist Toxicologic Pathology | First Published August 25, 2020 | Research Article | https://doi.org/10.1177/0192623320950633 Quantitative assessment of proliferation can be an important endpoint in toxicologic pathology. Traditionally, cell proliferation is quantified by labor-intensive manual counting of positive and negative cells after immunohistochemical staining for proliferation markers (eg, Ki67, bromo-2′-deoxyuridine, or proliferating cell nuclear antigen). Currently, there is a lot of interest in replacing manual...

Immunogradient Indicators for Antitumor Response Assessment by Automated Tumor-Stroma Interface Zone Detection

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HALO AI Publications, Publications
June 9, 2020

Allan Rasmusson, et al, The American Journal of Pathology, 2020
An international consortium of researchers characterized lung tissue from patients with COVID-19 using transcriptomic, histologic, and cellular analyses. Nienhold and colleagues report two phenotypes associated with lethal COVID-19 disease. One showed high levels of interferon stimulated genes in the lungs as well as limited lung damage and high levels of cytokines and viral loads. The second phenotype included severe lung damage with low levels of interferon stimulated genes, low viral loads,...

Prognostic significance of mesothelin expression in colorectal cancer disclosed by area-specific four-point tissue microarrays

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HALO AI Publications, Publications
June 9, 2020

Mesothelin (MSLN) is a cell surface glycoprotein present in many cancer types. Its expression is generally associated with an unfavorable prognosis. This study examined the prognostic significance of MSLN expression in different areas of individual colorectal cancers (CRCs) using tissue microarrays (TMAs) by enrolling 314 patients with stage II (T3–T4, N0, M0) CRCs. Using formalin-fixed paraffin-embedded tissue blocks from patients, TMA blocks were constructed. Tissue core specimens were obtained from submucosal invasive front (Fr-sm), subserosal invasive front (Fr-ss), central...

Detection of Lung Cancer Lymph Node Metastases from Whole-Slide Histopathologic Images Using a Two-Step Deep Learning Approach

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HALO AI Publications, Publications
December 3, 2019

Hoa Hoang Ngoc Pham, et al, The American Journal of Pathology, 2020
Pham and colleagues set out to address high false positivity of lymph nodes metastasis analysis using deep learning. As characterizing lymph node metastases in breast and lung cancer is of great clinical importance for treatment selection and prognosis, finding a method with high sensitivity and specificity would represent a major advance. Here, the researchers demonstrate a two-step approach with HALO AI where the first deep learning algorithm excludes...

A Deep Learning Convolutional Neural Network Can Recognize Common Patterns of Injury in Gastric Pathology

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HALO AI Publications, Publications
December 3, 2019

David R. Martin, et al, Archives of Pathology & Laboratory Medicine, 2019
Researchers from the University of New Mexico set out to investigate tissue classification using deep learning to evaluate nonneoplastic gastric biopsies. Ground truth diagnosis was established by gastrointestinal pathologists. HALO AI was trained to recognize Helicobacter pylori (H pylori) mediated gastritis, chemical gastropathy, normal mucosa, smooth muscle, and glass. The HALO AI classifier showed high sensitivity and specificity for control biopsies and gastropathy cases and represents the first deep...

Automated Analysis of Lymphocytic Infiltration, Tumor Budding, and Their Spatial Relationship Improves Prognostic Accuracy in Colorectal Cancer

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News, Publications
March 7, 2019

Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3þCD8þ T cells, and tumor buds (TBs), across whole slide images of three independent cohorts...

Peroxisome Proliferator-Activated Receptor g2 Controls the Rate of Adipose Tissue Lipid Storage and Determines Metabolic Flexibility

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Publications
September 7, 2018

/*! elementor - v3.8.0 - 30-10-2022 */.elementor-widget-image{text-align:center}.elementor-widget-image a{display:inline-block}.elementor-widget-image a img[src$=".svg"]{width:48px}.elementor-widget-image img{vertical-align:middle;display:inline-block} One understudied function of white adipose tissue (AT) is its role in postprandial lipid buffering. In this study, we demonstrate that mice lacking the adipose tissue-specific transcription factor peroxisome proliferator activated receptor g2 (PPARg2) exhibit a defect in their rate of adipose tissue lipid storage. Impaired adipose tissue storage rate reduces metabolic flexibility, without compromising fasted glucose tolerance or insulin sensitivity, even following prolonged high-fat feeding. However, acutely overfeeding...

FOXM1 contributes to treatment failure in acute myeloid leukemia

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Publications
August 14, 2018

Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML. A multiinstitution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We establish nuclear FOXM1 as an independent clinical predictor...

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Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity

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Publications
July 30, 2018

/*! elementor - v3.8.0 - 30-10-2022 */.elementor-widget-image{text-align:center}.elementor-widget-image a{display:inline-block}.elementor-widget-image a img[src$=".svg"]{width:48px}.elementor-widget-image img{vertical-align:middle;display:inline-block} SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic β-cell mass. Interestingly, in hyperglycemic...

Digital image analysis improves precision of PD‐L1 scoring in cutaneous melanoma

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Publications
June 15, 2018

Abstract Aims Immune checkpoint inhibitors have become a successful treatment in metastatic melanoma. The high response rates in a subset of patients suggest that a sensitive companion diagnostic test is required. The predictive value of programmed death ligand 1 (PD‐L1) staining in melanoma has been questioned due to inconsistent correlation with clinical outcome. Whether this is due to predictive irrelevance of PD‐L1 expression or inaccurate assessment techniques remains unclear. The aim of this study was to develop a standardised digital protocol...

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A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade

by admin
Publications
June 15, 2018

Abstract Evidence from mouse chronic viral infection models suggests that CD8+T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1–) from...

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The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung

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Publications
May 31, 2018

Abstract The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the neurotrophin co-receptor p75NTR and the proneurotrophin co-receptor sortilin, remains unclear. In the present study, analysis of these proteins was conducted by immunohistochemistry and digital quantification in a series of 204 lung cancers...

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

by admin
Publications
May 31, 2018

Abstract Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin...

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

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Publications
May 31, 2018

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests. Tumors containing more CD8+ T cells also had increased granulocytes, CD163+ (M2...

PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance

by admin
Publications
March 7, 2018

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis...

The R-enantiomer of ketorolac delays mammary tumor development in mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice

by admin
Publications
December 14, 2017

Abstract Epidemiologic studies report improved breast cancer survival in women receiving ketorolac (Toradol®) for post-operative pain relief compared to other analgesics. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. our goal was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor...

High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer

by admin
Publications
December 14, 2017

Abstract Conflicting reports regarding whether high tumor-associated neutrophils (TAN) are associated with outcomes in colorectal cancer (CRC) exist. Previous investigators have counted TAN using non-neutrophil-specific immunohistochemistry (IHC) stains. We examined whether TAN levels as determined by multi-field manual counting would predict prognosis. IRB approval was obtained and two pathologists, blinded to stage/outcome, counted TAN in 20 high power fields (HPF) per specimen. TAN score was defined as the mean of these counts. High TAN was defined as at or greater...

Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma

by admin
Publications
December 14, 2017

Abstract Importance  The programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway play an important immunosuppressive role in cancer and chronic viral infection, and have been effectively targeted in cancer therapy. Anal squamous cell carcinoma (SCC) is associated with both human papillomavirus and HIV infection. To date, patients with HIV have been excluded from most trials of immune checkpoint blocking agents, such as anti–PD-1 and anti–PD-L1, because it was assumed that their antitumor immunity was compromised compared with...

Cross-Platform Comparison of Computer-assisted Image Analysis Quantification of In Situ mRNA Hybridization in Investigative Pathology.

by admin
Publications
August 10, 2017

ABSTRACT Although availability of automated platforms has proliferated, there is no standard practice for computer-assisted generation of scores for mRNA in situ hybridization (ISH) visualized by brightfield microscopic imaging on tissue sections. To address this systematically, an ISH for peptidylprolyl isomerase B (PPIB) (cyclophilin B) mRNA was optimized and applied to a tissue microarray of archival non–small cell lung carcinoma cases, and then automated image analysis for PPIB was refined across 4 commercially available software platforms. Operator experience and scoring...

A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

by admin
Publications
July 26, 2017

Abstract We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)–EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for...

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Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice

by admin
Publications
February 23, 2017

Abstract Autoantigen-specific immunological tolerance represents a central objective for prevention of type 1 diabetes (T1D). Previous studies demonstrated mucosal antigen administration results in expansion of Foxp3+ and LAP+ regulatory T cells (Tregs), suggesting oral delivery of self-antigens might represent an effective means for modulating autoimmune disease. Early preclinical experiments using the non-obese diabetic (NOD) mouse model reported mucosal administration of T1D-related autoantigens [proinsulin or glutamic acid decarboxylase 65 (GAD)] delayed T1D onset, but published data are conflicting regarding dose, treatment...

Molecular Pathways: Mucins and Drug Delivery in Cancer

by admin
Publications
February 23, 2017

Abstract Over the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to efficiently mask the epithelial cells and ensure survival under hostile tumor microenvironment...

Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

by admin
Publications
February 14, 2017

Abstract Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization...

Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition

by admin
Publications
February 14, 2017

Abstract Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498–15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4−/− mice treated with an anti-glucagon receptor monoclonal antibody undergo...

Neutrophils dominate the immune cell composition in non-small cell lung cancer

by admin
Publications
February 14, 2017

Abstract The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC. The...

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

by admin
Publications
February 14, 2017

Abstract Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following...

Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

by admin
Publications
February 14, 2017

Abstract Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The...

Differential Cytokine Gene Expression in Granulomas from Lungs and Lymph Nodes of Cattle Experimentally Infected with Aerosolized Mycobacterium bovis

by admin
Publications
December 8, 2016

Abstract The hallmark lesion of tuberculosis in humans and animals is the granuloma. The granuloma represents a distinct host cellular immune response composed of epithelioid macrophages, lymphocytes, and multinucleated giant cells, often surrounding a caseous necrotic core. Within the granuloma, host-pathogen interactions determine disease outcome. Factors within the granulomas such as cytokines and chemokines drive cell recruitment, activity, function and ultimately the success or failure of the host’s ability to control infection. Hence, an understanding of the granuloma-level cytokine response...

Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells

by admin
Publications
September 27, 2016

Abstract This study provides an assessment of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. The system combines microfluidic technology and nanoliter-scale reactions. We sequenced 622 cells, allowing identification of 341 islet cells with high-quality gene expression profiles. The cells clustered into populations of α-cells (5%), β-cells (92%), δ-cells (1%), and pancreatic polypeptide cells (2%). We identified cell-type–specific transcription factors and pathways primarily involved in nutrient sensing and oxidation and cell signaling. Unexpectedly, 281 cells...

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

by admin
Publications
September 13, 2016

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined. We demonstrate herein that CaMKII expression and phosphorylation at T286 is increased in breast cancer when compared to normal breast tissue, and that increased CAMK2 mRNA is associated with poor breast cancer patient...

Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

by admin
Publications
August 18, 2016

BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety ofhyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells.Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here weshow how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytesthrough extracellular signal-regulated kinase (ERK) phos-phorylation and cell cycle progression. Topical...

Exacerbated Experimental Colitis in TNFAIP8-Deficient Mice

by admin
Publications
August 1, 2015

The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiologic and pathologic functions are unclear. In this study, we describe the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs, including lymphoid organs and intestines, were macroscopically and...

Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer

by admin
Publications
August 1, 2015

Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p =...

ANGPTL8/betatrophin does not control pancreatic beta cell expansion

by admin
Publications
August 1, 2015

Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought “betatrophin” that could control pancreatic beta cell proliferation. However, studies of Angptl8(?/?) mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8(?/?) mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles...

Islet-1 is essential for pancreatic beta cell function

by admin
Publications
August 1, 2015

Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal β-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, β-cell-specific Isl-1 loss-of-function mouse: Isl-1(L/L); Pdx1-CreER(Tm). Ablating Isl-1 in postnatal β-cells reduced glucose tolerance without significantly reducing β-cell mass or increasing β-cell apoptosis. Rather,...

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

by admin
Publications
August 1, 2015

/*! elementor - v3.8.0 - 30-10-2022 */.elementor-widget-image{text-align:center}.elementor-widget-image a{display:inline-block}.elementor-widget-image a img[src$=".svg"]{width:48px}.elementor-widget-image img{vertical-align:middle;display:inline-block} The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds...

Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys

by admin
Publications
August 1, 2015

Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating...

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