Unlocking the Role of a Genital Herpesvirus, Otarine Herpesvirus 1, in California Sea Lion Cervical Cancer

Animals

2021 Feb 13

Deming, A;Wellehan, J;Colegrove, K;Hall, A;Luff, J;Lowenstine, L;Duignan, P;Cortés-Hinojosa, G;Gulland, F;
| DOI: 10.3390/ani11020491

Urogenital carcinoma in California sea lions (Zalophus californianus) is the most common cancer of marine mammals. Primary tumors occur in the cervix, vagina, penis, or prepuce and aggressively metastasize resulting in death. This cancer has been strongly associated with a sexually transmitted herpesvirus, otarine herpesvirus 1 (OtHV1), but the virus has been detected in genital tracts of sea lions without cancer and a causative link has not been established. To determine if OtHV1 has a role in causing urogenital carcinoma we sequenced the viral genome, quantified viral load from cervical tissue from sea lions with (n = 95) and without (n = 163) urogenital carcinoma, and measured viral mRNA expression using in situ mRNA hybridization (Basescope ) to quantify and identify the location of OtHV1 mRNA expression. Of the 95 sea lions diagnosed with urogenital carcinoma, 100% were qPCR positive for OtHV1, and 36% of the sea lions with a normal cervix were positive for the virus. The non-cancer OtHV1 positive cases had significantly lower viral loads in their cervix compared to the cervices from sea lions with urogenital carcinoma. The OtHV1 genome had several genes similar to the known oncogenes, and RNA in situ hybridization demonstrated high OtHV1 mRNA expression within the carcinoma lesions but not in normal cervical epithelium. The high viral loads, high mRNA expression of OtHV1 in the cervical tumors, and the presence of suspected OtHV1 oncogenes support the hypothesis that OtHV1 plays a significant role in the development of sea lion urogenital carcinoma.

Increased Abundance of Tumour-Associated Neutrophils in HPV-Negative Compared to HPV-Positive Oropharyngeal Squamous Cell Carcinoma Is Mediated by IL-1R Signalling

Frontiers in Oral Health

2021 Feb 11

Al-Sahaf, S;Hendawi, N;Ollington, B;Bolt, R;Ottewell, P;Hunter, K;Murdoch, C;
| DOI: 10.3389/froh.2021.604565

The incidence of human papillomavirus (HPV)-associated cancer is increasing and HPV is now implicated in the aetiology of more than 60% of all oropharyngeal squamous cell carcinomas (OPSCC). In OPSCC, innate immune cells such as neutrophils and macrophages generally correlate with poor prognosis, whilst adaptive immune cells, such as lymphocytes, tend to correlate with improved prognosis. This may, in part, be due to differences in the immune response within the tumour microenvironment leading to the recruitment of specific tumour-associated leukocyte sub-populations. In this study, we aimed to examine if differences exist in the levels of infiltrated leukocyte sub-populations, with particular emphasis on tumour-associated neutrophils (TAN), and to determine the mechanism of chemokine-induced leukocyte recruitment in HPV-positive compared to HPV-negative OPSCC. Immunohistochemical analysis showed that HPV-negative OPSCC contained significantly more neutrophils than HPV-positive tumours, whilst levels of CD68+ macrophages and CD3+ lymphocytes were similar. Using a 3D tissue culture model to represent tumour-stromal interactions, we demonstrated that HPV-negative tumour-stromal co-cultures expressed significantly higher levels of CXCL8, leading to increased neutrophil recruitment compared to their HPV-positive counterparts. HPV-negative OPSCC cells have previously been shown to express higher levels of IL-1 than their HPV-positive counterparts, indicating that this cytokine may be responsible for driving increased chemokine production in the HPV-negative 3D model. Inhibition of IL-1R in the tumour-stromal models using the receptor-specific antagonist, anakinra, dramatically reduced chemokine secretion and significantly impaired neutrophil and monocyte recruitment, suggesting that this tumour-stromal response is mediated by the IL-1/IL-1R axis. Here, we identify a mechanism by which HPV-negative OPSCC may recruit more TAN than HPV-positive OPSCC. Since TAN are associated with poor prognosis in OPSCC, our study identifies potential therapeutic targets aimed at redressing the chemokine imbalance to reduce innate immune cell infiltration with the aim of improving patient outcome.

A Modeling Framework for Investigating the Role of Human Atrial Fibroblast Calcium Signaling in Fibrogenesis

Biophysical Journal

2021 Feb 01

Fogli Iseppe, A;Morotti, S;Tekook, M;Hoffmann, D;Edwards, A;Dobrev, D;Grandi, E;
| DOI: 10.1016/j.bpj.2020.11.561

Atrial fibrosis is a prominent feature of atrial fibrillation (AF), the most prevalent chronic arrhythmia, and contributes importantly to the vulnerable substrate that promotes and maintains the arrhythmia. While the importance of atrial fibrosis in AF is well-established, and underscored by its potential use as a marker to guide AF ablation therapy, the mechanisms of its formation are largely unknown. Calcium-dependent processes have been involved in AF-promoting structural remodeling, making calcium-handling abnormalities a potentially critical element in AF pathophysiology. However, the exact molecular pathways controlling atrial fibroblast (Fb) proliferation/differentiation and those regulating transcription of extracellular matrix proteins remain largely unknown in any tissue, species, or disease state. To address this unmet need, we have developed a multi-scale modeling framework to 1) quantitively define the major players regulating intracellular calcium homeostasis in human atrial Fbs in both normal sinus rhythm and AF conditions, and to 2) link mechanistically the changes in human atrial Fb calcium signals to downstream outcomes (Fb activation and proliferation and collagen expression) under various profibrotic stimuli. Specifically, this involved building of a new mathematical model of cardiac fibroblast electrophysiology and calcium handling, based on a novel extensive experimental dataset in human atrial Fbs, and coupling it with an experimentally-constrained logic-based network model reflecting the role of calcium in acute (phosphoregulatory) and delayed (transcriptional) human atrial Fb signaling. We demonstrate the use of our computational framework in predicting the effects of angiotensin-II (AngII), a well-known promoter of cardiac fibrosis, on acute human atrial Fb calcium signals and longer-term downstream fibrotic outcomes. We further utilize the model to identify key mechanisms involved in both acute and chronic calcium signaling dysregulation, which could hold therapeutic promise.

Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Jan 25

Steele, NG;Biffi, G;Kemp, SB;Zhang, Y;Drouillard, D;Syu, LJ;Hao, Y;Oni, TE;Brosnan, E;Elyada, E;Doshi, A;Hansma, C;Espinoza, C;Abbas, A;The, S;Irizarry-Negron, VM;Halbrook, CJ;Franks, N;Hoffman, M;Brown, KL;Carpenter, ES;Nwosu, ZC;Johnson, C;Lima, F;Anderson, MA;Park, Y;Crawford, HC;Lyssiotis, CA;Frankel, TL;Rao, A;Bednar, F;Dlugosz, AA;Preall, J;Tuveson, DA;Allen, B;Pasca di Magliano, M;
PMID: 33495315 | DOI: 10.1158/1078-0432.CCR-20-3715

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog (HH) pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of HH signaling in PDAC have been contradictory, with HH signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how HH pathway inhibition reprograms the PDAC microenvironment. We used a combination of pharmacologic inhibition, gain- and loss- of-function genetic experiments, CyTOF, and single cell RNA-sequencing to study the roles of HH signaling in PDAC. We find that HH signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAFs) compared to inflammatory CAFs (iCAFs). SHH overexpression promotes tumor growth, while HH pathway inhibition with the Smoothened antagonist LDE225 impairs tumor growth. Further, HH pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immune suppression. HH pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

The Impact of Avpr1a Expression and Host-Microbiome Interactions on Visceral Hypersensitivity

The Journal of Pain

2022 May 01

Kader, L;Willits, A;Baumbauer, K;Young, E;
| DOI: 10.1016/j.jpain.2022.03.026

Visceral hypersensitivity (VH) is commonly cited as a major driver of chronic abdominal pain in “functional” gastrointestinal disorders (e.g., irritable bowel syndrome) where persistent and/or recurrent abdominal pain is the primary unifying symptom regardless of any alterations in bowel habits. The complexity of VH is in part influenced by genetic factors and individual differences in gut microbiome composition, yet specific mechanisms that generate VH remain incompletely understood. Correspondingly, current treatments to primarily focus on symptom management rather than targeting physiological mechanisms responsible for generating VH. We have begun to examine the role of genetic susceptibility and microbiome response dynamics in VH development using a preclinical model of intracolonic zymosan (ZYM) administration in which there are strain differences to VH susceptibility. Preliminary data reveals differential susceptibility between ZYM-induced VH in two closely related C57BL/6 sub strains, one from Taconic Biosciences (C57BL/6NTac) and the other from Jackson Laboratory (C57BL/6J). We have identified a VH candidate gene that encodes the arginine-vasopressin receptor 1A (AVPR1A) protein. We have further observed dynamic strain differences in the location and composition of the gut microbiome in response to ZYM corresponding to VH susceptibility. Ongoing studies are focused on teasing apart the potential bidirectional relationship(s) between genetic susceptibility and host-microbiome interactions in the etiology of VH. Identifying underlying mechanisms that drive VH would provide novel targets for pharmacological intervention and decrease reliance on opioids, which are prescribed at a significantly higher rate to patients who report abdominal pain with no accompanying structural disease. Grant support from R21 NS104789/NS/NINDS (KMB), R03 NS096454/NS/NINDS (KMB), Rita Allen Foundation Award in Pain (KMB), P20GM103418 (EEY and KMB), and a K-INBRE recruitment startup package.

HCV Infection Alters Salivary Gland Histology and Saliva Composition

Journal of dental research

2022 Jan 20

Maldonado, JO;Beach, ME;Wang, Y;Perez, P;Yin, H;Pelayo, E;Fowler, S;Alevizos, I;Grisius, M;Baer, AN;Walitt, B;De Giorgi, V;Alter, HJ;Warner, BM;Chiorini, JA;
PMID: 35045743 | DOI: 10.1177/00220345211049395

Hepatitis C virus (HCV) infection is the most common blood-borne chronic infection in the United States. Chronic lymphocytic sialadenitis and sicca syndrome have been reported in chronic HCV infection. Up to 55% of these patients may have xerostomia; the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. The objectives of this project are to establish if xerostomia associates with SG and HCV infection and to characterize the structural changes in SG and saliva composition. Eighteen HCV-infected patients with xerostomia were evaluated for SG dysfunction; 6 of these patients (patients 1-6) were further evaluated for SG histopathological changes and changes in saliva composition. The techniques used include clinical and laboratory assessment, SG ultrasonography, histological evaluation, sialochemical and proteomics analysis, and RNA in situ hybridization. All the HCV patients had low saliva flow, chronic sialadenitis, and SG fibrosis and lacked Sjögren syndrome (SS) characteristic autoantibodies. Further evaluation of a subgroup of 6 HCV patients (patients 1-6) demonstrated diffuse lymphocytic infiltrates that are predominantly CD8+ T cells with a significant increase in the number of inflammatory cells. Alcian Blue/periodic acid-Schiff staining showed significant changes in the ratio and intensity of the acinar secretory units of the HCV patients' minor SG. The submandibular glands showed significant ultrasonographic abnormalities in the parenchyma relative to the parotid glands. Significant changes were also observed in the concentration of sodium and mucin 5b. Although no significant correlation was observed between the lymphocytic infiltrates and the years of HCV chronic infection, a positive correlation was observed between HCV RNA-positive epithelial cells and the years of HCV infection. Consistent with the low saliva flow and xerostomia, patients showed changes in several markers of SG acinar and ductal function. Changes in the composition of the saliva suggest that HCV infection can cause xerostomia by mechanisms distinct from SS.

Precision Cancer Medicine

Springer

2022 Jan 04

Jasani, B;Huss, R;Taylor, C;
| DOI: 10.1007/978-3-030-84087-7

Bharat Jasani, BSc, PhD, MBChB, FRCPath. Qualifying with honours in Biochemistry (University of Glasgow,1965-1969), PhD in Experimental Pathology and MBChB (honours distinction in Pathology) (University of Birmingham, 1970-1973), Dr Jasani initiated his clinical and research training in Histopathology, at Wales National School of Medicine in 1977, achieving MRCPath (1989), FRCPath (1997), and a Specialist Consultant’s status in Histopathology (Immunohistochemistry) (1993); and Personal Chair in Oncological Pathology (2003). Following his retirement as the Head of Histopathology and Academic Pathology (2003-2011), he continued as Professor of Pathology, Institute of Cancer & Genetics, Cardiff University & Associate Postgraduate Dean for Academic Medicine in Wales (2011-2015). He was then appointed as the Chair of Biomedical Sciences, Nazarbayev University School of Medicine. Astana, Kazakhstan, with Adjunct Professorship in Pathology, University of Pittsburgh School of Medicine, Pittsburg, USA (2015-2016). IN 2016 HE TOOK UP HIS CURRENT POSITION AS THE DIRECTOR OF PATHOLOGY, TARGOS MOLECULAR PATHOLOGY GMBH, KASSEL, GERMANY, WHICH WAS ACQUIRED BY DISCOVERY LIFE SCIENCES IN 2021. Over the past 40 years Dr Jasani has devoted himself to advancing cancer pathology based on the use of cancer biomarkers. As the Head of Molecular Diagnostic Unit, University Hospital of Wales (1982-2003), he led the development and establishment of diagnostic immunocytochemistry & molecular pathology services in Cardiff and Wales. He also promoted quality assurance and standardization of cancer biomarker analyses as Breast Cancer Module Leader of UKNEQAS of IHC/ISH, and UK’s lead representative on International Working Group on Standardization of Breast Cancer Biomarking, and the United States Sub-Committee on Quality Assurance for Immunocytochemistry. As Principal Investigator and Co-investigator of several translational research projects on development of predictive biomarkers for colorectal and breast cancer, he has also been invited to act as a Consultant and Key Opinion Leader to several leading biotech and pharmaceutical companies. He is an author of a book, over 50 chapters and reviews and more than 200 peer reviewed research publications.

Blocking Kallikrein 6 promotes developmental myelination

Glia

2021 Oct 09

Yoon, H;Triplet, EM;Simon, WL;Choi, CI;Kleppe, LS;De Vita, E;Miller, AK;Scarisbrick, IA;
PMID: 34626143 | DOI: 10.1002/glia.24100

Kallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and female mice as a model. Results demonstrate that constitutive loss of Klk6 expression accelerates oligodendrocyte differentiation developmentally, including increases in the expression of myelin proteins such as MBP, PLP and CNPase, in the number of CC-1+ mature oligodendrocytes, and myelin thickness by the end of the first postnatal week. Co-ordinate elevations in the pro-myelinating signaling pathways ERK and AKT, expression of fatty acid 2-hydroxylase, and myelin regulatory transcription factor were also observed in the spinal cord of 7d Klk6 knockouts. LC/MS/MS quantification of spinal cord lipids showed sphingosine and sphingomyelins to be elevated in Klk6 knockouts at the peak of myelination. Oligodendrocyte progenitor cells (OPCs)-derived from Klk6 knockouts, or wild type OPCs-treated with a Klk6 inhibitor (DFKZ-251), also showed increased MBP and PLP. Moreover, inhibition of Klk6 in OPC cultures enhanced brain derived neurotrophic factor-driven differentiation. Altogether, these findings suggest that oligodendrocyte-derived Klk6 may operate as an autocrine or paracrine rheostat, or brake, on pro-myelinating signaling serving to regulate myelin homeostasis developmentally and in the adult. These findings document for the first time that inhibition of Klk6 globally, or specifically in oligodendrocyte progenitors, is a strategy to increase early stages of oligodendrocyte differentiation and myelin production in the CNS.

Pulmonary implications of acetaminophen exposures independent of hepatic toxicity

American journal of physiology. Lung cellular and molecular physiology

2021 Nov 01

Dobrinskikh, E;Al-Juboori, SI;Zarate, MA;Zheng, L;De Dios, R;Balasubramaniyan, D;Sherlock, LG;Orlicky, DJ;Wright, CJ;
PMID: 34585971 | DOI: 10.1152/ajplung.00234.2021

Both preclinical and clinical studies have demonstrated that exposures to acetaminophen (APAP) at levels that cause hepatic injury cause pulmonary injury as well. However, whether exposures that do not result in hepatic injury have acute pulmonary implications is unknown. Thus, we sought to determine how APAP exposures at levels that do not result in significant hepatic injury impact the mature lung. Adult male ICR mice (8-12 wk) were exposed to a dose of APAP known to cause hepatotoxicity in adult mice [280 mg/kg, intraperitoneal (ip)], as well as a lower dose previously reported to not cause hepatic injury (140 mg/kg, ip). We confirm that the lower dose exposures did not result in significant hepatic injury. However, like high dose, lower exposure resulted in increased cellular content of the bronchoalveolar lavage fluid and induced a proinflammatory pulmonary transcriptome. Both the lower and higher dose exposures resulted in measurable changes in lung morphometrics, with the lower dose exposure causing alveolar wall thinning. Using RNAScope, we were able to detect dose-dependent, APAP-induced pulmonary Cyp2e1 expression. Finally, using FLIM we determined that both APAP exposures resulted in acute pulmonary metabolic changes consistent with mitochondrial overload in lower doses and a shift to glycolysis at a high dose. Our findings demonstrate that APAP exposures that do not cause significant hepatic injury result in acute inflammatory, morphometric, and metabolic changes in the mature lung. These previously unreported findings may help explain the potential relationship between APAP exposures and pulmonary-related morbidity.

RNA sequence analysis reveals ITGAL/CD11A as a stromal regulator of murine low-grade glioma growth

Neuro-oncology

2021 May 27

De Andrade Costa, A;Chatterjee, J;Cobb, O;Sanapala, S;Guo, X;Dahiya, S;Gutmann, DH;
PMID: 34043012 | DOI: 10.1093/neuonc/noab130

Emerging insights from numerous laboratories have revealed important roles for non-neoplastic cells in the development and progression of brain tumors. One of these non-neoplastic cellular constituents, glioma-associated microglia (GAM), represents a unique population of brain monocytes within the tumor microenvironment that have been reported to both promote and inhibit glioma proliferation. To elucidate the role of GAM in the setting of low-grade glioma (LGG), we leveraged RNA sequencing meta-analysis, genetically engineered mouse strains, and human biospecimens. Publically available disease-associated microglia (DAM) RNA-seq datasets were used, followed by immunohistochemistry and RNAScope validation. CD11a-deficient mouse microglia were used for in vitro functional studies, while LGG growth in mice was assessed using anti-CD11a neutralizing antibody treatment of Nf1 optic glioma mice in vivo. We identified Itgal/CD11a enrichment in GAM relative to other DAM populations, which was confirmed in several independently generated murine models of Neurofibromatosis type 1 (Nf1) optic glioma. Moreover, ITGAL/CD11A expression was similarly increased in human LGG (pilocytic astrocytoma) specimens from several different datasets, specifically in microglia from these tumors. Using CD11a-knockout mice, CD11a expression was shown to be critical for murine microglia CX3CL1 receptor (Cx3cr1) expression and CX3CL1-directed motility, as well as glioma mitogen (Ccl5) production. Consistent with an instructive role for CD11a + microglia in stromal control of LGG growth, antibody-mediated CD11a inhibition reduced mouse Nf1 LGG growth in vivo. Collectively, these findings establish ITGAL/CD11A as a critical microglia regulator of LGG biology relevant to future stroma-targeted brain tumor treatment strategies.

A N-Terminus Domain Determines Amelogenin\'s Stability to Guide the Development of Mouse Enamel Matrix

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2021 May 06

Huang, Y;Bai, Y;Chang, C;Bacino, M;Cheng, IC;Li, L;Habelitz, S;Li, W;Zhang, Y;
PMID: 33957008 | DOI: 10.1002/jbmr.4329

Amelogenins, the principal proteins in the developing enamel microenvironment, self-assemble into supramolecular structures to govern the remodeling of a proteinaceous organic matrix into longitudinally ordered hydroxyapatite nanocrystal arrays. Extensive in vitro studies using purified native or recombinant proteins have revealed the potential of N-terminal amelogenin on protein self-assembly and its ability to guide the mineral deposition. We have previously identified a 14-aa domain (P2) of N-terminal amelogenin that can self-assemble into amyloid-like fibrils in vitro. Here, we investigated how this domain affects the ability of amelogenin self-assembling and stability of enamel matrix protein scaffolding in an in vivo animal model. Mice harboring mutant amelogenin lacking P2 domain had a hypoplastic, hypomineralized, and aprismatic enamel. In vitro, the mutant recombinant amelogenin without P2 had a reduced tendency to self-assemble and was prone to accelerated hydrolysis by MMP20, the prevailing metalloproteinase in early developing enamel matrix. A reduced amount of amelogenins and a lack of elongated fibrous assemblies in the development enamel matrix of mutant mice were evident compared with that in the wild-type mouse enamel matrix. Our study is the first to demonstrate that a subdomain (P2) at the N-terminus of amelogenin controls amelogenin's assembly into a transient protein scaffold that resists rapid proteolysis during enamel development in an animal model. Understanding the building blocks of fibrous scaffold that guides the longitudinal growth of hydroxyapatites in enamel matrix sheds light on protein-mediated enamel bioengineering.

Estrogen regulation of the molecular phenotype and active translatome of AVPV kisspeptin neurons

Endocrinology

2021 Apr 15

Stephens, SBZ;Kauffman, AS;
PMID: 33856454 | DOI: 10.1210/endocr/bqab080

In females, ovarian estradiol (E2) exerts both negative and positive feedback regulation on the neural circuits governing reproductive hormone secretion, but the cellular and molecular mechanisms underlying this remain poorly understood. In rodents, ERα-expressing kisspeptin neurons in the hypothalamic anteroventral periventricular region (AVPV) are prime candidates to mediate E2 positive feedback induction of preovulatory GnRH and LH surges. E2 stimulates AVPV Kiss1 expression, but the full extent of estrogen effects in these neurons is unknown; whether E2 stimulates or inhibits other genes in AVPV Kiss1 cells has not been determined. Indeed, understanding of the function(s) of AVPV kisspeptin cells is limited, in part, by minimal knowledge of their overall molecular phenotype, as only a few genes are currently known to be co-expressed in AVPV Kiss1 cells. To provide a more detailed profiling of co-expressed genes in AVPV Kiss1 cells, including receptors and other signaling factors, and test how these genes respond to E2, we selectively isolated actively-translated mRNAs from AVPV Kiss1 cells of female mice and performed RNA-Seq. This identified >13,000 mRNAs co-expressed in AVPV Kiss1 cells, including multiple receptor and ligand transcripts positively or negatively regulated by E2. We also performed RNAscope to validate high co-expression of several transcripts identified by RNA-Seq, including Pdyn (prodynorphin), Penk (proenkephalin), Vgf (VGF), and Cartpt (CART), in female AVPV Kiss1 cells. Given the important role of AVPV kisspeptin cells in positive feedback, E2 effects on identified genes may relate to the LH surge mechanism and/or other physiological processes involving these AVPV kisspeptin cells.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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