"Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. "

Am J Clin Pathol.

2018 May 09

Lin F, Shi J, Wang HL, Ma XJ, Monroe R, Luo Y, Chen Z, Liu H.
PMID: 29746696 | DOI: 10.1093/ajcp/aqy030

Abstract

OBJECTIVES:

Inconsistent data on detection of albumin expression by ribonucleic acid (RNA) in situ hybridization have been reported. We investigated the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) in detection of albumin in hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (ICCs), and carcinomas from various organs using manual and automated staining.

METHODS:

RNAscope for albumin detection was performed on 482 cases on tissue microarray sections and on 22 cases of ICC, including 14 surgical resection and eight core biopsy specimens.

RESULTS:

Thirty-six of 37 (97%) HCCs had detectable mRNA, whereas all non-HCC and non-ICC cases, except one lung adenocarcinoma, were negative for albumin. Fourteen of 22 ICCs (64%) were positive for albumin.

CONCLUSIONS:

RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs; however, rare carcinomas (non-HCC, non-ICC, and those with no hepatoid histomorphology) can also have aberrant expression of albumin.

Liver macrophages regulate systemic metabolism through non-inflammatory factors

Nature Metabolism

2019 Mar 25

Morgantini C, Jager J, Li X, Levi L, Azzimato V, Sulen A, Barreby E, Xu C, Tencerova M, Näslund E, Kumar C, Verdeguer F, Straniero S, Hultenby K, Björkström NK, Ellis E, Rydén M, Kutter C, Hurrell T, Lauschke VM, Boucher J, Tomčala A, Krejčová G, Bajgar A and Aouadi M
| DOI: 10.1038/s42255-019-0044-9

Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor–binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites

Am J Clin Pathol

2019 May 20

Nasir A, Lehrke HD, Mounajjed T, Said S, Zhang L, Yasir S, Shah SS, Chandan VS, Smyrk TC, Moreira RK, Boland Froemming JM, Herrera Hernandez LP, Wu TT, Graham RP.
PMID: 31107526 | DOI: 10.1093/ajcp/aqz032

OBJECTIVES:

Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized.

METHODS:

Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays.

RESULTS:

Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases.

CONCLUSIONS:

Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall

Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma

Nature communications

2023 Feb 15

Li, Q;Zhang, XX;Hu, LP;Ni, B;Li, DX;Wang, X;Jiang, SH;Li, H;Yang, MW;Jiang, YS;Xu, CJ;Zhang, XL;Zhang, YL;Huang, PQ;Yang, Q;Zhou, Y;Gu, JR;Xiao, GG;Sun, YW;Li, J;Zhang, ZG;
PMID: 36792623 | DOI: 10.1038/s41467-023-36521-0

To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

Células e tecidos humanos em estudos pré-clínicos: gânglios raquidianos humanos

iasp-pain.org

2022 Jan 01

Dib-Hajj, SD;

A dor é uma experiência sensorial e emocional, comumente iniciada em resposta a um estímulo nóxico. Um grupo de neurónios sensoriais periféricos, conhecidos como nociceptores, são os primeiros neurónios a serem ativados pelo estímulo nóxico. Os corpos celulares dos neurónios sensoriais estão alojados no gânglio do trigémeo (TG) ou no gânglio raquidiano dorsal (DRG), situados bilateralmente e adjacentes ao tronco cerebral ou coluna vertebral. Estes neurónios pseudounipolares dão origem a um ramo periférico que inerva órgãos-alvo, por exemplo a pele e as vísceras, e um ramo central que termina no tronco cerebral ou no corno dorsal da medula espinhal [4]. Os neurónios sensoriais são altamente heterogéneos, com múltiplas subpopulações cada uma possuindo uma constelação de propriedades de resposta a estímulos não nociceptivos e nociceptivos. Os neurónios nociceptivos não são apenas responsáveis por sinalizar a presença de uma lesão aguda no tecido, mas parecem desempenhar um papel essencial na dor persistente e na hipersensibilidade associada a muitos estados de dor crónica. Assim, entender os fundamentos moleculares e celulares da transmissão de sinal em e através dos nociceptores é essencial para o desenvolvimento de tratamentos eficazes e seguros para a dor.

Fludarabine increases nuclease-free AAV- and CRISPR/Cas9-mediated homologous recombination in mice

Nature biotechnology

2022 Apr 07

Tsuji, S;Stephens, CJ;Bortolussi, G;Zhang, F;Baj, G;Jang, H;de Alencastro, G;Muro, AF;Pekrun, K;Kay, MA;
PMID: 35393561 | DOI: 10.1038/s41587-022-01240-2

Homologous recombination (HR)-based gene therapy using adeno-associated viruses (AAV-HR) without nucleases has several advantages over classic gene therapy, especially the potential for permanent transgene expression. However, the low efficiency of AAV-HR remains a major limitation. Here, we tested a series of small-molecule compounds and found that ribonucleotide reductase (RNR) inhibitors substantially enhance AAV-HR efficiency in mouse and human liver cell lines approximately threefold. Short-term administration of the RNR inhibitor fludarabine increased the in vivo efficiency of both non-nuclease- and CRISPR/Cas9-mediated AAV-HR two- to sevenfold in the murine liver, without causing overt toxicity. Fludarabine administration induced transient DNA damage signaling in both proliferating and quiescent hepatocytes. Notably, the majority of AAV-HR events occurred in non-proliferating hepatocytes in both fludarabine-treated and control mice, suggesting that the induction of transient DNA repair signaling in non-dividing hepatocytes was responsible for enhancing AAV-HR efficiency in mice. These results suggest that use of a clinically approved RNR inhibitor can potentiate AAV-HR-based genome-editing therapeutics.

UCP1 governs liver extracellular succinate and inflammatory pathogenesis

Nature metabolism

2021 May 01

Mills, EL;Harmon, C;Jedrychowski, MP;Xiao, H;Garrity, R;Tran, NV;Bradshaw, GA;Fu, A;Szpyt, J;Reddy, A;Prendeville, H;Danial, NN;Gygi, SP;Lynch, L;Chouchani, ET;
PMID: 34002097 | DOI: 10.1038/s42255-021-00389-5

Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.

	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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Probes for ALB

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Advanced Cell Diagnostics

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