Indica
Backed by cutting edge technology, an uncompromising focus on ease-of-use and dedicated customer service, Indica Labs’ software and services are being used to make vital discoveries in pathology labs and research organizations around the world.

Publications

Indica Labs / Publications
Neuron Publication Cover

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

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...

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

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...

Transmission of tauopathy strains is independent of their isoform composition

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...

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

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...

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

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...

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

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...

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

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

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

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

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

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 (training...

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

/*! 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 PPARg2-KO...

FOXM1 contributes to treatment failure in acute myeloid leukemia

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 of...

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

/*! 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 conditions...

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

Abstract AimsImmune 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 for...

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

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 non-small-cell...

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

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 of...

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

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 (Sst)-neurons...

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

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 immunosuppressive...

PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance

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 and...

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

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 virus-polyoma...

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

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 than...

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

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 immunocompetent...

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

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 results...

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

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 over...

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

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 duration,...

Molecular Pathways: Mucins and Drug Delivery in Cancer

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 conditions....

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

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 of...

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

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 elevation...

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

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 results...

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

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 3...

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

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 mitochondrial...

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

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 is...

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

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 had...

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

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 prognosis...

Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

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 treatment...

Exacerbated Experimental Colitis in TNFAIP8-Deficient Mice

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 microscopically...

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

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 = 0.0003)....

ANGPTL8/betatrophin does not control pancreatic beta cell expansion

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 plasma...

Islet-1 is essential for pancreatic beta cell function

Ediger BN, Du A, Liu J, Hunter CS, Walp ER, Schug J, Kaestner KH, Stein R, Stoffers DA, May CL. Diabetes. 2014 Dec;63(12):4206-17. 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:...

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

/*! 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 competitively...

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

Okamoto H, Kim J, Aglione J1, Lee J, Cavino K, Na E1, Rafique A, Kim JH, Harp J, Valenzuela DM, Yancopoulos GD, Murphy AJ, Gromada J. Endocrinology. 2015 Aug;156(8):2781-94. 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...