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Cancer Cytopathol. 2018 Nov 26.
2018 Nov 26
Jo VY, Krane JF, Pantanowitz L, Monaco SE.
PMID: 30475447 | DOI: 10.1002/cncy.22075
Abstract BACKGROUND: The majority of human papillomavirus (HPV)-associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV-associated neuroendocrine carcinomas (HPV-NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine-needle aspiration (FNA) cases of head and neck HPV-NEC. METHODS: Cytology cases of HPV-NEC were identified over a 3-year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated. RESULTS: Five FNA cases of HPV-NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV-18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5). CONCLUSIONS: Head and neck HPV-NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV-NEC is also important because of its worse prognosis in comparison with HPV-associated squamous cell carcinoma.
Diagnostics (Basel). 2019 Jan 18;9(1).
2019 Jan 18
O'Brien O, Wright MC, O'Brien C, Geoghegan O, Leonard N, Nicholson S, Cuffe S, Fabre A, Jochum W, Joerger M, Gray SG, Finn SP.
PMID: PMID: 30669306 | DOI: DOI:10.3390/diagnostics9010013
MET is a receptor tyrosine kinase (RTK) that plays important roles in carcinogenesis. Despite being frequently overexpressed in cancer, clinical responses to targeting this receptor have been limited. Recently novel splicing mutations involving the loss of exon 14 (called METex14 skipping) have emerged as potential biomarkers to predict for responsiveness to targeted therapies with Met inhibitors in non-small cell lung cancer (NSCLC). Currently, the diverse genomic alterations responsible for METex14 skipping pose a challenge for routine clinical diagnostic testing. In this report, we examine three different methodologies to detect METex14 and assess their potential utility for use as a diagnostic assay for both the identification of METex14 and intra-tumoural distribution in NSCLC.
Histopathology. 2019 Jan 22.
2019 Jan 22
Morgan S, Slodkowska E, Parra-Herran C, Mirkovic J.
PMID: PMID: 30667073 | DOI: DOI:10.1111/his.13825
Abstract AIM: Neuroendocrine carcinoma, small cell type of the uterine cervix (SmCC-Cx) is a rare HPV- related tumor with limited therapeutic options. Merkel cell carcinoma, another virus-associated neuroendocrine malignancy, has significant PD-L1 expression rates. PD-L1 expression has been reported in other malignancies of the cervix. We aimed to determine the prevalence of PD-L1 in the context of mismatch repair protein (MMR) and RB1 expression status in SmCC-Cx. METHODS AND RESULTS: Ten cases of SmCC-Cx were tested for immunohistochemistry expression of PD-L1, MLH1, MSH2, MSH6, PMS2, RB1, CD3, CD20 and HPV in situ hybridization (ISH). PD-L1 expression was scored quantitatively (H-score) in tumor cells and lymphocytes (tumoral/peritumoral). PD-L1 positivity was seen in 7 cases, focal in most cases (H-scores 3 to 140). 3/9 cases showed MMR deficiency. PD-L1 expression levels correlated with MMR expression status: all 3 MLH1/PMS2-deficient cases had a ≥5% PD-L1 staining and an H-score ≥10 (p=0.01). RB1 was lost in 4/9 cases, all PD-L1+, but this correlation was not statistically significant.7/9 tumors were positive for HPV-ISH; two of these had MLH1/PMS2 loss. Among the 2 HPV-ISH negative tumors, one had MLS1/PMS2 loss. CONCLUSIONS: PD-L1 expression, predominantly focal, is seen in 70% of SmCC-Cx, while loss of MMR expression is seen in 33% of SmCC-Cx in our cohort. PD-L1 expression in >10% of tumor cells is seen in a subset of tumors in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy as a promising alternative for this aggressive disease.
Endocr Relat Cancer. 2019 Mar 1;26(3):279-292.
2018 Jan 23
Long Z, Li Y, Gan Y, Zhao D, Wang G, Xie N, Lovnicki JM, Fazli L, Cao Q, Chen K, Dong X.
PMID: PMID: 30667363 | DOI: DOI:10.1530/ERC-18-0465
Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein complex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage.
Molecular Metabolism (2019)
2019 Jan 24
Pan W, Allison MB, Sabatini P, Rupp A, Adams J, Patterson C, Jones JC, Olson DP, Myers MG.
| DOI: doi:10.1016/j.molmet.2019.01.007
Abstract Objectives Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression. Methods Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3LepRbKO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons. Results While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3LepRbKO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3LepRbKO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals. Conclusions Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals.
JCI Insight. 2019 Jan 24;4(2).
2019 Jan 24
Germán B, Wei R, Hener P, Martins C, Ye T, Gottwick C, Yang J, Seneschal J, Boniface K, Li M.
PMID: PMID: 30674716 | DOI: DOI:10.1172/jci.insight.123390
Psoriasis is one of the most common skin inflammatory diseases worldwide. The vitamin D3 analog calcipotriol has been used alone or in combination with corticosteroids in treating plaque psoriasis, but how it suppresses psoriatic inflammation has not been fully understood. Using an experimental mouse psoriasis model, we show that topical calcipotriol inhibited the pivotal IL-23/IL-17 axis and neutrophil infiltration in psoriatic skin, and interestingly, such effects were mediated through the vitamin D receptor (VDR) in keratinocytes (KCs). We further reveal that IL-36α and IL-36γ, which have recently emerged as key players in psoriasis pathogenesis, were effectively repressed by calcipotriol via direct VDR signaling in mouse KCs. Accordingly, calcipotriol treatment suppressed IL-36α/γ expression in lesional skin from patients with plaque psoriasis, which was accompanied by a reduced IL-23/IL-17 expression. In contrast, dexamethasone indirectly reduced IL-36α/γ expression in mouse psoriatic skin through immune cells. Furthermore, we demonstrate that calcipotriol and dexamethasone, in combination, synergistically suppressed the expression of IL-36α/γ, IL-23, and IL-17 in the established mouse psoriasis. Our findings indicate that the combination of calcipotriol and corticosteroid efficiently disrupts the IL-36 and IL-23/IL-17 positive feedback loop, thus revealing a mechanism underlying the superior efficacy of calcipotriol and corticosteroid combination therapy for psoriasis.
Neuroscience. 2019 Jan 21.
2019 Jan 21
Rebellato P, Kaczynska D, Kanatani S, Rayyes IA, Zhang S, Villaescusa C, Falk A, Arenas E, Hermanson O, Louhivuori L, Uhlén P.
PMID: PMID: 30677486 | DOI: DOI:10.1016/j.neuroscience.2019.01.015
Here we report that the low voltage dependent T-type calcium (Ca2+) channel Cav3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca2+ activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. Cells exhibiting robust spontaneous Ca2+ signaling had increased caspase-3 activity unrelated to apoptosis. Inhibition of Cav3.2 by drugs or viral CACNA1H knock down resulted in decreased caspase-3 activity followed by suppressed neurogenesis. In contrast, when CACNA1H was over-expressed, increased neurogenesis was detected. Cortical slices from Cacna1h knockout mice showed decreased spontaneous Ca2+ activity, a significantly lower protein level of cleaved caspase-3, and microanatomical abnormalities in the subventricular/ventricular and cortical plate zones when compared to their respective embryonic controls. In summary, we demonstrate a novel relationship between Cav3.2 and caspase-3 signaling that affects neurogenesis in the developing brain.
Immunity. 2019 Jan 16.
2019 Jan 22
Liu X, Nemeth DP, McKim DB, Zhu L, DiSabato DJ, Berdysz O, Gorantla G, Oliver B, Witcher KG, Wang Y, Negray CE, Vegesna RS, Sheridan JF, Godbout JP, Robson MJ, Blakely RD, Popovich PG, Bilbo SD, Quan N.
PMID: PMID: 30683620 | DOI: DOI:10.1016/j.immuni.2018.12.012
Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain’s IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.
Neuron. 2019 Jan 16.
2019 Jan 23
Tan C, Lu NN, Wang CK, Chen DY, Sun NH, Lyu H, Körbelin J, Shi WX, Fukunaga K, Lu YM, Han F.
PMID: PMID: 30685224 | DOI: DOI:10.1016/j.neuron.2018.12.036
The proper interactions between blood vessels and neurons are critical for maintaining the strength of neural circuits and cognitive function. However, the precise molecular events underlying these interactions remain largely unknown. Here, we report that the selective knockout of semaphorin 3G (Sema3G) in endothelial cells impaired hippocampal-dependent memory and reduced dendritic spine density in CA1 neurons in mice; these effects were reversed after restoration of Sema3G levels in the hippocampus by AAV transfection. We further show that Sema3G increased excitatory synapse density via neuropilin-2/PlexinA4 signaling and through activation of Rac1. These results provide the first evidence that, in the central nervous system, endothelial Sema3G serves as a vascular-derived synaptic organizer that regulates synaptic plasticity and hippocampal-dependent memory. Our findings highlight the role of vascular endothelial cells in regulating cognitive function through intercellular communication with neurons in the hippocampus.
Nature (2019)
2019 Jan 23
Jäkel S, Agirre E, Falcão AM, van Bruggen D, Lee KW, Knuesel I, Malhotra D, ffrench-Constant C, Williams A, Castelo-Branco G.
| DOI: doi: 10.1038/s41586-019-0903-2
Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases as OLs both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system (CNS) thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, suggesting that other factors contribute to this variability. One such factor may be OL heterogeneity. Not all OLs are the same—mouse spinal cord OLs inherently produce longer myelin sheaths than cortical OLs2, and single-cell analysis of mouse CNS identified further differences3,4. However, the extent of human OL heterogeneity and its possible contribution to MS pathology remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and MS patients. We identified sub-clusters of oligodendroglia in Ctr human WM, some similar to mouse, and defined new markers for these cell states. Strikingly, some sub-clusters were under-represented in MS tissue, while others were more prevalent. These differences in mature OL sub-clusters may indicate different functional states of OLs in MS lesions. Since this is similar in normal appearing white matter (NAWM), MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important to understanding disease progression and developing therapeutic approaches.
Pathogens. 2019 Jan 15;8(1).
2019 Jan 15
Johnson DM, Jokinen JD, Lukashevich IS.
PMID: PMID: 30650607 | DOI: DOI:10.3390/pathogens8010009
Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1-/- mice. Formulation of ML29 with IPs will improve the breadth of the host's immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements.
Nat Med. 2019 Jan 21.
2019 Jan 21
Maeder ML, Stefanidakis M, Wilson CJ, Baral R, Barrera LA, Bounoutas GS, Bumcrot D, Chao H, Ciulla DM, DaSilva JA, Dass A, Dhanapal V, Fennell TJ, Friedland AE, Giannoukos G, Gloskowski SW, Glucksmann A, Gotta GM, Jayaram H, Haskett SJ, Hopkins B, Horng JE, Joshi S, Marco E, Mepani R, Reyon D, Ta T, Tabbaa DG, Samuelsson SJ, Shen S, Skor MN, Stetkiewicz P, Wang T, Yudkoff C, Myer VE, Albright CF, Jiang H.
PMID: PMID: 30664785 | DOI: DOI:10.1038/s41591-018-0327-9
Leber congenital amaurosis type 10 is a severe retinal dystrophy caused by mutations in the CEP290 gene1,2. We developed EDIT-101, a candidate genome-editing therapeutic, to remove the aberrant splice donor created by the IVS26 mutation in the CEP290 gene and restore normal CEP290 expression. Key to this therapeutic, we identified a pair of Staphylococcus aureus Cas9 guide RNAs that were highly active and specific to the human CEP290 target sequence. In vitro experiments in human cells and retinal explants demonstrated the molecular mechanism of action and nuclease specificity. Subretinal delivery of EDIT-101 in humanized CEP290 mice showed rapid and sustained CEP290 gene editing. A comparable surrogate non-human primate (NHP) vector also achieved productive editing of the NHP CEP290 gene at levels that met the target therapeutic threshold, and demonstrated the ability of CRISPR/Cas9 to edit somatic primate cells in vivo. These results support further development of EDIT-101 for LCA10 and additional CRISPR-based medicines for other inherited retinal disorders.
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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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