Merkel Cell Polyomavirus Small T Antigen Induces Cancer and Embryonic Merkel Cell Proliferation in a Transgenic Mouse Model.

PubMed

Shuda, Masahiro; Guastafierro, Anna; Geng, Xuehui; Shuda, Yoko; Ostrowski, Stephen M; Lukianov, Stefan; Jenkins, Frank J; Honda, Kord; Maricich, Stephen M; Moore, Patrick S; Chang, Yuan

2015-01-01

Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro. To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT and Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting.

Treatment Options by Stage (Merkel Cell Carcinoma)

MedlinePlus

... of Skin Cancer Skin Cancer Screening Research Merkel Cell Carcinoma Treatment (PDQ®)–Patient Version General Information About Merkel Cell Carcinoma Go to Health Professional Version Key Points ...

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma

PubMed Central

Pulitzer, Melissa P; Brannon, A Rose; Berger, Michael F; Louis, Peter; Scott, Sasinya N; Jungbluth, Achim A; Coit, Daniel G; Brownell, Isaac; Busam, Klaus J

2016-01-01

Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven ‘pure’ Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52–89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression. PMID:26022453

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma.

PubMed

Pulitzer, Melissa P; Brannon, A Rose; Berger, Michael F; Louis, Peter; Scott, Sasinya N; Jungbluth, Achim A; Coit, Daniel G; Brownell, Isaac; Busam, Klaus J

2015-08-01

Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven 'pure' Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52-89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression.

Merkel cells are long-lived cells whose production is stimulated by skin injury✰

PubMed Central

Wright, Margaret C.; Logan, Gregory J.; Bolock, Alexa M.; Kubicki, Adam C.; Hemphill, Julie A.; Sanders, Timothy A.; Maricich, Stephen M.

2017-01-01

Mechanosensitive Merkel cells are thought to have finite lifespans, but controversy surrounds the frequency of their replacement and which precursor cells maintain the population. We found by embryonic EdU administration that Merkel cells undergo terminal cell division in late embryogenesis and survive long into adulthood. We also found that new Merkel cells are produced infrequently during normal skin homeostasis and that their numbers do not change during natural or induced hair cycles. In contrast, live imaging and EdU experiments showed that mild mechanical injury produced by skin shaving dramatically increases Merkel cell production. We confirmed with genetic cell ablation and fate-mapping experiments that new touch dome Merkel cells in adult mice arise from touch dome keratinocytes. Together, these independent lines of evidence show that Merkel cells in adult mice are long-lived, are replaced rarely during normal adult skin homeostasis, and that their production can be induced by repeated shaving. These results have profound implications for understanding sensory neurobiology and human diseases such as Merkel cell carcinoma. PMID:27998808

Merkel cells are long-lived cells whose production is stimulated by skin injury.

PubMed

Wright, Margaret C; Logan, Gregory J; Bolock, Alexa M; Kubicki, Adam C; Hemphill, Julie A; Sanders, Timothy A; Maricich, Stephen M

2017-02-01

Mechanosensitive Merkel cells are thought to have finite lifespans, but controversy surrounds the frequency of their replacement and which precursor cells maintain the population. We found by embryonic EdU administration that Merkel cells undergo terminal cell division in late embryogenesis and survive long into adulthood. We also found that new Merkel cells are produced infrequently during normal skin homeostasis and that their numbers do not change during natural or induced hair cycles. In contrast, live imaging and EdU experiments showed that mild mechanical injury produced by skin shaving dramatically increases Merkel cell production. We confirmed with genetic cell ablation and fate-mapping experiments that new touch dome Merkel cells in adult mice arise from touch dome keratinocytes. Together, these independent lines of evidence show that Merkel cells in adult mice are long-lived, are replaced rarely during normal adult skin homeostasis, and that their production can be induced by repeated shaving. These results have profound implications for understanding sensory neurobiology and human diseases such as Merkel cell carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Dual Innervation of Neonatal Merkel Cells in Mouse Touch Domes

PubMed Central

Luo, Wenqin

2014-01-01

Merkel cell-neurite complexes are specialized mechanosensory end organs that mediate discriminative touch sensation. It is well established that type I slowly adapting (SAI) mechanoreceptors, which express neural filament heavy chain (NFH), innervate Merkel cells. It was previously shown that neurotrophic factor NT3 and its receptor TrkC play crucial roles in controlling touch dome Merkel cell innervation of NFH+ fibers. In addition, nerve fibers expressing another neurotrophic tyrosine receptor kinase (NTRK), Ret, innervate touch dome Merkel cells as well. However, the relationship between afferents responsive to NT3/TrkC signaling and those expressing Ret is unclear. It is also controversial if these Ret+ fibers belong to the early or late Ret+ DRG neurons, which are defined based on the co-expression and developmental dependence of TrkA. To address these questions, we genetically traced Ret+ and TrkC+ fibers and analyzed their developmental dependence on TrkA. We found that Merkel cells in neonatal mouse touch domes receive innervation of two types of fibers: one group is Ret+, while the other subset expresses TrkC and NFH. In addition, Ret+ fibers depend on TrkA for their survival and normal innervation whereas NFH+ Merkel cell innervating fibers are almost unaltered in TrkA mutant mice, supporting that Ret+ and NFH+/TrkC+ afferents are two distinct groups. Ret signaling, on the other hand, plays a minor role for the innervation of neonatal touch domes. In contrast, Merkel cells in the glabrous skin are mainly contacted by NFH+/TrkC+ afferents. Taken together, our results suggest that neonatal Merkel cells around hair follicles receive dual innervation while Merkel cells in the glabrous skin are mainly innervated by only SAI mechanoreceptors. In addition, our results suggest that neonatal Ret+ Merkel cell innervating fibers most likely belong to the late but not early Ret+ DRG neurons. PMID:24637732

Merkel cell polyomavirus small T antigen initiates Merkel cell carcinoma-like tumor development in mice

PubMed Central

Verhaegen, Monique E.; Mangelberger, Doris; Harms, Paul W.; Eberl, Markus; Wilbert, Dawn M.; Meireles, Julia; Bichakjian, Christopher K.; Saunders, Thomas L.; Wong, Sunny Y.; Dlugosz, Andrzej A.

2017-01-01

Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a non-proliferative population of neuroendocrine cells which arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor’s cell of origin, are unknown. Using a panel of pre-term transgenic mice, we show that epidermis-targeted co-expression of sT and the cell fate determinant atonal bHLH transcription factor 1 (Atoh1) leads to development of widespread cellular aggregates with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Co-expression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with Atoh1. MCPyV sT, when co-expressed with Atoh1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. PMID:28512245

Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice.

PubMed

Verhaegen, Monique E; Mangelberger, Doris; Harms, Paul W; Eberl, Markus; Wilbert, Dawn M; Meireles, Julia; Bichakjian, Christopher K; Saunders, Thomas L; Wong, Sunny Y; Dlugosz, Andrzej A

2017-06-15

Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Characterization of a Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cell Line CVG-1.

PubMed

Velásquez, Celestino; Amako, Yutaka; Harold, Alexis; Toptan, Tuna; Chang, Yuan; Shuda, Masahiro

2018-01-01

Merkel cell polyomavirus (MCV) plays a causal role in ∼80% of Merkel cell carcinomas (MCC). MCV is clonally integrated into the MCC tumor genome, which results in persistent expression of large T (LT) and small T (sT) antigen oncoproteins encoded by the early locus. In MCV-positive MCC tumors, LT is truncated by premature stop codons or deletions that lead to loss of the C-terminal origin binding (OBD) and helicase domains important for replication. The N-terminal Rb binding domain remains intact. MCV-positive cell lines derived from MCC explants have been valuable tools to study the molecular mechanism of MCV-induced Merkel cell carcinogenesis. Although all cell lines have integrated MCV and express truncated LT antigens, the molecular sizes of the LT proteins differ between cell lines. The copy number of integrated viral genome also varies across cell lines, leading to significantly different levels of viral protein expression. Nevertheless, these cell lines share phenotypic similarities in cell morphology, growth characteristics, and neuroendocrine marker expression. Several low-passage MCV-positive MCC cell lines have been established since the identification of MCV. We describe a new MCV-positive MCV cell line, CVG-1, with features distinct from previously reported cell lines. CVG-1 tumor cells grow in more discohesive clusters in loose round cell suspension, and individual cells show dramatic size heterogeneity. It is the first cell line to encode an MCV sT polymorphism resulting in a unique leucine (L) to proline (P) substitution mutation at amino acid 144. CVG-1 possesses a LT truncation pattern near identical to that of MKL-1 cells differing by the last two C-terminal amino acids and also shows an LT protein expression level similar to MKL-1. Viral T antigen knockdown reveals that, like other MCV-positive MCC cell lines, CVG-1 requires T antigen expression for cell proliferation.

Merkel cell polyomavirus in Merkel cell carcinogenesis: small T antigen-mediates c-Jun phosphorylation.

PubMed

Wu, Julie H; Simonette, Rebecca A; Nguyen, Harrison P; Rady, Peter L; Tyring, Stephen K

2016-06-01

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer associated with the Merkel cell polyomavirus (MCPyV). The MCPyV genome, which is clonally integrated in the majority of MCCs, encodes the regulatory small T (sT) antigen. Previously, reports have established MCPyV sT antigen as a potent oncogene capable of inducing cell transformation. In the current study, we demonstrate a distinct role for c-Jun hyperactivation in MCPyV sT antigen pathogenesis. As MCPyV sT antigen's association with aggressive cancer growth has been previously established, this finding may represent a potential therapeutic target for the treatment of MCCs.

Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma.

PubMed

Starrett, Gabriel J; Marcelus, Christina; Cantalupo, Paul G; Katz, Joshua P; Cheng, Jingwei; Akagi, Keiko; Thakuria, Manisha; Rabinowits, Guilherme; Wang, Linda C; Symer, David E; Pipas, James M; Harris, Reuben S; DeCaprio, James A

2017-01-03

Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors. Copyright © 2017 Starrett et al.

Presumed choroidal metastasis of Merkel cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Small, K.W.; Rosenwasser, G.O.; Alexander, E. III

1990-05-01

Merkel cell carcinoma is a rare skin tumor of neural crest origin and is part of the amine precursor uptake and decarboxylase system. It typically occurs on the face of elderly people. Distant metastasis is almost uniformly fatal. Choroidal metastasis, to our knowledge, has not been described. We report a patient with Merkel cell carcinoma who had a synchronous solid choroidal tumor and a biopsy-proven brain metastasis. Our 56-year-old patient presented with a rapidly growing, violaceous preauricular skin tumor. Computed tomography of the head disclosed incidental brain and choroidal tumors. Light and electron microscopy of biopsy specimens of both themore » skin and the brain lesions showed Merkel cell carcinoma. Ophthalmoscopy, fluorescein angiography, and A and B echography revealed a solid choroidal mass. The brain and skin tumors responded well to irradiation. A radioactive episcleral plaque was applied subsequently to the choroidal tumor. All tumors regressed, and the patient was doing well 28 months later. To our knowledge this is the first case of presumed choroidal metastasis of Merkel cell carcinoma.« less

Merkel Cell Carcinoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Merkel cell carcinoma treatment options include surgery, radiation therapy, and chemotherapy. Get detailed information about the diagnosis and treatment of newly diagnosed and recurrent Merkel cell carcinoma in this summary for clinicians.

[Advances in the research of function of Merkel cells in tactile formation of skin].

PubMed

You, X; Wei, Z R

2018-01-20

Skin is the largest sense organ of human, with many mechanoreceptor cells under epidermis or dermis of skin and Merkel cell is one of them. It has been confirmed that Merkel cells play an important role in the process of mechanical transmission of mammalian soft tactile stimulation. Researches showed that Merkel cells had close relation to tactile formation and functioned by Merkel cell-neurite complexes and ion channels Piezo2. This article reviews Merkel cells and the function, problem and prospect of Merkel cells in tactile formation.

Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes.

PubMed

Reed-Geaghan, Erin G; Wright, Margaret C; See, Lauren A; Adelman, Peter C; Lee, Kuan Hsien; Koerber, H Richard; Maricich, Stephen M

2016-04-13

The extent to which the skin instructs peripheral somatosensory neuron maturation is unknown. We studied this question in Merkel cell-neurite complexes, where slowly adapting type I (SAI) neurons innervate skin-derived Merkel cells. Transgenic mice lacking Merkel cells had normal dorsal root ganglion (DRG) neuron numbers, but fewer DRG neurons expressed the SAI markers TrkB, TrkC, and Ret. Merkel cell ablation also decreased downstream TrkB signaling in DRGs, and altered the expression of genes associated with SAI development and function. Skin- and Merkel cell-specific deletion of Bdnf during embryogenesis, but not postnatal Bdnf deletion or Ntf3 deletion, reproduced these results. Furthermore, prototypical SAI electrophysiological signatures were absent from skin regions where Bdnf was deleted in embryonic Merkel cells. We conclude that BDNF produced by Merkel cells during a precise embryonic period guides SAI neuron development, providing the first direct evidence that the skin instructs sensory neuron molecular and functional maturation. Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation. Copyright © 2016 the authors 0270-6474/16/364362-15$15.00/0.

Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma.

PubMed

Ferrarotto, Renata; Cardnell, Robert; Su, Shirley; Diao, Lixia; Eterovic, A Karina; Prieto, Victor; Morrisson, William H; Wang, Jing; Kies, Merrill S; Glisson, Bonnie S; Byers, Lauren Averett; Bell, Diana

2018-03-23

Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP-ribose polymerase-1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome-sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA-damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV-negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. Based on PARP1 overexpression, DNA-damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma. © 2018 Wiley Periodicals, Inc.

History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection.

PubMed

Sahi, Helka; Sihto, Harri; Artama, Miia; Koljonen, Virve; Böhling, Tom; Pukkala, Eero

2017-01-17

We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC). Merkel cell carcinoma cases diagnosed in 1978-2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes. Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03-1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09-1.80) and diabetic conditions (OR 1.51, 95% CI 1.03-2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05). Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID.

Merkel cells transduce and encode tactile stimuli to drive Aβ-afferent impulses

PubMed Central

Ikeda, Ryo; Cha, Myeounghoon; Ling, Jennifer; Jia, Zhanfeng; Coyle, Dennis; Gu, Jianguo G.

2014-01-01

SUMMARY Sensory systems for detecting tactile stimuli have evolved from touch-sensing nerves in invertebrates to complicated tactile end-organs in mammals. Merkel discs are tactile end-organs consisting of Merkel cells and Aβ-afferent nerve endings, and are localized in fingertips, whisker hair follicles and other touch-sensitive spots. Merkel discs transduce touch into slowly adapting impulses to enable tactile discrimination, but their transduction and encoding mechanisms remain unknown. Using rat whisker hair follicles, we show that Merkel cells rather than Aβ-afferent nerve endings are primary sites of tactile transduction, and identify the Piezo2 ion channel as the Merkel cell mechanical transducer. Piezo2 transduces tactile stimuli into Ca2+-action potentials in Merkel cells, which drive Aβ-afferent nerve endings to fire slowly adapting impulses. We further demonstrate that Piezo2 and Ca2+-action potentials in Merkel cells are required for behavioral tactile responses. Our findings provide insights into how tactile end-organs function and have clinical implications for tactile dysfunctions. PMID:24746027

Merkel cell carcinoma with seborrheic keratosis: A unique association.

PubMed

Anand, Murthy S; Krishnamurthy, Shantha; Ravindranath, Suvarna; Ranganathan, Jyothi

2018-01-01

Merkel cell carcinoma (MCC) is a rare, clinically aggressive neuroendocrine carcinoma of the skin; MCC is 40 times less common as compared to melanoma. The most frequently reported sites have been the head and neck, extremities, and trunk. Potential mimics include malignant melanoma, lymphoma, or metastatic small cell (neuroendocrine) carcinomas. Histopathology of MCC resembles small cell carcinoma both morphologically and on IHC. The possible cell of origin was proposed as the Merkel cell, which functions as a mechanoreceptor. It has a high chance of local recurrence, regional and distant spread. In recent times, Merkel cell polyomavirus has been implicated as the causative agent for this tumor. The same agent has a reported etiologic association with other skin lesions, including seborrheic keratosis.

Merkel Cell Carcinoma of the Buccal Mucosa and Lower Lip.

PubMed

Islam, Mohammed N; Chehal, Hardeep; Smith, Molly Housley; Islam, Sarah; Bhattacharyya, Indraneel

2018-06-01

Merkel cell carcinoma (MCC) is an uncommon relatively aggressive neuroendocrine dermal neoplasm first described in 1972 as a tumor of the sun exposed skin. Although most MCC affect the skin of the head and neck, rare primarily oral mucosal cases have been documented. Merkel cells are nondendritic neuroendocrine cells that are found not only in the skin but also the oral mucosa and give rise to MCC. Neuroendocrine cells may be found as aggregates in organs or as diffuse or isolated cells within organs and their epithelial lining. They contain peptide hormones and biogenic amines and occur in two forms: dendritic, which are not associated with nerve fibers and non-dendritic, which are associated with nerve fibers. Merkel cells as well as MCC express simple epithelium-type Cytokeratins (8, 18, 19, 20), neurosecretory substances; chromogranin A, synaptophysin, neuron-specific enolase (NSE), adhesion molecules, and villin (intermediate filament). Though weakly, they also express neural markers such as S-100 protein. Cytokeratin 20, and Cluster of differentiation 56, are the two key diagnostic markers for Merkel cells and MCC. Etiology includes UV radiation, the recently described Merkel cell polyomavirus, and long term systemic immunosuppression. The cutaneous and mucosal variants of MCC are considered aggressive tumors with a high risk for local recurrence and metastasis and should be considered in the differential diagnosis of head and neck mucosal lesions. We present two cases of primary Merkel cell carcinoma, one on the buccal mucosa and the other on the lower lip, and discuss the salient histologic, immunohistochemical and clinical features.

Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network.

PubMed

Perdigoto, Carolina N; Bardot, Evan S; Valdes, Victor J; Santoriello, Francis J; Ezhkova, Elena

2014-12-01

Merkel cell-neurite complexes are located in touch-sensitive areas of the mammalian skin and are involved in recognition of the texture and shape of objects. Merkel cells are essential for these tactile discriminations, as they generate action potentials in response to touch stimuli and induce the firing of innervating afferent nerves. It has been shown that Merkel cells originate from epidermal stem cells, but the cellular and molecular mechanisms of their development are largely unknown. In this study, we analyzed Merkel cell differentiation during development and found that it is a temporally regulated maturation process characterized by a sequential activation of Merkel cell-specific genes. We uncovered key transcription factors controlling this process and showed that the transcription factor Atoh1 is required for initial Merkel cell specification. The subsequent maturation steps of Merkel cell differentiation are controlled by cooperative function of the transcription factors Sox2 and Isl1, which physically interact and work to sustain Atoh1 expression. These findings reveal the presence of a robust transcriptional network required to produce functional Merkel cells that are required for tactile discrimination. © 2014. Published by The Company of Biologists Ltd.

FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells.

PubMed

Nguyen, Minh Binh; Cohen, Idan; Kumar, Vinod; Xu, Zijian; Bar, Carmit; Dauber-Decker, Katherine L; Tsai, Pai-Chi; Marangoni, Pauline; Klein, Ophir D; Hsu, Ya-Chieh; Chen, Ting; Mikkola, Marja L; Ezhkova, Elena

2018-06-13

Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.

Clinical features and treatment of vulvar Merkel cell carcinoma: a systematic review.

PubMed

Nguyen, Austin Huy; Tahseen, Ahmed I; Vaudreuil, Adam M; Caponetti, Gabriel C; Huerter, Christopher J

2017-01-01

Merkel cell carcinoma is a rare and aggressive neoplasm originating from mechanoreceptor Merkel cells of the stratum basale of the epidermis. Cases affecting the vulva are exceedingly rare, with the currently available literature primarily in case report form. Systematic review of the PubMed database returned 17 cases of Merkel cell carcinoma affecting the vulva. Patients presented at a mean age of 59.6 years with a firm, mobile vulvar mass. Symptoms of pain, erythema, pruritus, edema, and ulceration have been reported. Tumor histology is consistent with that of neuroendocrine tumors and typical Merkel cell carcinomas. Neuroendocrine and cytokeratin immunostains are frequently utilized in histopathological workup. Surgical management was the unanimous first-line therapy with adjuvant radiation in most cases. Recurrence occurred in 70.6% of patients at a mean follow-up of 6.3 months. Mortality was at 47.0% at a mean of 7.8 months after initial operation. Merkel cell carcinoma affecting the vulva is an extremely rare and highly aggressive neoplasm. The present review of published cases serves to comprehensively describe the clinical course and treatment approaches for vulvar Merkel cell carcinoma.

Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice

PubMed Central

Wright, Margaret C.; Reed-Geaghan, Erin G.; Bolock, Alexa M.; Fujiyama, Tomoyuki; Hoshino, Mikio

2015-01-01

Resident progenitor cells in mammalian skin generate new cells as a part of tissue homeostasis. We sought to identify the progenitors of Merkel cells, a unique skin cell type that plays critical roles in mechanosensation. We found that some Atoh1-expressing cells in the hairy skin and whisker follicles are mitotically active at embryonic and postnatal ages. Genetic fate-mapping revealed that these Atoh1-expressing cells give rise solely to Merkel cells. Furthermore, selective ablation of Atoh1+ skin cells in adult mice led to a permanent reduction in Merkel cell numbers, demonstrating that other stem cell populations are incapable of producing Merkel cells. These data identify a novel, unipotent progenitor population in the skin that gives rise to Merkel cells both during development and adulthood. PMID:25624394

Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development

PubMed Central

Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J.; Cohen, Idan; Santoriello, Francis J.; Zhao, Dejian; Hsu, Ya-Chieh; Ezhkova, Elena

2016-01-01

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. PMID:27414999

Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.

PubMed

Perdigoto, Carolina N; Dauber, Katherine L; Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J; Cohen, Idan; Santoriello, Francis J; Zhao, Dejian; Zheng, Deyou; Hsu, Ya-Chieh; Ezhkova, Elena

2016-07-01

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.

PubMed

González-Vela, María Del Carmen; Curiel-Olmo, Soraya; Derdak, Sophia; Beltran, Sergi; Santibañez, Miguel; Martínez, Nerea; Castillo-Trujillo, Alfredo; Gut, Martha; Sánchez-Pacheco, Roxana; Almaraz, Carmen; Cereceda, Laura; Llombart, Beatriz; Agraz-Doblas, Antonio; Revert-Arce, José; López Guerrero, José Antonio; Mollejo, Manuela; Marrón, Pablo Isidro; Ortiz-Romero, Pablo; Fernandez-Cuesta, Lynnette; Varela, Ignacio; Gut, Ivo; Cerroni, Lorenzo; Piris, Miguel Ángel; Vaqué, José Pedro

2017-01-01

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

[Merkel cell carcinoma: cutaneous manifestation of a highly malignant pre-/pro-B cell neoplasia? : Novel concept about the cellular origin of Merkel cell carcinoma].

PubMed

Sauer, C M; Chteinberg, E; Rennspiess, D; Kurz, A K; Zur Hausen, A

2017-03-01

Merkel cell carcinoma (MCC) is a relatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre‑/pro-B cells. Here we review putative cells of MCC, including Merkel cells, (epi‑)dermal stem cells, and pro‑/pre-B cells. In the present work, the focus is on the concept of pre‑/pro-B cells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.

Seeking Standards for the Detection of Merkel Cell Polyomavirus and its Clinical Significance.

PubMed

Eid, Mary; Nguyen, Jannett; Brownell, Isaac

2017-04-01

Merkel cell carcinoma is a rare skin cancer associated with Merkel cell polyomavirus in most cases. Prior studies associating Merkel cell carcinoma viral status with prognosis have inconsistent findings. Moshiri et al. used multimodal virus detection to determine that the 81% of patients with virus-positive Merkel cell carcinoma tumors had earlier stage disease and better outcomes relative to virus-negative cases. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Merkel cell carcinoma of the head and neck: poorer prognosis than non-head and neck sites.

PubMed

Morand, G B; Madana, J; Da Silva, S D; Hier, M P; Mlynarek, A M; Black, M J

2016-04-01

Merkel cell carcinoma is a rare, aggressive neurocutaneous malignancy. This study investigated whether patients with Merkel cell carcinoma in the head and neck had poorer outcomes than patients with Merkel cell carcinoma located elsewhere. A retrospective study was performed of patients with Merkel cell carcinoma treated at the Jewish General Hospital in Montréal, Canada, from 1993 to 2013. Associations between clinicopathological characteristics and disease-free and disease-specific survival rates were examined according to the Kaplan-Meier method. Twenty-seven patients were identified. Although basic clinicopathological characteristics and treatments were similar between head and neck and non-head and neck Merkel cell carcinoma groups, disease-free and disease-specific survival rates were significantly lower in the head and neck Merkel cell carcinoma group (log-rank test; p = 0.043 and p = 0.001, respectively). Mortality was mainly due to distant metastasis. Patients with head and neck Merkel cell carcinoma had poorer survival rates than patients with non-head and neck Merkel cell carcinoma in our study. The tendency to obtain close margins, a less predictable metastatic pattern, and/or intrinsic tumour factors related to the head and neck may explain this discrepancy.

Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.

PubMed

Busam, Klaus J; Pulitzer, Melissa P; Coit, Daniel C; Arcila, Maria; Leng, Danielle; Jungbluth, Achim A; Wiesner, Thomas

2017-06-01

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

Avelumab for the treatment of metastatic Merkel cell carcinoma.

PubMed

Cordes, L M; Gulley, J L

2017-07-01

Avelumab is a promising new therapeutic agent for patients with metastatic Merkel cell carcinoma, a rare and aggressive type of neuroendocrine tumor of the skin. Until the recent approval of avelumab (Bavencio), no therapies were approved by the U.S. Food and Drug Administration for the treatment of metastatic Merkel cell carcinoma. In a recent trial, avelumab, an anti-programmed death ligand-1 antibody, demonstrated an objective response in 28 of 88 patients (31.8% [95.9% CI, 21.9-43.1]) with advanced, chemotherapy-refractory Merkel cell carcinoma. Overall, avelumab was well tolerated at a dose of 10 mg/kg administered intravenously every 2 weeks. Serious treatment-related adverse events were reported in 5 patients (6%), but no grade 4 adverse events or treatment-related deaths were reported. Preliminary data evaluating avelumab in chemotherapy-naive patients is also encouraging. Copyright 2017 Clarivate Analytics.

Rationale for immune-based therapies in Merkel polyomavirus-positive and -negative Merkel cell carcinomas.

PubMed

Vandeven, Natalie; Nghiem, Paul

2016-07-01

Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (˜80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virus-negative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immune-based approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation.

PubMed

Harms, Paul W; Collie, Angela M B; Hovelson, Daniel H; Cani, Andi K; Verhaegen, Monique E; Patel, Rajiv M; Fullen, Douglas R; Omata, Kei; Dlugosz, Andrzej A; Tomlins, Scott A; Billings, Steven D

2016-03-01

Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin 20 (CK20) is expressed in ~95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small-cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (10 Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high-confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping genetic changes

Next Generation Sequencing of Cytokeratin 20-Negative Merkel Cell Carcinoma Reveals Ultraviolet Signature Mutations and Recurrent TP53 and RB1 Inactivation

PubMed Central

Harms, Paul W.; Collie, Angela M. B.; Hovelson, Daniel H.; Cani, Andi K.; Verhaegen, Monique E.; Patel, Rajiv M.; Fullen, Douglas R.; Omata, Kei; Dlugosz, Andrzej A.; Tomlins, Scott A.; Billings, Steven D.

2016-01-01

Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin-20 (CK20) is expressed in approximately 95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (ten Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%)) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping

In vitro formation of the Merkel cell-neurite complex in embryonic mouse whiskers using organotypic co-cultures.

PubMed

Ishida, Kentaro; Saito, Tetsuichiro; Mitsui, Toshiyuki

2018-06-01

A Merkel cell-neurite complex is a touch receptor composed of specialized epithelial cells named Merkel cells and peripheral sensory nerves in the skin. Merkel cells are found in touch-sensitive skin components including whisker follicles. The nerve fibers that innervate Merkel cells of a whisker follicle extend from the maxillary branch of the trigeminal ganglion. Whiskers as a sensory organ attribute to the complicated architecture of the Merkel cell-neurite complex, and therefore it is intriguing how the structure is formed. However, observing the dynamic process of the formation of a Merkel cell-neurite complex in whiskers during embryonic development is still difficult. In this study, we tried to develop an organotypic co-culture method of a whisker pad and a trigeminal ganglion explant to form the Merkel cell-neurite complex in vitro. We initially developed two distinct culture methods of a single whisker row and a trigeminal ganglion explant, and then combined them. By dissecting and cultivating a single row from a whisker pad, the morphogenesis of whisker follicles could be observed under a microscope. After the co-cultivation of the whisker row with a trigeminal ganglion explant, a Merkel cell-neurite complex composed of Merkel cells, which were positive for both cytokeratin 8 and SOX2, Neurofilament-H-positive trigeminal nerve fibers and Schwann cells expressing Nestin, SOX2 and SOX10 was observed via immunohistochemical analyses. These results suggest that the process for the formation of a Merkel cell-neurite complex can be observed under a microscope using our organotypic co-culture method. © 2018 Japanese Society of Developmental Biologists.

Examining Merkel Cell Polyomavirus Minor Capsid Proteins | Center for Cancer Research

Cancer.gov

Merkel cell polyomavirus (MCV or MCPyV) is a recently discovered member of the viral family Polyomaviridae. It is a skin-dwelling polyomavirus species that appears to cause a rare but highly lethal form of skin cancer called Merkel cell carcinoma (MCC). Despite MCC being uncommon, chronic MCV infection of human skin is widespread, and most infected people have no known

Multifunctional Merkel cells: their roles in electromagnetic reception, finger-print formation, Reiki, epigenetic inheritance and hair form.

PubMed

Irmak, M Kemal

2010-08-01

Merkel cells are located in glabrous and hairy skin and in some mucosa. They are characterized by dense-core secretory granules and cytoskeletal filaments. They are attached to neighboring keratinocytes by desmosomes and contain melanosomes similar to keratinocytes. They are excitable cells in close contact with sensory nerve endings but their function is still unclear. In this review, following roles are attributed for the first time to the Merkel cells: (1) melanosomes in Merkel cells may be involved in mammalian magnetoreception. In this model melanosome as a biological magnetite is connected by cytoskeletal filaments to mechanically gated ion channels embedded in the Merkel cell membrane. The movement of melanosome with the changing electromagnetic field may open ion channels directly producing a receptor potential that can be transmitted to brain via sensory neurons. (2) Merkel cells may be involved in finger-print formation: Merkel cells in glabrous skin are located at the base of the epidermal ridges the type of which defines the finger-print pattern. Finger-print formation starts at the 10th week of pregnancy after the arrival of Merkel cells. Keratinocyte proliferation and the buckling process observed in the basal layer of epidermis resulting in the epidermal ridges may be controlled and formed by Merkel cells. (3) Brain-Merkel cell connection is bi-directional and Merkel cells not only absorb but also radiate the electromagnetic frequencies. Hence, efferent aspects of the palmar and plantar Merkel nerve endings may form the basis of the biofield modalities such as Reiki, therapeutic touch and telekinesis. (4) Adaptive geographic variations such as skin color, craniofacial morphology and hair form result from interactions between environmental factors and epigenetic inheritance system. While environmental factors produce modifications in the body, they simultaneously induce epigenetic modifications in the oocytes and in this way adaptive changes could be

Tropomyosin Receptor Kinase A Expression on Merkel Cell Carcinoma Cells.

PubMed

Wehkamp, Ulrike; Stern, Sophie; Krüger, Sandra; Hauschild, Axel; Röcken, Christoph; Egberts, Friederike

2017-11-01

Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor frequently associated with the Merkel cell polyomavirus. Immune checkpoint therapy showed remarkable results, although not all patients are responsive to this therapy. Anti-tropomyosin receptor kinase A (TrkA)-targeted treatment has shown promising results in several tumor entities. To determine TrkA expression in MCC as a rationale for potential targeted therapy. This case series study investigated the MCC specimens of 55 patients treated at the Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany, from January 1, 2005, through December 31, 2015. Thirty-nine of the 55 samples were suitable for further histopathologic examination. Expression of TrkA was explored by immunohistochemical analysis. Diagnosis of MCC was confirmed by staining positive for cytokeratin 20 (CK20) and synaptophysin. Expression of TrkA on the tumor cells. Specimens of 39 patients (21 women and 18 men; mean [SD] age, 75.0 [7.8] years) underwent immunohistochemical investigation. Thirty-eight of 38 specimens expressed CK20 and synaptophysin on the MCC tumor cells (100% expression). Merkel cell polyomavirus was detected in 32 of 38 specimens (84%). Tropomyosin receptor kinase A was found in all 36 evaluable specimens on the tumor cells; 34 (94%) showed a weak and 2 (6%) showed a strong cytoplasmic expression. In addition, strongly positive perinuclear dots were observed in 30 of 36 specimens (83%). Tropomyosin receptor kinase A was expressed on MCC tumor cells in 100% of evaluable specimens. This result may lead to the exploration of new targeted treatment options in MCC, especially for patients who do not respond to anti-programmed cell death protein 1 treatment.

A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.

PubMed

Xiao, Ying; Thoresen, Daniel T; Miao, Lingling; Williams, Jonathan S; Wang, Chaochen; Atit, Radhika P; Wong, Sunny Y; Brownell, Isaac

2016-07-01

The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

Merkel cells and permanent disesthesia in the oral mucosa after soft tissue grafts.

PubMed

Aimetti, M; Romano, F; Cricenti, L; Perotto, S; Gotti, S; Panzica, G; Graziano, A

2010-07-01

Connective tissue grafts are routinely procedures in the treatment of gingival defects. The clinical success of the gingival tissue graft procedures anyway should ensure not only the aesthetic integration between the tissues but also the physiological activity of the graft in terms of sensitivity and immunity because the skin and the mucosae constitute the first natural aspecific borders against pathogens. The aim of this paper was to investigate nervous net recovery after connective graft procedure, in relation with sensorial alteration in the injured area. Results showed that there is a close link among the number of Merkel cells and the alteration of sensations. Merkel cells can be found isolated standing in the basal layer, supposed to have neuroendocrine functions in the epithelia or in larger group not associated with nerves; when found in association with nerves they are named Merkel complexes, acting as slow adapter mechanical receptor. Our data can be explained in two ways: Merkel cells increase as a consequence of tissue injury, a sort of "SOS cells" that secrete neuroendocrine signals to guide tissue healing; as an alternative the presence of the Merkel cells could be read as a derailment of tissue regeneration with the stop of cellular differentiation in the direction of an abnormal proliferation, a sort of mad stem cell. (c) 2010 Wiley-Liss, Inc.

Merkel cell carcinoma occurring in a black woman: a case report.

PubMed

Kadiri, Selma; Aissa, Abdellah; Berhili, Soufiane; Khmou, Mouna; Elmajjaoui, Sanaa; Kebdani, Tayeb; El Khannoussi, Basma; Elkacemi, Hanan; Benjaafar, Noureddine

2017-01-31

Merkel cell carcinoma is a rare, very aggressive neuroectodermal tumor of the skin. It is typically located on sun-exposed skin and frequently found in white men aged between 70 and 80 years. We report a case of a 58-year-old black woman diagnosed with Merkel cell carcinoma of the posterior face of the right elbow. She had biopsy excision and was lost to follow-up. Four months later, she presented with recurrent disease on the inferior third of the right arm with three ipsilateral axillary lymph node metastases. Amputation of the right arm and ipsilateral axillary lymph node dissection were performed, followed by adjuvant radiotherapy. Six months later, the patient died as a result of respiratory failure caused by lung metastasis. To the best of our knowledge, no specific studies have been done comparing the course and the characteristics of Merkel cell carcinoma in white and black populations, and no similar case has been reported in the literature. The Merkel cell carcinoma is very rare in black people. As described elsewhere in the literature, our patient had a poor outcome despite radical management. To date, to the best of our knowledge, there has been no comparison of the prognosis of this tumor in white and black populations.

Ectopic Atoh1 expression drives Merkel cell production in embryonic, postnatal and adult mouse epidermis.

PubMed

Ostrowski, Stephen M; Wright, Margaret C; Bolock, Alexa M; Geng, Xuehui; Maricich, Stephen M

2015-07-15

Merkel cells are mechanosensitive skin cells whose production requires the basic helix-loop-helix transcription factor Atoh1. We induced ectopic Atoh1 expression in the skin of transgenic mice to determine whether Atoh1 was sufficient to create additional Merkel cells. In embryos, ectopic Atoh1 expression drove ectopic expression of the Merkel cell marker keratin 8 (K8) throughout the epidermis. Epidermal Atoh1 induction in adolescent mice similarly drove widespread K8 expression in glabrous skin of the paws, but in the whisker pads and body skin ectopic K8+ cells were confined to hair follicles and absent from interfollicular regions. Ectopic K8+ cells acquired several characteristics of mature Merkel cells in a time frame similar to that seen during postnatal development of normal Merkel cells. Although ectopic K8+ cell numbers decreased over time, small numbers of these cells remained in deep regions of body skin hair follicles at 3 months post-induction. In adult mice, greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis. Our data demonstrate that Atoh1 expression is sufficient to produce new Merkel cells in the epidermis, that epidermal cell competency to respond to Atoh1 varies by skin location, developmental age and hair cycle stage, and that the Notch pathway plays a key role in limiting epidermal cell competency to respond to Atoh1 expression. © 2015. Published by The Company of Biologists Ltd.

Recurrent Merkel cell carcinoma of the testis with unknown primary site: a case report.

PubMed

Mweempwa, Angela; Tan, Alvin; Dray, Michael

2016-11-05

Merkel cell carcinoma is a rare and aggressive neuroendocrine tumor that commonly arises in the skin. It is rare for it to occur in the testes. There are only seven cases of testicular Merkel cell carcinoma reported in the literature. A 66-year-old Maori man presented to our hospital with left testicular swelling. His alpha-fetoprotein and beta-human chorionic gonadotrophin levels were within normal limits. His lactate dehydrogenase concentration was elevated to 267 U/L. Ultrasound imaging confirmed a large testicular mass, and he underwent left orchiectomy. His histological examination revealed a neuroendocrine tumor with an immunostaining pattern suggesting Merkel cell carcinoma. He presented to our hospital again 3 months later with right testicular swelling that was confirmed on ultrasound sonography to be a tumor. He underwent a right orchiectomy, and his histological examination revealed metastatic Merkel cell carcinoma. A primary lesion was not identified, and computed tomographic imaging did not reveal spread to other organs. He received six cycles of adjuvant carboplatin and etoposide chemotherapy and remained disease-free 18 months after completion of chemotherapy. Given the paucity of studies, standard adjuvant treatment for testicular Merkel cell carcinoma remains uncertain, although platinum-based chemotherapy seems to be an appropriate option.

RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells.

PubMed

Hesbacher, Sonja; Pfitzer, Lisa; Wiedorfer, Katharina; Angermeyer, Sabrina; Borst, Andreas; Haferkamp, Sebastian; Scholz, Claus-Jürgen; Wobser, Marion; Schrama, David; Houben, Roland

2016-05-31

The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.

Merkel Cell Carcinoma: An Update of Key Imaging Techniques, Prognostic Factors, Treatment, and Follow-up.

PubMed

Llombart, B; Kindem, S; Chust, M

2017-03-01

Merkel cell carcinoma, though rare, is one of the most aggressive tumors a dermatologist faces. More than a third of patients with this diagnosis die from the disease. Numerous researchers have attempted to identify clinical and pathologic predictors to guide prognosis, but their studies have produced inconsistent results. Because the incidence of Merkel cell carcinoma is low and it appears in patients of advanced age, prospective studies have not been done and no clear treatment algorithm has been developed. This review aims to provide an exhaustive, up-to-date account of Merkel cell carcinoma for the dermatologist. We describe prognostic factors and the imaging techniques that are most appropriate for evaluating disease spread. We also discuss current debates on treating Merkel cell carcinoma. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Gastric metastasis of merkel cell cancer--uncommon complication of a rare neoplasm.

PubMed

Syal, N Gaurav; Dang, Shyam; Rose, James; Chen, Chien; Aduli, Farshad

2012-12-01

Merkel cell cancer is an aggressive cutaneous malignancy of neuroendocrine cell lineage which carries a poor prognosis. It usually affects elderly Caucasians and presents as a firm, painless, nodular lesion on the sun exposed areas of the body. Though it is highly metastatic, metastasis to the gastrointestinal tract is rarely reported. We describe a case of gastric metastasis from merkel cell cancer presenting with upper gastrointestinal bleeding. To our knowledge, only 8 such cases have been reported in English literature so far.

Merkel Cell Spinal Metastasis: Management in the Setting of a Poor Prognosis.

PubMed

Goodwin, C Rory; Mehta, Ankit I; Adogwa, Owoicho; Sarabia-Estrada, Rachel; Sciubba, Daniel M

2015-08-01

Study Design Case report. Objective Merkel cell carcinoma is an aggressive neuroendocrine carcinoma with a poor prognosis. Metastatic epidural spinal cord compression (MESCC) is a debilitating disease causing neurologic deficits. The surgical management for MESCC depends on pathology. Methods We report a case of Merkel cell carcinoma of the spine and evaluate the treatment paradigms utilized in the prior reports. Result A 76-year-old man with a history of Merkel cell carcinoma presented with 2-week history of progressive difficulty ambulating and a solitary T5 epidural mass encasing the spinal cord. The patient underwent a T5 corpectomy with cage placement and T3 to T7 posterior fusion with postoperative neurologic improvement and a return to ambulation. Three weeks postoperatively, the patient re-presented with new-onset weakness and widespread metastatic spinal disease with epidural compression at the T8 level. Six weeks postoperatively, he was placed in hospice care. Conclusion Prior reports in the literature demonstrated a poor prognosis for Merkel cell carcinoma metastasis to the spine with survival ranging from 1 to 9 months after diagnosis. Although neurologic decline necessitates a surgical intervention, the assessment of operative benefit should take into account the prognosis associated with the primary tumor subtype.

High load of Merkel cell polyomavirus DNA detected in the normal skin of Japanese patients with Merkel cell carcinoma.

PubMed

Hashida, Yumiko; Nakajima, Kimiko; Nakajima, Hideki; Shiga, Takeo; Tanaka, Moe; Murakami, Masanao; Matsuzaki, Shigenobu; Naganuma, Seiji; Kuroda, Naoki; Seki, Yasutaka; Katano, Harutaka; Sano, Shigetoshi; Daibata, Masanori

2016-09-01

Although Merkel cell polyomavirus (MCPyV) has the potential to cause Merkel cell carcinoma (MCC), it is also found in the normal skin of healthy individuals. However, the mechanism for transformation of MCPyV to an oncogenic form is unknown. To investigate the levels of MCPyV infection in the normal skin patients with MCC compared with those in a control cohort. We studied a total of six Japanese patients with cutaneous MCC. Sun-exposed and sun-unexposed skin swabs were obtained and analyzed for MCPyV loads using quantitative real-time polymerase chain reaction. At first, we found a patient with MCC carrying an extremely high load of MCPyV DNA in normal skin. This unique case prompted us to further explore the levels of MCPyV as skin microbiota in patients with MCC. We showed that MCPyV DNA levels were significantly higher in swabs obtained from normal skin samples of six patients with MCC compared with those from 30 age-matched healthy individuals and 19 patients with other cutaneous cancers. Whereas MCPyV strains obtained from the normal skin of patients with MCC had gene sequences without structural alterations, sequences of the tumor-derived strains showed truncating mutations or deletions. Although the number of patients with MCC studied was small, our findings suggest that MCC may occur with a background of high MCPyV load in the skin, and are expected to stimulate further studies on whether such skin virome levels could be one of predictive markers for the development of MCC. Copyright © 2016 Elsevier B.V. All rights reserved.

Avelumab Impresses in Merkel Cell Carcinoma.

PubMed

2017-06-01

The PD-L1 inhibitor avelumab-approved by the FDA in March for the treatment of Merkel cell carcinoma-demonstrated a high number of durable responses in an international, open-label, prospective phase II study. The results of the study, which supported the FDA's decision, were presented in April at the American Association for Cancer Research (AACR) Annual Meeting 2017. ©2017 American Association for Cancer Research.

Active touch and self-motion encoding by Merkel cell-associated afferents

PubMed Central

Severson, Kyle S.; Xu, Duo; Van de Loo, Margaret; Bai, Ling; Ginty, David D.; O’Connor, Daniel H.

2017-01-01

Summary Touch perception depends on integrating signals from multiple types of peripheral mechanoreceptors. Merkel-cell associated afferents are thought to play a major role in form perception by encoding surface features of touched objects. However, activity of Merkel afferents during active touch has not been directly measured. Here, we show that Merkel and unidentified slowly adapting afferents in the whisker system of behaving mice respond to both self-motion and active touch. Touch responses were dominated by sensitivity to bending moment (torque) at the base of the whisker and its rate of change, and largely explained by a simple mechanical model. Self-motion responses encoded whisker position within a whisk cycle (phase), not absolute whisker angle, and arose from stresses reflecting whisker inertia and activity of specific muscles. Thus, Merkel afferents send to the brain multiplexed information about whisker position and surface features, suggesting that proprioception and touch converge at the earliest neural level. PMID:28434802

Aberrant Promoter Hypermethylation of RASSF Family Members in Merkel Cell Carcinoma

PubMed Central

Richter, Antje M.; Haag, Tanja; Walesch, Sara; Herrmann-Trost, Peter; Marsch, Wolfgang C.; Kutzner, Heinz; Helmbold, Peter; Dammann, Reinhard H.

2013-01-01

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C and RASSF10 by combined bisulfite restriction analysis (COBRA) in MCC samples and control tissue. We found RASSF2 to be methylated in three out of 43 (7%), RASSF5A in 17 out of 39 (44%, but also 43% in normal tissue), RASSF5C in two out of 26 (8%) and RASSF10 in 19 out of 84 (23%) of the cancer samples. No correlation between the methylation status of the analyzed RASSFs or between RASSF methylation and MCC characteristics (primary versus metastatic, Merkel cell polyoma virus infection, age, sex) was found. Our results show that RASSF2, RASSF5C and RASSF10 are aberrantly hypermethylated in MCC to a varying degree and this might contribute to Merkel cell carcinogenesis. PMID:24252868

Histologic pattern of Merkel cell carcinoma sentinel lymph node metastasis improves stratification of Stage III patients

PubMed Central

Ko, Jennifer S; Prieto, Victor G; Elson, Paul; Vilain, Ricardo E; Pulitzer, Melissa; Scolyer, Richard A; Reynolds, Jordan P; Piliang, Melissa; Ernstoff, Marc S; Gastman, Brian; Billings, Steven D

2016-01-01

Sentinel lymph node biopsy is used to stage Merkel cell carcinoma, but its prognostic value has been questioned. Furthermore, predictors of outcome in sentinel lymph node positive Merkel cell carcinoma patients are poorly defined. In breast carcinoma, isolated immunohistochemically positive tumor cells have no impact, but in melanoma they are considered significant. The significance of sentinel lymph node metastasis tumor burden (including isolated tumor cells) and pattern of involvement in Merkel cell carcinoma are unknown. In this study, 64 Merkel cell carcinomas involving sentinel lymph nodes and corresponding immunohistochemical stains were reviewed and clinicopathologic predictors of outcome were sought. Five metastatic patterns were identified: 1, sheet-like (n=38, 59%); 2, non-solid parafollicular (n=4, 6%); 3, sinusoidal, (n=11, 17%); 4, perivascular hilar (n=1, 2%) and 5, rare scattered parenchymal cells (n=10, 16%). At the time of follow-up, 30/63 (48%) patients had died with 21(33%) attributable to Merkel cell carcinoma. Patients with pattern 1 metastases had poorer overall survival compared with patients with patterns 2–5 metastases (p=0.03), with 22/30 (73%) deaths occurring in pattern 1 patients. 3 (10%) deaths occurred in patients showing pattern 5, all of whom were immunosuppressed. 4 (13%) deaths occurred in pattern 3 patients and 1 (3%) death occurred in a pattern 2 patient. In multivariable analysis, the number of positive sentinel lymph node (1 or 2 versus >2, p<.0001), age (<70 versus ≥70, p=.01), sentinel lymph node metastasis pattern (patterns 2–5 versus 1, p=.02), and immune status (immunocompetent versus suppressed, p=.03) were independent predictors of outcome, and could be used to stratify Stage III patients into 3 groups with markedly different outcomes. In Merkel cell carcinoma, the pattern of sentinel lymph node involvement provides important prognostic information and utilizing this data with other clinicopathologic features

Histological pattern of Merkel cell carcinoma sentinel lymph node metastasis improves stratification of Stage III patients.

PubMed

Ko, Jennifer S; Prieto, Victor G; Elson, Paul J; Vilain, Ricardo E; Pulitzer, Melissa P; Scolyer, Richard A; Reynolds, Jordan P; Piliang, Melissa P; Ernstoff, Marc S; Gastman, Brian R; Billings, Steven D

2016-02-01

Sentinel lymph node biopsy is used to stage Merkel cell carcinoma, but its prognostic value has been questioned. Furthermore, predictors of outcome in sentinel lymph node positive Merkel cell carcinoma patients are poorly defined. In breast carcinoma, isolated immunohistochemically positive tumor cells have no impact, but in melanoma they are considered significant. The significance of sentinel lymph node metastasis tumor burden (including isolated tumor cells) and pattern of involvement in Merkel cell carcinoma are unknown. In this study, 64 Merkel cell carcinomas involving sentinel lymph nodes and corresponding immunohistochemical stains were reviewed and clinicopathological predictors of outcome were sought. Five metastatic patterns were identified: (1) sheet-like (n=38, 59%); (2) non-solid parafollicular (n=4, 6%); (3) sinusoidal, (n=11, 17%); (4) perivascular hilar (n=1, 2%); and (5) rare scattered parenchymal cells (n=10, 16%). At the time of follow-up, 30/63 (48%) patients had died with 21 (33%) attributable to Merkel cell carcinoma. Patients with pattern 1 metastases had poorer overall survival compared with patients with patterns 2-5 metastases (P=0.03), with 22/30 (73%) deaths occurring in pattern 1 patients. Three (10%) deaths occurred in patients showing pattern 5, all of whom were immunosuppressed. Four (13%) deaths occurred in pattern 3 patients and 1 (3%) death occurred in a pattern 2 patient. In multivariable analysis, the number of positive sentinel lymph nodes (1 or 2 versus >2, P<0.0001), age (<70 versus ≥70, P=0.01), sentinel lymph node metastasis pattern (patterns 2-5 versus 1, P=0.02), and immune status (immunocompetent versus suppressed, P=0.03) were independent predictors of outcome, and could be used to stratify Stage III patients into three groups with markedly different outcomes. In Merkel cell carcinoma, the pattern of sentinel lymph node involvement provides important prognostic information and utilizing this data with other

Merkel cell carcinoma: Do you know your guidelines?

PubMed

Miles, Brett A; Goldenberg, David

2016-05-01

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy that exhibits clinically aggressive features and is associated with a poor prognosis. The incidence of MCC seems to be increasing for reasons unknown, and is estimated to be 0.32/100,000 in the United States. This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of MCC. Resection of MCC with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. High-risk patients should undergo adjuvant radiotherapy, which improves oncologic outcomes. The role of chemotherapy is less clear and is currently reserved for advanced-stage MCC and palliative therapy. The pathogenesis of MCC has recently been impacted with the discovery of the Merkel cell polyomavirus (MCPyV). Research to establish targeted and immunologic therapeutic options are ongoing. © 2015 Wiley Periodicals, Inc.

Avelumab and other recent advances in Merkel cell carcinoma.

PubMed

Bommareddy, Praveen K; Kaufman, Howard L

2017-12-01

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer that occurs in the elderly, is associated with UV radiation and immunosuppression. Initial treatment consists of wide excision with adjuvant radiation. Although the tumor is sensitive to chemotherapy, long-term survival is unusual and there had been no US FDA-approved drugs prior to 2017. The recognition that MCC is associated with the Merkel cell polyomavirus occurs more commonly in immune-compromised patients and tumors express PD-L1 suggested testing immunotherapy. A study of an anti-PD-L1 antibody, avelumab, in chemotherapy-refractory MCC demonstrated a response rate of 31.8% resulting in FDA approval in March 2017 and EMA in September 2017. This review will discuss the disease, role of avelumab and other emerging treatment strategies for MCC.

The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas.

PubMed

Li, Long; Molberg, Kyle; Cheedella, Naga; Thibodeaux, Joel; Hinson, Stacy; Lucas, Elena

2018-01-01

Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33-year-old HIV-positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium-sized cells with high nuclear-cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound-guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes. © 2017 Wiley Periodicals, Inc.

Merkel cell carcinoma with fingolimod treatment for multiple sclerosis: A case report.

PubMed

Mahajan, Kedar R; Ko, Jennifer S; Tetzlaff, Michael T; Hudgens, Courtney W; Billings, Steven D; Cohen, Jeffrey A

2017-10-01

Neoplasms and reactivation of latent viruses have been observed in individuals taking fingolimod. Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer, is associated with immunosuppression and can be triggered by the oncogenic Merkel cell polyoma virus (MCPyV). We report a case of a 61-year-old man with multiple sclerosis who developed MCPyV-positive MCC 4 years after starting fingolimod. This is the second report of MCC associated with MCPyV in an individual on fingolimod. Copyright © 2017 Elsevier B.V. All rights reserved.

Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma.

PubMed

Batinica, M; Akgül, B; Silling, S; Mauch, C; Zigrino, P

2015-07-01

Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease. To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression. This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status. 83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/β-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity. In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease

Merkel Cell Carcinoma Therapeutic Update.

PubMed

Cassler, Nicole M; Merrill, Dean; Bichakjian, Christopher K; Brownell, Isaac

2016-07-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Tumor-Infiltrating Merkel Cell Polyomavirus-Specific T Cells Are Diverse and Associated with Improved Patient Survival. | Office of Cancer Genomics

Cancer.gov

Tumor-infiltrating CD8+ T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8+ T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, "KLL") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome.

Reviewing the current evidence supporting early B-cells as the cellular origin of Merkel cell carcinoma.

PubMed

Sauer, C M; Haugg, A M; Chteinberg, E; Rennspiess, D; Winnepenninckx, V; Speel, E-J; Becker, J C; Kurz, A K; Zur Hausen, A

2017-08-01

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics.

PubMed

Cohen, Philip R; Tomson, Brett N; Elkin, Sheryl K; Marchlik, Erica; Carter, Jennifer L; Kurzrock, Razelle

2016-04-26

Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.

Examining Merkel Cell Polyomavirus Minor Capsid Proteins | Center for Cancer Research

Cancer.gov

Merkel cell polyomavirus (MCV or MCPyV) is a recently discovered member of the viral family Polyomaviridae. It is a skin-dwelling polyomavirus species that appears to cause a rare but highly lethal form of skin cancer called Merkel cell carcinoma (MCC). Despite MCC being uncommon, chronic MCV infection of human skin is widespread, and most infected people have no known symptoms. The surface of polyomavirus virions is made up of pentameric knobs of the major capsid protein VP1. VP1 enables attachment of the virus to the cell surface, permitting infectious entry and delivery of the viral genome to host cells. The VP1 protein of previously studied polyomaviruses, such as simian virus 40 and murine polyomavirus, associates with two minor capsid proteins, VP2 and VP3, which are considered to play important roles during the infectious entry process.

A monoclonal antibody against SV40 large T antigen (PAb416) does not label Merkel cell carcinoma.

PubMed

Pelletier, Daniel J; Czeczok, Thomas W; Bellizzi, Andrew M

2018-07-01

Merkel cell carcinoma represents poorly differentiated neuroendocrine carcinoma of cutaneous origin. In most studies, the vast majority of Merkel cell carcinomas are Merkel cell polyomavirus (MCPyV)-associated. SV40 polyomavirus immunohistochemistry is typically used in the diagnosis of other polyomavirus-associated diseases, including tubulointerstitial nephritis and progressive multifocal leukoencephalopathy, given cross-reactivity with BK and JC polyomaviruses. MCPyV-specific immunohistochemistry is commercially available, but, if antibodies against SV40 also cross-reacted with MCPyV, that would be advantageous from a resource-utilisation perspective. Tissue microarrays were constructed from 39 Merkel cell carcinomas, 24 small-cell lung carcinomas, and 18 extrapulmonary visceral small-cell carcinomas. SV40 large T antigen immunohistochemistry (clone PAb416) was performed; MCPyV large T antigen immunohistochemistry (clone CM2B4) had been previously performed. UniProt was used to compare the amino acid sequences of the SV40, BK, JC and MCPyV large T antigens, focusing on areas recognised by the PAb416 and CM2B4 clones. SV40 immunohistochemistry was negative in all tumours; MCPyV immunohistochemistry was positive in 38% of Merkel cell carcinomas and in 0% of non-cutaneous poorly differentiated neuroendocrine carcinomas. UniProt analysis revealed a high degree of similarity between SV40, BK, and JC viruses in the region recognised by PAb416. There was less homology between SV40 and MCPyV in this region, which was also interrupted by two long stretches of amino acids unique to MCPyV. The CM2B4 clone recognises a unique epitope in one of these stretches. The PAb416 antibody against the SV40 large T antigen does not cross-react with MCPyV large T antigen, and thus does not label Merkel cell carcinoma. © 2018 John Wiley & Sons Ltd.

Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma.

PubMed

Schadendorf, Dirk; Nghiem, Paul; Bhatia, Shailender; Hauschild, Axel; Saiag, Philippe; Mahnke, Lisa; Hariharan, Subramanian; Kaufman, Howard L

2017-01-01

Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance. Unlike chemotherapy, treatment with anti-PD-L1 (avelumab) or anti-PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers.

Neuroendocrine Merkel cell nodal carcinoma of unknown primary site: management and outcomes of a rare entity.

PubMed

Kotteas, E A; Pavlidis, N

2015-04-01

Merkel cell nodal carcinoma of unknown primary (MCCUP) is a rare neuroendocrine tumour with distinct clinical and biological behaviour. We conducted a review of retrospective data extracted from 90 patients focusing on the management and outcome of this disease. We also compared life expectancy of these patients with the outcome of patients with known Merkel primaries and with neuroendocrine cancers of unidentifiable primary. There is a limited body of data for this type of malignancy, however, patients with Merkel cell nodal carcinoma of unknown primary site, seem to have better survival when treated aggressively than patients with cutaneous Merkel tumours of the same stage and equal survival with patients with low-grade neuroendocrine tumour of unknown origin. The lack of prospective trials, and the inadequate data, hamper the management of these tumours. Establishment of treatment guidelines is urgently needed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Treatment of a Patient with Merkel Cell Skin Carcinoma Using Radiation Therapy - A Case Report.

PubMed

Petrov, Andrej; Kraleva, Slavica; Kubelka-Sabit, Katerina; Petrova, Deva

2018-04-15

Merkel cell carcinoma (MCC) is a rare, very aggressive tumour. The pathogenesis remains unclear, but UV radiation, immunosuppression, and the presence of Merkel cell polyomavirus in the tumour genome appear to have a key role. Merkel cell carcinoma is a highly aggressive tumour that often has a lethal end. A patient at 93 years of age comes for an examination by a dermatologist due to a rapidly growing nodular tumour growth in the forehead area. A tumour was about 3 cm in size. It had no signs of basal-cell carcinoma, no arborising vascularisation, no pigmentations on dermoscopy. Clinically, an eventual Merkel cell carcinoma was considered for the patient, but other primary skin tumours had to be excluded, as well as the possibility that regarding the patient's age, it may be a metastatic deposit. A skin biopsy was performed, as well as H-E examination and immunohistochemical analyses (positive CD56, positivity of neuroendocrine markers synaptophysin, chromogranin) which were in favour of Merkel cell carcinoma of the skin. After setting the diagnosis, our patient was treated with therapy which led to a complete withdrawal of a tumour. However, after 3 months the patient had repeated relapse of a tumour at the same site on the forehead and metastases in the retroauricular lymph nodes bilaterally. It shows that the radiotherapy as monotherapy has a great effect on the removal of the tumour formation, but unfortunately, it has no impact on lesion recurrence. It is also compatible with the literature data. In many adult patients, as our case suggests, radiotherapy could be a good palliative treatment opportunity that should be considered, as well as a combination of radiation therapy with other oncologic therapeutic options.

Recent Insights and Advances in the Management of Merkel Cell Carcinoma.

PubMed

Banks, Patricia D; Sandhu, Shahneen; Gyorki, David E; Johnston, Meredith L; Rischin, Danny

2016-07-01

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches. Copyright © 2016 by American Society of Clinical Oncology.

Merkel-like cell distribution in the epithelium of the human vagina. An immunohistochemical and TEM study.

PubMed

Polakovičová, Simona; Csöbönyeiová, Mária; Filova, Barbora; Borovský, Miroslav; Maršík, Ladislav; Kvasilová, Alena; Polák, Štefan

2018-02-16

Human Merkel cells (MCs) were first described by Friedrich S. Merkel in 1875 and named "Tastzellen" (touch cells). Merkel cells are primarily localized in the basal layer of the epidermis and concentrated in touch-sensitive areas. In our previous work, we reported on the distribution of MCs in the human esophagus, so therefore we chose other parts of the human body to study them. We selected the human vagina, because it has a similar epithelium as the esophagus and plays very important roles in reproduction and sexual pleasure. Due to the fact that there are very few research studies focusing on the innervation of this region, we decided to investigate the occurrence of MCs in the anterior wall of the vagina. The aim of our research was to identify MCs in the stratified squamous non-keratinized epithelium of the human vagina in 20 patients. For the identification of Merkel cells by light microscopy, we used antibodies against simple-epithelial cytokeratins (especially anti-cytokeratin 20). We also tried to identify them using transmission electron microscopy. Our investigation confirmed that 10 (50 %) of 20 patients had increased number of predominantly intraepithelial CK20 positive "Merkel-like" cells (MLCs) in the human vaginal epithelium. Subepithelial CK20 positive MLCs were observed in only one patient (5%). We tried to identify them also using transmission electron microscopy. Our investigation detected some unique cells that may be MCs. The purpose of vaginal innervation is still unclear. There are no data available concerning the distribution of MCs in the human vagina, so it would be interesting to study the role of MCs in the vaginal epithelium, in the context of innervation and epithelial biology.

Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma.

PubMed

Kervarrec, Thibault; Samimi, Mahtab; Gaboriaud, Pauline; Gheit, Tarik; Beby-Defaux, Agnès; Houben, Roland; Schrama, David; Fromont, Gaëlle; Tommasino, Massimo; Le Corre, Yannick; Hainaut-Wierzbicka, Eva; Aubin, Francois; Bens, Guido; Maillard, Hervé; Furudoï, Adeline; Michenet, Patrick; Touzé, Antoine; Guyétant, Serge

2018-05-01

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as "combined" or "conventional." Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of

Merkel cell carcinoma in the community setting: a case report.

PubMed

Callaghan, Cameron M; Amornmarn, Rumpa

2018-04-12

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin initially believed to arise from the Merkel cells. In the community setting a general radiation oncologist may only encounter this pathology in a handful of cases over the course of their career. Due to the low incidence of this malignancy, few prospective randomized controlled trials have ever been conducted and therefore guidelines are based on relatively lower levels of evidence upon which the clinical recommendations are made. We discuss the case of a female in her 90s presenting with a classic MCC primary lesion, as well as satellite lesions proximal to both the primary and the draining regional lymph nodes with no evidence of nodal involvement. Here we discuss the presentation, management, treatment planning, underlying pathology, results and sequelae of treatment. We also review new treatment modalities, and the most current staging systems and guidelines.

An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy.

PubMed

Chatzinasiou, Foteini; Papadavid, Euaggelia; Korkolopoulou, Penelope; Levidou, Georgia; Panayiotides, Ioannis; Theodoropoulos, Konstadinos; Pogka, Vasiliki; Asimakopoulos, Charalampos; Rigopoulos, Dimitrios

2015-01-01

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC-positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy. © 2015 Wiley Periodicals, Inc.

Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis.

PubMed

Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Nagata, Keiko; Kato, Masako; Kuwamoto, Satoshi; Murakami, Ichiro; Hayashi, Kazuhiko

2016-02-01

Merkel cell carcinoma (MCC) is a clinically aggressive neuroendocrine skin cancer; 80% of the cases are associated with the Merkel cell polyomavirus (MCPyV). We previously reported that MCPyV-negative MCCs have more irregular nuclei with abundant cytoplasm and significantly unfavorable outcomes than do MCPyV-positive MCCs. These results suggest that some cell adhesion or structural stabilization molecules are differently expressed depending on MCPyV infection status. Thus, we investigated the association of prognosis or MCPyV infection status in MCCs with cell adhesion molecule 1 (CADM1)/differentially expressed in adenocarcinoma of the lung protein 1 (DAL-1)/membrane protein, palmitoylated 3 (MPP3) tripartite complex and mal T-cell differentiation protein (MAL) expression, which play important roles in cell adhesion and oncogenesis and are related to cancer outcomes in various malignancies, to elucidate the role of these molecules. We analyzed the pathological and molecular characteristics of 26 MCPyV-positive and 15 MCPyV-negative MCCs. Univariate Cox regression analysis showed that advanced age (hazard ratio [HR], 8.249; P = .007) and high CADM1 expression (HR, 5.214; P = .012) were significantly unfavorable overall survival parameters, whereas MCPyV infection (HR, 0.043, P < .001) and lower MAL expression (HR, 0.273; P = .018) were significantly favorable. On multivariate analysis, only MCPyV infection was significantly favorable for overall survival (HR, 0.04; P = .005). Hypermethylation of CADM1, DAL-1, and MAL promoters was detected in 1 of 18, 15 of 27, and 1 of 13 cases, respectively. Double immunostaining for cytokeratin 20 and CADM1, DAL-1, or MAL showed that nonneoplastic Merkel cells expressed DAL-1 and MAL but not CADM1. This study revealed that MCPyV-negative MCCs significantly expressed higher CADM1 and lower MAL than MCPyV-positive MCCs; these expression levels were markedly related to unfavorable outcomes. These data will give us important

Sentinel lymph node biopsy in periocular merkel cell carcinoma: a case report.

PubMed

Filitis, Dan C; Paragh, Gyorgy; Samie, Faramarz H; Zeitouni, Nathalie C

2017-09-20

The National Comprehensive Cancer Network guidelines for Merkel cell carcinoma recommend performance of the sentinel lymph node biopsy in all patients with clinically negative nodal disease for staging and treatment. Nevertheless, sentinel lymph node biopsy in the periocular region is debated as tumors are typically smaller and lymphatic variability can make performance procedurally problematic. We present a case of a Caucasian patient in their seventies who presented with a 1.0 cm periocular Merkel cell carcinoma, who underwent Mohs surgery with a Tenzel flap repair, that was found to have a positive sentinel lymph node biopsy, but who, despite parotidectomy, selective neck dissection, and radiation, succumbed to the disease. Evidence in both the site-specific and non-specific literature demonstrates: (1) Worsening prognosis with extent of lymph node burden, (2) improvements in our abilities to perform lymphoscintigraphy, (3) locoregional and distant metastatic disease in patients with tumor sizes ≤1 cm, and (4) significant rates of sentinel lymph node positivity in patients with tumor sizes ≤1 cm. Our case supports that sentinel lymph node biopsy should be considered in all clinically nodal negative periocular Merkel cell carcinoma, regardless of size, and despite limited site-specific studies on the subject.

The expression of Toll-like receptors 2, 4, 5, 7 and 9 in Merkel cell carcinoma.

PubMed

Jouhi, Lauri; Koljonen, Virve; Böhling, Tom; Haglund, Caj; Hagström, Jaana

2015-04-01

We sought to clarify whether the expression of toll-like receptors (TLR) in Merkel cell carcinoma (MCC) is linked to tumor and patient characteristics, especially the presence of Merkel cell polyoma virus (MCV). The study comprised of 128 patients with data on Merkel cell polyomavirus (MCV) status and clinical features were included in the study. Immunohistochemistry for TLR expression was performed on tissue microarray (TMA) slides. TLR 2, 4, 5, 7 and 9 expression was noted in most of the tumor specimens. Decreased expression of TLR 9 correlated strongly with MCV positivity. Cytoplasmic TLR 2 expression correlated with small tumor size, while nuclear TLR 2 and TLR 5 expressions with larger tumors. Increased nuclear TLR 4 expression and decreased TLR 7 expression were associated with older age. TLR 2, 4, 5, 7 and 9 appear to reflect certain clinicopathological variables and prognostic markers of MCC tumors. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Merkel Cell Polyomavirus: A New DNA Virus Associated with Human Cancer.

PubMed

MacDonald, Margo; You, Jianxin

2017-01-01

Merkel cell polyomavirus (MCPyV or MCV) is a novel human polyomavirus that has been discovered in Merkel cell carcinoma (MCC), a highly aggressive skin cancer. MCPyV infection is widespread in the general population. MCPyV-associated MCC is one of the most aggressive skin cancers, killing more patients than other well-known cancers such as cutaneous T-cell lymphoma and chronic myelogenous leukemia (CML). Currently, however, there is no effective drug for curing this cancer. The incidence of MCC has tripled over the past two decades. With the widespread infection of MCPyV and the increase in MCC diagnoses, it is critical to better understand the biology of MCPyV and its oncogenic potential. In this chapter, we summarize recent discoveries regarding MCPyV molecular virology, host cellular tropism, mechanisms of MCPyV oncoprotein-mediated oncogenesis, and current therapeutic strategies for MCPyV-associated MCC. We also present epidemiological evidence for MCPyV infection in HIV patients and links between MCPyV and non-MCC human cancers.

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity.

PubMed

García-Mesa, Y; García-Piqueras, J; García, B; Feito, J; Cabo, R; Cobo, J; Vega, J A; García-Suárez, O

2017-12-01

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell-neurite complexes, Meissner-like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20 + , chromogranin A + and synaptophisin + ) Merkel cells. Most of them were in close contact with Piezo2 - nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2 + , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans. © 2017 Anatomical Society.

Histogenesis of pure and combined Merkel cell carcinomas: An immunohistochemical study of 14 cases.

PubMed

Narisawa, Yutaka; Koba, Shinichi; Inoue, Takuya; Nagase, Kotaro

2015-05-01

The histogenesis of Merkel cell carcinoma (MCC) has remained unresolved. Moreover, one of the questions is whether pure MCC and combined MCC represent the same histogenesis and entity. The existence of combined MCC suggests that MCC likely arise from pluripotent stem cells. Merkel cells (MC) localize within the bulge area, which is populated by hair follicle stem cells. We used hair follicle stem cell markers to investigate whether MCC share certain characteristics of these stem cells. Fourteen MCC specimens were examined histologically and immunohistochemically. There were six pure MCC and eight combined MCC. In six combined MCC, both MCC components and squamous components at least focally shared the expression of one or more of cytokeratin (CK)15, CK19 and CD200, which are hair follicle stem cell markers. On the other hand, four cases of pure MCC showed partially distinct CK19 expression, but did not show CK15 and/or CD200 expression. There was a distinct difference between pure MCC and combined MCC on the expression of hair follicle stem cell markers. The normal skin expressed CK15, CK19 and CD200 in the bulge area, whereas CK15 and CD200 were absent in the MC-rich glabrous skin and touch domes. The results led us to hypothesize that combined MCC originate from the hair follicle stem cells. We postulate that combined MCC undergo multidirectional differentiation into squamous, glandular, mesenchymal and Merkel cells. Further investigation is warranted to confirm the histogenesis of pure MCC and combined MCC. © 2015 Japanese Dermatological Association.

Fluorescence in situ hybridization and qPCR to detect Merkel cell polyomavirus physical status and load in Merkel cell carcinomas.

PubMed

Haugg, Anke M; Rennspiess, Dorit; zur Hausen, Axel; Speel, Ernst-Jan M; Cathomas, Gieri; Becker, Jürgen C; Schrama, David

2014-12-15

The Merkel cell polyomavirus (MCPyV) is detected in 80% of Merkel cell carcinomas (MCC). Clonal integration and tumor-specific mutations in the large T antigen are strong arguments that MCPyV is a human tumor virus. However, the relationship between viral presence and cancer induction remains discussed controversially. Since almost all studies on virus prevalence are based on PCR techniques, we performed MCPyV fluorescence in situ hybridization (FISH) on MCC to gain information about the quality of the viral presence on the single cell level. MCPyV-FISH was performed on tissue microarrays containing 62 formalin-fixed and paraffin-embedded tissue samples including all tumor grades of 42 patients. The hybridization patterns were correlated to the qPCR data determined on corresponding whole tissue sections. Indeed, MCPyV-FISH and qPCR data were highly correlated, i.e. 83% for FISH-positive and 93% for FISH-negative cores. Accordingly, the mean of the qPCR values of all MCPyV-positive cores differed significantly from the mean of the negative cores (p = 0.0076). Importantly, two hybridization patterns were definable in the MCPyV-FISH: a punctate pattern (85%) indicating viral integration, which correlated with a moderate viral abundance and a combination of the punctate with a diffuse pattern (15%), suggesting a possible coexistence of integrated and episomal virus which was associated with very high viral load and VP1 expression. Thus, MCPyV-FISH adds important information on the single cell level within the histomorphological context and could therefore be an important tool to further elucidate MCPyV related carcinogenesis. © 2014 UICC.

Update on Merkel Cell Carcinoma: Epidemiology, Etiopathogenesis, Clinical Features, Diagnosis, and Staging.

PubMed

Llombart, B; Requena, C; Cruz, J

2017-03-01

Merkel cell carcinoma (MCC) is a rare, highly aggressive tumor, and local or regional disease recurrence is common, as is metastasis. MCC usually develops in sun-exposed skin in patients of advanced age. Its incidence has risen 4-fold in recent decades as the population has aged and immunohistochemical techniques have led to more diagnoses. The pathogenesis of MCC remains unclear but UV radiation, immunosuppression, and the presence of Merkel cell polyomavirus in the tumor genome seem to play key roles. This review seeks to update our understanding of the epidemiology, etiology, pathogenesis, and clinical features of MCC. We also review histologic and immunohistochemical features required for diagnosis. MCC staging is discussed, given its great importance in establishing a prognosis for these patients. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Merkel cell carcinoma - recent advances in the biology, diagnostics and treatment.

PubMed

Czapiewski, Piotr; Biernat, Wojciech

2014-08-01

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous carcinoma with neuroendocrine differentiation. Since recent discovery of MCCs strong association with Merkel cell polyomavirus (MCPyV), there has been a rapid increase in the understanding of the carcinomas genetics, molecular biology and pathogenesis. In our study, we reviewed recent advances and controversies concerning MCC histogenesis, epidemiology, diagnostic and prognostic markers. We analyzed the association of MCPyV with MCC and the possible new targets for therapy. We also examined English-based literature regarding MCC pathogenesis published between 2008 and 2013, which lead to a deeper understanding of the topic. Our study showed that the association of MCPyV strongly influences the course of MCC. Additionally, it has been shown that a immunological response to MCPyV may in the future give hope to identify new therapeutic strategies in treatment of this fatal malignancy. This article is part of a Directed Issue entitled: Rare Cancers. Copyright © 2014 Elsevier Ltd. All rights reserved.

Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting.

PubMed

Kwun, H J; Wendzicki, J A; Shuda, Y; Moore, P S; Chang, Y

2017-12-07

The formation of a bipolar mitotic spindle is an essential process for the equal segregation of duplicated DNA into two daughter cells during mitosis. As a result of deregulated cellular signaling pathways, cancer cells often suffer a loss of genome integrity that might etiologically contribute to carcinogenesis. Merkel cell polyomavirus (MCV) small T (sT) oncoprotein induces centrosome overduplication, aneuploidy, chromosome breakage and the formation of micronuclei by targeting cellular ligases through a sT domain that also inhibits MCV large T oncoprotein turnover. These results provide important insight as to how centrosome number and chromosomal stability can be affected by the E3 ligase targeting capacity of viral oncoproteins such as MCV sT, which may contribute to Merkel cell carcinogenesis.

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

PubMed Central

Kaufman, Howard L; Russell, Jeffery; Hamid, Omid; Bhatia, Shailender; Terheyden, Patrick; D’Angelo, Sandra P; Shih, Kent C; Lebbé, Céleste; Linette, Gerald P; Milella, Michele; Brownell, Isaac; Lewis, Karl D; Lorch, Jochen H; Chin, Kevin; Mahnke, Lisa; von Heydebreck, Anja; Cuillerot, Jean-Marie; Nghiem, Paul

2017-01-01

Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88

Avelumab: A Review in Metastatic Merkel Cell Carcinoma.

PubMed

Shirley, Matt

2018-05-24

Avelumab (Bavencio ® ) is a fully human IgG1 monoclonal antibody that is directed against programmed cell death ligand 1 (PD-L1). Avelumab functions as an immune checkpoint inhibitor and has recently been approved in the USA, the EU and Japan for the treatment of metastatic Merkel cell carcinoma (MCC). It is thus the first therapeutic agent specifically approved for use in this indication, and is approved for use independent of line of treatment. Approval for avelumab in metastatic MCC was based on the two-part, single-arm, phase II trial, JAVELIN Merkel 200. In Part A of the study, confirmed objective responses were observed in approximately one-third of patients with chemotherapy-refractory metastatic MCC treated with avelumab. The responses were observed early and appeared to be durable, with an estimated 74% of responses having a duration ≥ 12 months. Furthermore, interim results from a separate cohort of patients (Part B) indicate an objective response rate for avelumab of > 60% in patients who were chemotherapy-naïve in the metastatic disease setting. Avelumab is associated with a risk of immune-related adverse events but, overall, has an acceptable and manageable safety and tolerability profile. In conclusion, currently available data suggest that avelumab presents a clinically beneficial new treatment option for metastatic MCC, a rare but aggressive cancer associated with a poor prognosis.

Merkel Cell Polyomavirus Small T Antigen Drives Cell Motility via Rho-GTPase-Induced Filopodium Formation.

PubMed

Stakaitytė, Gabrielė; Nwogu, Nnenna; Dobson, Samuel J; Knight, Laura M; Wasson, Christopher W; Salguero, Francisco J; Blackbourn, David J; Blair, G Eric; Mankouri, Jamel; Macdonald, Andrew; Whitehouse, Adrian

2018-01-15

Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis. Motility is dependent on the activities of integrin receptors and Rho family GTPases, resulting in the remodeling of the actin cytoskeleton and formation of various motile actin-based protrusions. Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high likelihood of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases, and MCPyV-induced tumorigenesis largely depends on the expression of the small tumor antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumorigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we described the action of MCPyV ST on the microtubule network and how it impacts cell motility and migration. Here, we demonstrate that MCPyV ST affects the actin cytoskeleton to promote the formation of filopodia through a mechanism involving the catalytic subunit of protein phosphatase 4 (PP4C). We also show that MCPyV ST-induced cell motility is dependent upon the activities of the Rho family GTPases Cdc42 and RhoA. In addition, our results indicate that the MCPyV ST-PP4C interaction results in the dephosphorylation of β 1 integrin, likely driving the cell motility pathway. These findings describe a novel mechanism by which a tumor virus induces cell motility, which may ultimately lead to cancer metastasis, and provides opportunities and strategies for targeted interventions for disseminated MCC. IMPORTANCE Merkel cell polyomavirus (MCPyV) is the most recently discovered human tumor virus. It causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer. However, the molecular mechanisms implicating MCPyV-encoded proteins in cancer development are yet to be fully elucidated. This study builds

Detection and quantification of Merkel cell polyomavirus. Analysis of Merkel cell carcinoma cases from 1977 to 2015.

PubMed

Álvarez-Argüelles, Marta E; Melón, Santiago; Rojo, Susana; Fernandez-Blázquez, Ana; Boga, Jose A; Palacio, Ana; Vivanco, Blanca; de Oña, María

2017-12-01

This study investigates the presence of Merkel cell polyomavirus (MCPyV) in skin lesions of patients with Merkel cell carcinoma (MCC). MCPyV was quantified using quantitative Real-Time-PCR (qRT-PCR) in 34 paraffinized MCC samples (resected/biopsied) originally taken between 1977 and 2015, and six non-MCC samples. In 31 (91.2%) MCC-individuals, MCPyV was detected. No virus was observed in any non-MCC tumor. Average age at diagnosis was 78.2 ± 9.35 (55-97) years for women (n = 19) and 69.5 ± 14.7 (45-91) for men (n = 15) (P = 0.04). MCC tumor location, known in 25 cases, was: 11 (44%) in the head region, 6 (24%) in upper limbs, 4 (16%) in lower limbs, and 4 (16%) in the trunk. All but one patient had received some sort of treatment: 15 (45.45%) underwent both radio and chemotherapy, 13 (39.39%) only surgery, 2 (6.06%) surgery, plus radio and chemotherapy, 2 (6.06%) surgery and chemotherapy, and 1 (3.03%) only radiotherapy. Follow up data were available for 21/34 patients: recurrence was recorded for 4 (19.04%), and metastasis for 13 (61.9%). Recorded data showed that 10 men and 5 women (total 44.1%) died during follow up, 7 (46.7%) of them within 2 years of diagnosis. Viral load was 5.8 ± 1.4 log copies/10 5 cells (3.1-8.6), independent of any variable. MCPyV was very frequent in MCC. It was principally associated with head and limb tumors, it more commonly affected men, who in this study were, on average, younger than women, and had high rates of recurrence and mortality. The amplification techniques described here are easily applied and suitable for detecting the presence of MCPyV virus in MCC. © 2017 Wiley Periodicals, Inc.

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report.

PubMed

Rhee, Ye-Young; Kim, Soo Hee; Kim, Eun Kyung; Kim, Se Hoon

2018-05-01

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs.

PubMed

Schadendorf, Dirk; Lebbé, Céleste; Zur Hausen, Axel; Avril, Marie-Françoise; Hariharan, Subramanian; Bharmal, Murtuza; Becker, Jürgen C

2017-01-01

Merkel cell carcinoma (MCC) is a rare skin cancer that is associated with Merkel cell polyomavirus infection in most cases. Incidence rates of MCC have increased in past decades. Risk factors for MCC include ultraviolet light exposure, immunosuppression and advanced age. MCC is an aggressive malignancy with frequent recurrences and a high mortality rate, although patient outcomes are generally more favourable if the patient is referred for treatment at an early stage. Although advances have been made recently in the MCC field, large gaps remain with regard to definitive biomarkers and prognostic indicators. Although MCC is chemosensitive, responses in advanced stages are mostly of short duration, and the associated clinical benefit on overall survival is unclear. Recent nonrandomised phase 2 clinical trials with anti-PD-L1/PD-1 antibodies have demonstrated safety and efficacy; however, there are still no approved treatments for patients with metastatic MCC. Patients with advanced disease are encouraged to participate in clinical trials for treatment, indicating the largely unmet need for durable, safe treatment within this population. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

18F-FDG PET/CT for Monitoring Response of Merkel Cell Carcinoma to the Novel Programmed Cell Death Ligand 1 Inhibitor Avelumab.

PubMed

Eshghi, Naghmehossadat; Lundeen, Tamara F; MacKinnon, Lea; Avery, Ryan; Kuo, Phillip H

2018-05-01

An 85-year-old man with stage IIIA Merkel cell carcinoma of the left arm was initially treated with local excision and axillary node dissection followed by radiation therapy. Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy. Given his age and comorbidities, he was considered a poor candidate for chemotherapy, and therefore the novel programmed cell death ligand 1 inhibitor avelumab was initiated. FDG PET/CT after 4 cycles showed complete resolution of hepatic and nodal metastases. Whole-body FDG PET/CT can be used for monitoring response of multisystem metastases from Merkel cell carcinoma to active immunotherapy.

Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma.

PubMed

Kuromi, Teruyuki; Matsushita, Michiko; Iwasaki, Takeshi; Nonaka, Daisuke; Kuwamoto, Satoshi; Nagata, Keiko; Kato, Masako; Akizuki, Gen; Kitamura, Yukisato; Hayashi, Kazuhiko

2017-11-01

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that mostly occurs in the elderly. Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of MCCs and is associated with carcinogenesis. Hedgehog signaling pathway plays a role in human embryogenesis and organogenesis. In addition, reactivation of this pathway later in life can cause tumors. Twenty-nineMCPyV-positive and 21 MCPyV-negative MCCs were immunohistochemically stained with primary antibodies for hedgehog signaling (SHH, IHH, PTCH1, SMO, GLI1, GLI2, and GLI3) and evaluated using H-score. Polymerase chain reaction and sequence analysis for SHH and GLI1 exons were also performed. Expression of SHH was higher in MCPyV-positive MCCs than in MCPyV-negative MCCs (P<.001). Higher expression of GLI1, MCPyV infection, male sex, and Japanese ethnicity were associated with better overall survival (P=.034, P=.001, P=.042, and P=.036, respectively). Higher expression of SHH and MCPyV infection were associated with improved MCC-specific survival (P=.037 and P=.002, respectively). The mutation analysis of prognosis-related GLI1 and SHH genes in our study revealed a low frequency of mutations in the 10 exons examined, except GLI1 exon 5 (18/22 cases), all having the same silent mutation of c.576G>A. Only 2 mutations with amino acid changes were detected in MCPyV-negative MCCs only: 1 missense mutation in GLI1 exon 4 and 1 nonsense mutation in SHH-3B. Expression of SHH and GLI1 may be useful prognostic markers of MCC because increased expression was associated with better prognosis. The high rate of c.576G>A silent mutation in GLI1 exon 5 was a feature of MCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Paraneoplastic cerebellar degeneration and lambert-eaton myasthenia in a patient with merkel cell carcinoma and voltage-gated calcium channel antibodies.

PubMed

Pavolucci, Lucia; Giannini, Giulia; Giannoccaro, Maria Pia; Foschini, Maria Pia; Lang, Bethan; Avoni, Patrizia; Tinuper, Paolo; Vincent, Angela; Liguori, Rocco

2017-11-01

Merkel cell carcinoma is a rare cutaneous, aggressive tumor. Although it shares many neuroendocrine features with small cell lung carcinoma, it has only occasionally been reported with paraneoplastic neurological syndromes. A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia. He underwent a full diagnostic workup and was found to have a high titer of voltage-gated calcium channel antibodies in serum and cerebrospinal fluid, neurophysiological findings compatible with Lambert-Eaton myasthenia and neurological signs compatible with cerebellar degeneration. A positron emission tomography study revealed a hypermetabolic lesion in the axilla, subsequently biopsied and consistent with Merkel cell carcinoma. In most previous reports, neurological symptoms preceded the Merkel cell carcinoma diagnosis, and the primary localization was in lymph nodes. This tumor should be considered in patients with paraneoplastic syndrome, and particularly Lambert-Eaton myasthenia after exclusion of small cell lung carcinoma. Muscle Nerve 56: 998-1000, 2017. © 2016 Wiley Periodicals, Inc.

Merkel Cell Polyomavirus Infection of Animal Dermal Fibroblasts.

PubMed

Liu, Wei; Krump, Nathan A; MacDonald, Margo; You, Jianxin

2018-02-15

Merkel cell polyomavirus (MCPyV) is the first polyomavirus to be associated with human cancer. Mechanistic studies attempting to fully elucidate MCPyV's oncogenic mechanisms have been hampered by the lack of animal models for MCPyV infection. In this study, we examined the ability of MCPyV-GFP pseudovirus (containing a green fluorescent protein [GFP] reporter construct), MCPyV recombinant virions, and several MCPyV chimeric viruses to infect dermal fibroblasts isolated from various model animals, including mouse ( Mus musculus ), rabbit ( Oryctolagus cuniculus ), rat ( Rattus norvegicus ), chimpanzee ( Pan troglodytes ), rhesus macaque ( Macaca mulatta ), patas monkey ( Erythrocebus patas ), common woolly monkey ( Lagothrix lagotricha ), red-chested mustached tamarin ( Saguinus labiatus ), and tree shrew ( Tupaia belangeri ). We found that MCPyV-GFP pseudovirus was able to enter the dermal fibroblasts of all species tested. Chimpanzee dermal fibroblasts were the only type that supported vigorous MCPyV gene expression and viral replication, and they did so to a level beyond that of human dermal fibroblasts. We further demonstrated that both human and chimpanzee dermal fibroblasts produce infectious MCPyV virions that can successfully infect new cells. In addition, rat dermal fibroblasts supported robust MCPyV large T antigen expression after infection with an MCPyV chimeric virus in which the entire enhancer region of the MCPyV early promoter has been replaced with the simian virus 40 (SV40) analog. Our results suggest that viral transcription and/or replication events represent the major hurdle for MCPyV cross-species transmission. The capacity of rat dermal fibroblasts to support MCPyV early gene expression suggests that the rat is a candidate model organism for studying viral oncogene function during Merkel cell carcinoma (MCC) oncogenic progression. IMPORTANCE MCPyV plays an important role in the development of a highly aggressive form of skin cancer, Merkel

A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.

PubMed

Walsh, Noreen M; Fleming, Kirsten E; Hanly, John G; Dakin Hache, Kelly; Doucette, Steve; Ferrara, Gerardo; Cerroni, Lorenzo

2016-06-01

The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases. Copyright © 2016 Elsevier Inc. All rights reserved.

Replication of Merkel cell polyomavirus induces reorganization of promyelocytic leukemia nuclear bodies.

PubMed

Neumann, Friederike; Czech-Sioli, Manja; Dobner, Thomas; Grundhoff, Adam; Schreiner, Sabrina; Fischer, Nicole

2016-11-01

Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma (MCC), a rare but aggressive skin cancer. The virus is highly prevalent: 60-80 % of adults are seropositive; however, cells permissive for MCPyV infection are unknown. Consequently, very little information about the MCPyV life cycle is available. Until recently, MCPyV replication could only be studied using a semi-permissive in vitro replication system (Neumann et al., 2011; Feng et al., 2011, Schowalter et al., 2011). MCPyV replication most likely depends on subnuclear structures such as promyelocytic leukemia protein nuclear bodies (PML-NBs), which are known to play regulatory roles in the infection of many DNA viruses. Here, we investigated PML-NB components as candidate host factors to control MCPyV DNA replication. We showed that PML-NBs change in number and size in cells actively replicating MCPyV proviral DNA. We observed a significant increase in PML-NBs in cells positive for MCPyV viral DNA replication. Interestingly, a significant amount of cells actively replicating MCPyV did not show any Sp100 expression. While PML and Daxx had no effect on MCPyV DNA replication, MCPyV replication was increased in cells depleted for Sp100, strongly suggesting that Sp100 is a negative regulator of MCPyV DNA replication.

Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice.

PubMed

Knips, Jill; Czech-Sioli, Manja; Spohn, Michael; Heiland, Max; Moll, Ingrid; Grundhoff, Adam; Schumacher, Udo; Fischer, Nicole

2017-07-01

Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC-derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV-positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signalling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation. © 2017 UICC.

Immunotherapy in Merkel cell carcinoma: role of Avelumab.

PubMed

Palla, Amruth R; Doll, Donald

2018-01-01

Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer.

Pedunculated and Telangiectatic Merkel Cell Carcinoma: An Unusual Clinical Presentation

PubMed Central

Errichetti, Enzo; Piccirillo, Angelo; Ricciuti, Federico; Ricciuti, Francesco

2013-01-01

Merkel cell carcinoma (MCC) is an uncommon aggressive neuroendocrine tumor of the skin that classically presents on chronic sun-damaged skin as a skin-colored, red or violaceous, firm and nontender papule or nodule with a smooth and shiny surface. Ulcerations can be observed very seldom and only in very advanced lesions. We present a unique case of a MCC presenting with two unusual clinical features: The Telangiectatic surface and the pedunculated aspect. PMID:23723504

Pedunculated and telangiectatic merkel cell carcinoma: an unusual clinical presentation.

PubMed

Errichetti, Enzo; Piccirillo, Angelo; Ricciuti, Federico; Ricciuti, Francesco

2013-05-01

Merkel cell carcinoma (MCC) is an uncommon aggressive neuroendocrine tumor of the skin that classically presents on chronic sun-damaged skin as a skin-colored, red or violaceous, firm and nontender papule or nodule with a smooth and shiny surface. Ulcerations can be observed very seldom and only in very advanced lesions. We present a unique case of a MCC presenting with two unusual clinical features: The Telangiectatic surface and the pedunculated aspect.

Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus

PubMed Central

Stakaitytė, Gabrielė; Wood, Jennifer J.; Knight, Laura M.; Abdul-Sada, Hussein; Adzahar, Noor Suhana; Nwogu, Nnenna; Macdonald, Andrew; Whitehouse, Adrian

2014-01-01

A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC. PMID:24978434

PD-L1 blockade with avelumab: A new paradigm for treating Merkel cell carcinoma.

PubMed

Barkdull, Savannah; Brownell, Isaac

2017-12-02

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Until recently, no durable treatment options were available for patients with advanced disease. As an immunogenic cancer, MCC was hypothesized to be a candidate for PD-L1/PD-1 targeted therapy. On March 23, 2017 the US Food and Drug Administration granted accelerated approval for avelumab, an anti-PD-L1 monoclonal antibody, for the treatment of metastatic MCC on the basis of the JAVELIN Merkel 200 trial. Here we examine the results and implications of this pivotal study, published in Lancet Oncology by Kaufman et al., as well as current developments in the use of immune-checkpoint therapies for treating patients with MCC.

Loss of Aβ-nerve endings associated with the Merkel cell-neurite complex in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis.

PubMed

Carrión, Daniela Calderón; Korkmaz, Yüksel; Cho, Britta; Kopp, Marion; Bloch, Wilhelm; Addicks, Klaus; Niedermeier, Wilhelm

2016-03-30

The Merkel cell-neurite complex initiates the perception of touch and mediates Aβ slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry (the avidin-biotin-peroxidase complex and double immunofluorescence methods) using pan cytokeratin, cytokeratin 20 (K20, a Merkel cell marker), and neurofilament 200 (NF200, a myelinated Aβ- and Aδ-nerve fibre marker) antibodies. NF200-immunoreactive (ir) nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hyperkeratosis.

Loss of Aβ-nerve endings associated with the Merkel cell-neurite complex in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis

PubMed Central

Carrión, Daniela Calderón; Korkmaz, Yüksel; Cho, Britta; Kopp, Marion; Bloch, Wilhelm; Addicks, Klaus; Niedermeier, Wilhelm

2016-01-01

The Merkel cell-neurite complex initiates the perception of touch and mediates Aβ slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry (the avidin-biotin-peroxidase complex and double immunofluorescence methods) using pan cytokeratin, cytokeratin 20 (K20, a Merkel cell marker), and neurofilament 200 (NF200, a myelinated Aβ- and Aδ-nerve fibre marker) antibodies. NF200-immunoreactive (ir) nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hyperkeratosis. PMID:27025263

Immunotherapy in Merkel cell carcinoma: role of Avelumab

PubMed Central

Palla, Amruth R; Doll, Donald

2018-01-01

Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer. PMID:29535979

[Care of Merkel cell carcinoma and role of the radiotherapy].

PubMed

Rehailia-Blanchard, Amel; Pigné, Grégoire; Guy, Jean-Baptiste; Vallard, Alexis; El Meddeb Hamrouni, Anis; Rancoule, Chloé; Magné, Nicolas

2017-01-01

Merkel cell carcinoma is a rare neuro-endocrine tumor of skin with a poor prognosis. Data available in literature are scarce. Current treatment for locoregional disease is based on combined treatment by surgery and radiotherapy. However these treatments are controversial. The aim of the present review is to sum up the different available studies and to compare national and international guidelines. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck.

PubMed

Strom, Tobin; Naghavi, Arash O; Messina, Jane L; Kim, Sungjune; Torres-Roca, Javier F; Russell, Jeffery; Sondak, Vernon K; Padhya, Tapan A; Trotti, Andy M; Caudell, Jimmy J; Harrison, Louis B

2017-01-01

We hypothesized that radiotherapy (RT) would improve both local and regional control with Merkel cell carcinoma of the head and neck. A single-institution institutional review board-approved study was performed including 113 patients with nonmetastatic Merkel cell carcinoma of the head and neck. Postoperative RT was delivered to the primary tumor bed (71.7% cases) ± draining lymphatics (33.3% RT cases). Postoperative local RT was associated with improved local control (3-year actuarial local control 89.4% vs 68.1%; p = .005; Cox hazard ratio [HR] 0.18; 95% confidence interval [CI] = 0.06-0.55; p = .002). Similarly, regional RT was associated with improved regional control (3-year actuarial regional control 95.0% vs 66.7%; p = .008; Cox HR = 0.09; 95% CI = 0.01-0.69; p = .02). Regional RT played an important role for both clinical node-negative patients (3-year regional control 100% vs 44.7%; p = .03) and clinical/pathological node-positive patients (3-year regional control 90.9% vs 55.6%; p = .047). Local RT was beneficial for all patients with Merkel cell carcinoma of the head and neck, whereas regional RT was beneficial for clinical node-negative and clinical/pathological node-positive patients. © 2016 Wiley Periodicals, Inc. Head Neck 39: 48-55, 2017. © 2016 Wiley Periodicals, Inc.

Huntingtin-interacting protein 1: a Merkel cell carcinoma marker that interacts with c-Kit.

PubMed

Ames, Heather M; Bichakjian, Christopher K; Liu, Grace Y; Oravecz-Wilson, Katherine I; Fullen, Douglas R; Verhaegen, Monique E; Johnson, Timothy M; Dlugosz, Andrzej A; Ross, Theodora S

2011-10-01

Merkel cell carcinoma (MCC) is a neoplasm thought to originate from the neuroendocrine Merkel cells of the skin. Although the prevalence of MCC has been increasing, treatments for this disease remain limited because of a paucity of information regarding MCC biology. We have found that the endocytic oncoprotein Huntingtin-interacting protein 1 (HIP1) is expressed at high levels in ∼90% of MCC tumors and serves as a more reliable histological cytoplasmic stain than the gold standard, cytokeratin 20. Furthermore, high anti-HIP1 antibody reactivity in the sera of a cohort of MCC patients predicts the presence of metastases. Another protein that is frequently expressed at high levels in MCC tumors is the stem cell factor (SCF) receptor tyrosine kinase, c-Kit. In working toward an understanding of how HIP1 might contribute to MCC tumorigenesis, we have discovered that HIP1 interacts with SCF-activated c-Kit. These data not only identify HIP1 as a molecular marker for management of MCC patients but also show that HIP1 interacts with and slows the degradation of c-Kit.

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

PubMed Central

Shuda, Masahiro; Feng, Huichen; Kwun, Hyun Jin; Rosen, Steven T.; Gjoerup, Ole; Moore, Patrick S.; Chang, Yuan

2008-01-01

Merkel cell polyomavirus (MCV) is a virus discovered in our laboratory at the University of Pittsburgh that is monoclonally integrated into the genome of ≈80% of human Merkel cell carcinomas (MCCs). Transcript mapping was performed to show that MCV expresses transcripts in MCCs similar to large T (LT), small T (ST), and 17kT transcripts of SV40. Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation. Using coimmunoprecipitation and origin replication assays, we show that tumor-derived virus mutations do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity. Identification of an MCC cell line (MKL-1) having monoclonal MCV integration and the signature LT mutation allowed us to functionally test both tumor-derived and wild type (WT) T antigens. Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a “passenger virus” that secondarily infects MCC tumors. PMID:18812503

Merkel Cell Carcinoma: 27-Year Experience at the Peter MacCallum Cancer Centre

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hui, Andrew C., E-mail: achui@bigpond.net.au; Stillie, Alison L.; Seel, Matthew

2011-08-01

Purpose: To retrospectively evaluate the treatment outcome of patients with Merkel cell carcinoma after local and/or regional treatment. Methods and Materials: Patients presenting to our center between January 1980 and July 2006 with Merkel cell carcinoma and without distant metastases were reviewed. The primary endpoint was locoregional control. Secondary endpoints were distant recurrence, survival and treatment toxicity. Results: A total of 176 patients were identified. The median age was 79 years. The median follow-up was 2.2 years for all patients and 3.9 years for those alive at the last follow-up visit. The most common primary site was the head andmore » neck (56%), and 62 patients(35%) had regional disease at presentation. The initial surgery to the primary tumor involved (wide) local excision in 140 patients and biopsy only in 28 patients (8 patients had no identifiable primary tumor); 33 patients underwent nodal surgery. Of the 176 patients, 165 (94%) underwent radiotherapy (RT) and 29 of them also underwent concurrent chemotherapy. The median radiation dose was 50 Gy (range, 18-60). Locoregional recurrence developed in 33 patients(19%), with a median interval to recurrence of 8 months. Distant metastases developed in 43 patients(24%). Age, primary tumor size, and RT (no RT vs. <45 Gy vs. {>=}45 Gy) were predictive of locoregional control on univariate analysis. However, only RT remained significant on multivariate analysis. The estimated 5-year actuarial rate for locoregional control, progression-free survival, and overall survival was 76%, 60%, and 45%, respectively. Conclusion: The locoregional control rate for Merkel cell carcinoma in our study was comparable to those from other series using combined modality treatment with RT an integral part of treatment.« less

Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load.

PubMed

Leroux-Kozal, Valérie; Lévêque, Nicolas; Brodard, Véronique; Lesage, Candice; Dudez, Oriane; Makeieff, Marc; Kanagaratnam, Lukshe; Diebold, Marie-Danièle

2015-03-01

Merkel cell carcinoma (MCC) is a neuroendocrine skin malignancy frequently associated with Merkel cell polyomavirus (MCPyV), which is suspected to be oncogenic. In a series of MCC patients, we compared clinical, histopathologic, and prognostic features according to the expression of viral large T antigen (LTA) correlated with viral load. We evaluated the LTA expression by immunohistochemistry using CM2B4 antibody and quantified viral load by real-time polymerase chain reaction. We analyzed formalin-fixed, paraffin-embedded (FFPE) tissue samples (n = 36) and corresponding fresh-frozen biopsies when available (n = 12), of the primary tumor and/or metastasis from 24 patients. MCPyV was detected in 88% and 58% of MCC patients by real-time polymerase chain reaction and immunohistochemistry, respectively. The relevance of viral load measurements was demonstrated by the strong consistency of viral load level between FFPE and corresponding frozen tissues as well as between primary tumor and metastases. From FFPE samples, 2 MCC subgroups were distinguished based on a viral load threshold defined by the positivity of CM2B4 immunostaining. In the LTA-negative subgroup with no or low viral load (nonsignificant), tumor cells showed more anisokaryosis (P = .01), and a solar elastosis around the tumor was more frequently observed (P = .03). LTA-positive MCCs with significant viral load had a lower proliferation index (P = .03) and a longer survival of corresponding patients (P = .008). Depending on MCPyV involvement, 2 MCC subgroups can be distinguished on histopathologic criteria, and the CM2B4 antibody is able to differentiate them reliably. Furthermore, the presence of a significant viral load in tumors is predictive of better prognosis. Copyright © 2015 Elsevier Inc. All rights reserved.

PD-1 and PD-L1 in neoplastic cells and the tumor microenvironment of Merkel cell carcinoma.

PubMed

Mitteldorf, Christina; Berisha, Arbeneshe; Tronnier, Michael; Pfaltz, Monique C; Kempf, Werner

2017-09-01

Merkel cell carcinoma (MCC) is an aggressive neoplasm, which is often associated with Merkel cell polyomavirus (MCPyV). Programmed death-1 (PD-1) and its ligand PD-L1 are key players of the tumor microenvironment (TME). Fourteen paraffin-embedded tissue samples of MCC were stratified by their MCPyV detection. Apart from PD-L1 and PD-1, the TME was further characterized for the expression of CD33, FOXP3 and MxA. We observed PD-1 in 2 of 12 tumors. PD-L1 expression by tumor cells was found in 7 of 8 MCPyV(+) samples and was detected particularly in the periphery. The tumor cells were surrounded by a shield of PD-L1/CD33 immune cells. Expression of PD-L1 by the tumor cells was higher in areas with a denser immune infiltrate. CD33(+) cells without direct tumor contact were PD-L1 negative. Only a low number of FOXP3(+) regulatory T-cells was admixed. Tumor cells of MCPyV(-) samples were mostly PD-L1 negative. Our data demonstrate that PD-L1 expression occurs in tumor and immune cells, in areas in which they are close in contact. Interferon seems to play a role in this interaction. We postulate that PD-L1(+)/CD33(+) cells shield the tumor against attacking PD-1(+) immune cells. Therefore, next to anti-PD-1/PD-L1 antibodies, blockade of CD33 seems to be a promising therapeutic approach. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pembrolizumab-associated Mucous Membrane Pemphigoid in a Merkel cell carcinoma patient.

PubMed

Haug, V; Behle, V; Benoit, S; Kneitz, H; Schilling, B; Goebeler, M; Gesierich, A

2018-05-14

the anti-programmed death-1 (PD-1) antibody pembrolizumab, routinely used for treatment of metastatic melanoma or non-small cell lung cancer, was recently shown to have clinical meaningful activity in metastatic Merkel cell carcinoma (MCC). Several cases of bullous pemphigoid (BP) induced by PD-1 antibodies in melanoma have been reported so far. Here we report a case of oral mucous membrane pemphigoid (MMP) - a previously unknown, severe immune-related adverse event (irAE) occurring during pembrolizumab therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities

PubMed Central

Cheng, Jingwei; Rozenblatt-Rosen, Orit; Paulson, Kelly G.; Nghiem, Paul

2013-01-01

Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region. PMID:23514892

Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis.

PubMed

Cheng, Jingwei; Park, Donglim Esther; Berrios, Christian; White, Elizabeth A; Arora, Reety; Yoon, Rosa; Branigan, Timothy; Xiao, Tengfei; Westerling, Thomas; Federation, Alexander; Zeid, Rhamy; Strober, Benjamin; Swanson, Selene K; Florens, Laurence; Bradner, James E; Brown, Myles; Howley, Peter M; Padi, Megha; Washburn, Michael P; DeCaprio, James A

2017-10-01

Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MYCL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MYCL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MYCL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MYCL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MYCL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.

Huntingtin Interacting Protein 1: a Merkel Cell Carcinoma Marker That Interacts with c-Kit

PubMed Central

Ames, Heather M.; Bichakjian, Christopher K.; Liu, Grace Y.; Oravecz-Wilson, Katherine I.; Fullen, Douglas R.; Verhaegen, Monique; Johnson, Timothy M.; Dlugosz, Andrzej A.; Ross, Theodora S.

2011-01-01

Merkel Cell Carcinoma (MCC) is a neoplasm thought to originate from the neuroendocrine Merkel cells of the skin. While the prevalence of MCC has been increasing, treatments for this disease remain limited due to a paucity of information regarding MCC biology. We have found that the endocytic oncoprotein Huntingtin interacting protein 1 (HIP1) is expressed at high levels in close to 90% of MCC tumors and serves as a more reliable histological cytoplasmic stain than the gold standard, cytokeratin 20 (CK20). Furthermore, high anti-HIP1 antibody reactivity in the sera of a cohort of MCC patients predicts the presence of metastases. Another protein that is frequently expressed at high levels in MCC tumors is the stem cell factor (SCF) receptor tyrosine kinase, c-Kit. In working towards an understanding of how HIP1 might contribute to MCC tumorigenesis, we have discovered that HIP1 interacts with SCF activated c-Kit. These data not only identify HIP1 as a molecular marker for management of MCC patients but also show that HIP1 interacts with and slows the degradation of c-Kit. PMID:21697888

Merkel Cell Carcinoma of Unknown Primary Origin

PubMed Central

Deneve, Jeremiah L.; Messina, Jane L.; Marzban, Suroosh S.; Gonzalez, Ricardo J.; Walls, Brooke M.; Fisher, Kate J.; Ann Chen, Y.; Wayne Cruse, C.; Sondak, Vernon K.; Zager, Jonathan S.

2015-01-01

Background Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. MCC from an unknown primary origin (MCCUP) can present a diagnostic and therapeutic challenge. We describe our single-institution experience with the diagnosis and management of MCCUP presenting as metastases to lymph nodes. Methods After institutional review board approval, our institutional database spanning the years 1998–2010 was queried for patients with MCCUP. Clinicopathologic variables and outcomes were assessed. Results From a database of 321 patients with MCC, 38 (12%) were identified as having nodal MCCUP. Median age was 67 years, and 79% were men. Nodal basins involved at presentation were cervical (58%), axillary/epitrochlear (21%), or inguinal/iliac (21%). CK20 staining was positive in 93% of tumors tested, and all were negative for thyroid transcription factor-1. Twenty-nine patients (76%) underwent complete regional lymph node dissection (LND): 3 had LND alone, ten had LND and adjuvant radiotherapy, and 16 underwent LND followed by chemoradiotherapy. Definitive chemoradiotherapy without surgery was provided to six patients (16%), while radiotherapy alone was provided to three (8%). Recurrence was observed in 34% of patients. Median recurrence-free survival was 35 months. Ten patients (26%) died, five of disease and five of other causes. The median overall survival was 104 months. Conclusions Nodal MCCUP is a rare disease affecting primarily elderly white men. Recurrence is observed in approximately one-third of patients, with a 104 month median overall survival after a multimodal treatment approach consisting of surgery along with adjuvant chemotherapy and radiotherapy in the majority of patients. PMID:22271206

Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation

PubMed Central

Keibler, Mark A.; Park, Donglim Esther; Molla, Vadim; Cheng, Jingwei; Stephanopoulos, Gregory

2016-01-01

Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis. PMID:27880818

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

PubMed

Kaufman, Howard L; Russell, Jeffery; Hamid, Omid; Bhatia, Shailender; Terheyden, Patrick; D'Angelo, Sandra P; Shih, Kent C; Lebbé, Céleste; Linette, Gerald P; Milella, Michele; Brownell, Isaac; Lewis, Karl D; Lorch, Jochen H; Chin, Kevin; Mahnke, Lisa; von Heydebreck, Anja; Cuillerot, Jean-Marie; Nghiem, Paul

2016-10-01

Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at

Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma.

PubMed

Kaufman, Howard L; Hunger, Matthias; Hennessy, Meliessa; Schlichting, Michael; Bharmal, Murtuza

2018-02-01

To assess the association between tumor response and health-related quality of life (HRQoL) in patients with metastatic Merkel cell carcinoma treated with the anti-PD-L1 avelumab. Phase II single-arm trial (NCT02155647) data of 88 patients were analyzed. Correlations between percentage reduction in tumor size and change from baseline in Functional Assessment of Cancer Therapy - General (FACT-G), FACT - Melanoma (FACT-M) and EuroQol-5 Dimension scores were calculated. HRQoL and utility by tumor response (per the Response Evaluation Criteria In Solid Tumors version 1.1) was estimated. Tumor shrinkage correlated positively with patients' change from baseline in the FACT-M total (0.364 [95% CI: 0.050-0.607]) and subscale scores. Differences in HRQoL and utility between nonprogressive disease and progressive disease were clinically relevant. In patients with metastatic Merkel cell carcinoma, nonprogression during treatment with avelumab correlated with gains in HRQoL.

Merkel Cell Polyomavirus: A Newly Discovered Human Virus with Oncogenic Potential

PubMed Central

Spurgeon, Megan E.; Lambert, Paul F.

2012-01-01

A marked escalation in the rate of discovery of new types of human polyomavirus has occurred over the last five years largely owing to recent technological advances in their detection. Among the newly discovered viruses, Merkel Cell Polyomavirus (MCPyV or MCV) has gained the most attention due to its link with a rare human cancer. Infection with MCPyV is common in the human population, and the virus is detected in several anatomical locations, but most frequently in skin. Study of MCPyV molecular virology has been complicated by the lack of straightforward cell culture models, but recent in vitro studies are making strides towards understanding the virus life cycle, its cellular tropism, and mode of transmission. While MCPyV shares several traditional traits with other human polyomaviruses, the burst of research since its discovery reveals insight into a virus with many unique genetic and mechanistic features. The evidence for a causal link between MCPyV and the rare neuroendocrine cancer, Merkel Cell Carcinoma (MCC), is compelling. A majority of MCCs contain clonally integrated viral DNA, express viral T antigen transcripts and protein, and exhibit an addiction to the viral large T and small t antigen oncoproteins. The MCPyV large T antigen contains MCC tumor-specific mutations that ablate its replication capacity but preserve its oncogenic functions, and the small t antigen promotes an environment favorable for cap-dependent translation. The mechanisms of MCPyV-induced transformation have not been fully elucidated, but the likely etiological role of this new polyomavirus in human cancer provides a strong opportunity to expand knowledge of virus-host interactions and viral oncology. PMID:23217622

Is this the end of cytotoxic chemotherapy in Merkel cell carcinoma?

PubMed Central

Rabinowits, Guilherme

2017-01-01

Although cytotoxic chemotherapy has been used often in the management of Merkel cell carcinoma (MCC), its benefit remains uncertain. Despite being considered a chemosensitive disease, the duration of response is generally short, and the survival benefit is unclear. With the recent FDA approval of the anti-programmed cell death ligand 1 (PD-L1) antibody avelumab for patients with advanced MCC and the limited and controversial data on chemotherapy, it is important to put in perspective whether conventional chemotherapy should remain an option for these patients. Here, we review the evidence and controversies around chemotherapy in MCC as well as two recent studies on immunotherapy that changed the treatment paradigm for this disease. PMID:29033592

Primary male neuroendocrine adenocarcinoma involving the nipple simulating Merkel cell carcinoma - a diagnostic pitfall.

PubMed

Mecca, Patricia; Busam, Klaus

2008-02-01

Male breast cancer is a rare entity accounting for < 1% of all breast cancer cases in the United States, but with a rate that has been rising over the last 25 years. Nipple skin/subcutaneous tumors in men are even rarer. Likewise, true neuroendocrine carcinoma of the breast, defined as > 50% of tumor cells staining for either chromogranin or synaptophysin, is not a common entity, usually occurring in older women. We present the case of a 70-year-old man with a slowly growing nipple mass that had enlarged over the previous 1.5 years. The histology consisted of nests, trabeculae and sheets of basaloid cells with rare abortive gland formation and a pushing edge. The case was originally misdiagnosed as a Merkel cell carcinoma, based largely on histologic morphology. Strong staining for synaptophysin (in greater than 50% of cells), CD56, keratins AE1 : AE3 and Cam 5.2, as well as estrogen receptor and progesterone receptor was noted. Myoepithelial cells within in situ areas were identified using stains for calponin and 4A4, supporting a primary mammary duct origin. Additionally, a substantial portion of cells stained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), confirming some overlap with sweat duct differentiation. To the best of our knowledge, although reported in the male breast, no case of primary nipple neuroendocrine carcinoma in a male patient has been reported in the literature. The gender of the patient and association with the skin of the chest wall probably contributed to the original misdiagnosis of Merkel cell carcinoma in this patient.

PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.

PubMed

Gaiser, Maria Rita; Bongiorno, Michelle; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that lacks durable responses to traditional chemotherapy. Areas covered: After MCC was shown to be an immunogenic tumor, small trials revealed high objective response rates to PD-1/PD-L1 checkpoint inhibitors. The JAVELIN Merkel 200 (NCT02155647) trial tested the use of avelumab, a human IgG1 monoclonal antibody against PD-L1, in metastatic MCC. Avelumab recently became the first approved drug for metastatic MCC. Expert commentary: By conducting broad phase I studies assessing the safety of avelumab and a small phase II study demonstrating efficacy in this rare orphan tumor type, avelumab gained accelerated approval for the treatment of metastatic MCC. Additional studies are needed to determine how the antibody-dependent cellular cytotoxicity (ADCC) competent Fc region of avelumab contributes to disease control. Remaining questions: Longer follow-up will determine the durability of checkpoint blockade in controlling metastatic MCC. Additional studies will assess the utility and safety of adjuvant checkpoint blockade in patients with excised MCC. How to increase response rates by combining PD-1/PD-L1 blockade with other treatment approaches needs to be explored. In addition, treatment options for MCC patients who fail or do not respond to avelumab need to be identified.

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma

PubMed Central

Russell, Jeffery; Lebbé, Céleste; Chmielowski, Bartosz; Gambichler, Thilo; Grob, Jean-Jacques; Kiecker, Felix; Rabinowits, Guilherme; Terheyden, Patrick; Zwiener, Isabella; Bajars, Marcis; Hennessy, Meliessa; Kaufman, Howard L.

2018-01-01

Importance Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti–programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC). Objective To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC. Design, Setting, and Participants JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing. Interventions Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred. Main Outcomes and Measures Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability. Results As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

PubMed Central

Kwun, Hyun Jin; Shuda, Masahiro; Camacho, Carlos J.; Gamper, Armin M.; Thant, Mamie; Chang, Yuan

2015-01-01

ABSTRACT Merkel cell polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purification followed by mass spectroscopy (MS) analysis, which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential cellular interacting proteins. PP2A targeting is critical for the transforming properties of nonhuman polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A Aα and PP2A C, MCV sT coimmunopurified with PP2A Aα, PP2A Aβ, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite molecular surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56α into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55α, B56α and B56ε into PP2A. We conclude that MCV sT is required for Merkel cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting. IMPORTANCE Merkel cell polyomavirus is a newly discovered human cancer virus that promotes cancer, in part, through expression of its small T (sT) oncoprotein. Animal polyomavirus sT oncoproteins have been found to cause experimental tumors by blocking the activities of a group of phosphatases called protein phosphatase 2A (PP2A). Our structural analysis reveals that MCV sT also displaces the B subunit of PP2A to inhibit PP2A activity. MCV sT, however, only

Phosphohistone-H3 (PHH3) is prognostic relevant in Merkel cell carcinomas but Merkel cell polyomavirus is a more powerful prognostic factor than AJCC clinical stage, PHH3, Ki-67 or mitotic indices.

PubMed

Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Kato, Masako; Nagata, Keiko; Murakami, Ichiro; Hayashi, Kazuhiko

2015-08-01

Merkel cell carcinomas (MCCs) associated with Merkel cell polyomavirus (MCPyV) have better prognosis than those without MCPyV. The relationship between mitotic index (MI) and MCC outcome has remained elusive because of the difficulty in differentiating mitotic cells from apoptotic ones. We evaluated the role of phosphohistone-H3 (PHH3) (Ser10), a new mitotic count biomarker, in MCPyV-positive or -negative MCC patients, and assessed its prognostic value in comparison to Ki-67 labeling index or MI using hematoxylin and eosin (HE) staining. We compared the prognostic value of PHH3 mitotic index with that of MI by HE in 19 MCPyV-positive and 9 MCPyV-negative MCC patients. PHH3-positive immunoreactivity was mostly observed in mitotic figures. Multivariate analysis significantly showed that MCPyV status (HR, 0.004; 95% CI 0.0003-0.058) and the American Joint Committee of Cancer (AJCC) stage (HR, 5.02; 95% CI 1.23-20.51) were observed as significantly independent prognostic factors for OS. PHH3-positive cell counts/10 HPF was a slightly significant independent prognostic factor for OS (HR, 4.96; 95% CI 0.93-26.55). PHH3-positive MI and MCPyV status in MCC patients are useful in prognostication, although MCPyV-infection is a more powerful prognostic factor in MCCs than the AJCC scheme on proliferation or mitotic indices. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

Moist air state above counterflow wet-cooling tower fill based on Merkel, generalised Merkel and Klimanek & Białecky models

NASA Astrophysics Data System (ADS)

Hyhlík, Tomáš

2017-09-01

The article deals with an evaluation of moist air state above counterflow wet-cooling tower fill. The results based on Klimanek & Białecky model are compared with results of Merkel model and generalised Merkel model. Based on the numerical simulation it is shown that temperature is predicted correctly by using generalised Merkel model in the case of saturated or super-saturated air above the fill, but the temperature is underpredicted in the case of unsaturated moist air above the fill. The classical Merkel model always under predicts temperature above the fill. The density of moist air above the fill, which is calculated using generalised Merkel model, is strongly over predicted in the case of unsaturated moist air above the fill.

Detection of Merkel Cell Polyomavirus DNA in Serum Samples of Healthy Blood Donors

PubMed Central

Mazzoni, Elisa; Rotondo, John C.; Marracino, Luisa; Selvatici, Rita; Bononi, Ilaria; Torreggiani, Elena; Touzé, Antoine; Martini, Fernanda; Tognon, Mauro G.

2017-01-01

Merkel cell polyomavirus (MCPyV) has been detected in 80% of Merkel cell carcinomas (MCC). In the host, the MCPyV reservoir remains elusive. MCPyV DNA sequences were revealed in blood donor buffy coats. In this study, MCPyV DNA sequences were investigated in the sera (n = 190) of healthy blood donors. Two MCPyV DNA sequences, coding for the viral oncoprotein large T antigen (LT), were investigated using polymerase chain reaction (PCR) methods and DNA sequencing. Circulating MCPyV sequences were detected in sera with a prevalence of 2.6% (5/190), at low-DNA viral load, which is in the range of 1–4 and 1–5 copies/μl by real-time PCR and droplet digital PCR, respectively. DNA sequencing carried out in the five MCPyV-positive samples indicated that the two MCPyV LT sequences which were analyzed belong to the MKL-1 strain. Circulating MCPyV LT sequences are present in blood donor sera. MCPyV-positive samples from blood donors could represent a potential vehicle for MCPyV infection in receivers, whereas an increase in viral load may occur with multiple blood transfusions. In certain patient conditions, such as immune-depression/suppression, additional disease or old age, transfusion of MCPyV-positive samples could be an additional risk factor for MCC onset. PMID:29238698

Radiation sensitivity of Merkel cell carcinoma cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leonard, J.H.; Ramsay, J.R.; Birrell, G.W.

1995-07-30

Merkel cell carcinoma (MCC), being a small cell carcinoma, would be expected to be sensitive to radiation. Clinical analysis of patients at our center, especially those with macroscopic disease, would suggest the response is quite variable. We have recently established a number of MCC cell lines from patients prior to radiotherapy, and for the first time are in a position to determine their sensitivity under controlled conditions. Some of the MCC lines grew as suspension cultures and could not be single cell cloned; therefore, it was not possible to use clonogenic survival for all cell lines. A tetrazolium based (MTT)more » assay was used for these lines, to estimate cell growth after {gamma} irradiation. Control experiments were conducted on lymphoblastoid cell lines (LCL) and the adherent MCC line, MCC13, to demonstrate that the two assays were comparable under the conditions used. We have examined cell lines from MCC, small cell lung cancer (SCLC), malignant melanomas, Epstein Barr virus (EBV) transformed lymphocytes (LCL), and skin fibroblasts for their sensitivity to {gamma} irradiation using both clonogenic cell survival and MTT assays. The results show that the tumor cell lines have a range of sensitivities, with melanoma being more resistant (surviving fraction at 2 Gy (SF2) 0.57 and 0.56) than the small cell carcinoma lines, MCC (SF2 range 0.21-0.45, mean SF2 0.30, n = 8) and SCLC (SF2 0.31). Fibroblasts were the most sensitive (SF2 0.13-0.20, mean 0.16, n = 5). The MTT assay, when compared to clonogenic assay for the MCC13 adherent line and the LCL, gave comparable results under the conditions used. Both assays gave a range of SF2 values for the MCC cell lines, suggesting that these cancers would give a heterogeneous response in vivo. The results with the two derivative clones of MCC14 (SF2 for MCC14/1 0.38, MCC14/2 0.45) would further suggest that some of them may develop resistance during clonogenic evolution. 25 refs., 3 figs., 1 tab.« less

Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents.

PubMed

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; Gu, Jianguo G

2017-05-01

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In this study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, γ-aminobutyric acid (GABA), and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (I h ), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of I h currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. © 2017 International Society for Neurochemistry.

Unknown primary Merkel cell carcinoma: 23 new cases and a review.

PubMed

Tarantola, Tina I; Vallow, Laura A; Halyard, Michele Y; Weenig, Roger H; Warschaw, Karen E; Weaver, Amy L; Roenigk, Randall K; Brewer, Jerry D; Otley, Clark C

2013-03-01

Knowledge is limited regarding unknown primary Merkel cell carcinoma (UPMCC). We sought to document the characteristics and behavior of UPMCC, and determine the most appropriate treatment. A multicenter, retrospective, consecutive study reviewing patients given a diagnosis of UPMCC between 1981 and 2008 was completed. In addition, a literature review of cases of UPMCC was performed. In all, 23 patients with UPMCC are described and 34 cases from previous reports are compiled. Among the 23 new cases of UPMCC, the average age at diagnosis was 66.0 years; the majority of patients were male (87%) and Caucasian (100% of those reported). One patient was immunosuppressed, and 39% had a history of other cancer. After the initial biopsy, 16 patients had further evaluation of the involved lymph node basin. Half of these had additional positive nodes (8 of 16). The majority of patients had lymph node basin involvement only (78%), whereas 22% had lymph node basin and distant metastasis. The most common lymph node basin involved was inguinal. The median size of the involved lymph node at diagnosis was 5.0 cm. At 2 years, the overall survival of stage IIIB UPMCC was significantly improved versus stage IIIB known primary Merkel cell carcinoma (MCC): 76.9% to 36.4%. Limited number of cases and retrospective review are limitations. Our data demonstrate improved overall survival in patients with stage IIIB UPMCC versus those with stage IIIB known primary MCC. Because of the unpredictable natural history of UPMCC, we recommend individualization of care based on the details of each patient's clinical presentation. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy.

PubMed

Amaral, Teresa; Leiter, Ulrike; Garbe, Claus

2017-12-01

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation. In the metastatic setting, chemotherapy has been the standard treatment. However, two recently published trials with immune checkpoint inhibitors in first and second line showed promising results with a tolerable safety profile and these might become the standard therapy shortly. Somatostatin receptors are expressed in many MCC but such expression is not associated with disease severity. Presently there are no biomarkers predictive of response that could help to better select patients to these new therapies, and additional research is essential.

Advances in Merkel cell carcinoma from a pathologist's perspective.

PubMed

Barksdale, Sarah Kay

2017-10-01

Merkel cell carcinoma (MCC) is a rarely made but potentially devastating diagnosis. While local disease might be cured by surgery and radiotherapy, advanced disease is usually rapidly progressive and fatal. Until very recently, the only approach to metastatic MCC was cytotoxic chemotherapy with results so disappointing that current treatment guidelines discourage its use and recommend clinical trial as a more viable treatment option. Fortunately, recent advances in the understanding of the molecular pathogenesis of this tumour have produced a wide variety of experimental treatments for MCC, some of which are quite promising. The most current information regarding the diagnosis, staging, management of this tumour is briefly presented as well as new insights into the molecular basis of MCC and therapeutic approaches to MCC. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Complete Spontaneous Regression of Merkel Cell Carcinoma After Biopsy: A Case Report and Review of the Literature.

PubMed

Ahmadi Moghaddam, Parnian; Cornejo, Kristine M; Hutchinson, Lloyd; Tomaszewicz, Keith; Dresser, Karen; Deng, April; OʼDonnell, Patrick

2016-11-01

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that typically occurs on the head and neck of the elderly and follows an aggressive clinical course. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases and has been shown to participate in MCC tumorigenesis. Complete spontaneous regression of MCC has been rarely reported in the literature. We describe a case of a 79-year-old man that presented with a rapidly growing, 3-cm mass on the left jaw. An incisional biopsy revealed MCC. Additional health issues were discovered in the preoperative workup of this patient which delayed treatment. One month after the biopsy, the lesion showed clinical regression in the absence of treatment. Wide excision of the biopsy site with sentinel lymph node dissection revealed no evidence of MCC 2 months later. The tumor cells in the patient's biopsy specimen were negative for MCPyV by polymerase chain reaction and immunohistochemistry (CM2B4 antibody, Santa Cruz, CA). The exact mechanism for complete spontaneous regression in MCC is unknown. To our knowledge, only 2 previous studies evaluated the presence of MCPyV by polymerase chain reaction in MCC with spontaneous regression. Whether the presence or absence of MCPyV correlates with spontaneous regression warrants further investigation.

Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas.

PubMed

Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Nagata, Keiko; Nakajima, Hideki; Sano, Shigetoshi; Hayashi, Kazuhiko

2015-02-01

Merkel cell polyomavirus (MCPyV) integrates monoclonally into the genomes of approximately 80% of Merkel cell carcinomas (MCCs), affecting their clinicopathological features. The molecular mechanisms underlying MCC development after MCPyV infection remain unclear. We investigated the association of MCPyV infection with activation of the Akt/mammalian target of rapamycin (mTOR)/4E-binding protein 1 (4E-BP1) signaling pathway in MCCs to elucidate the role of these signal transductions and to identify molecular targets for treatment. We analyzed the molecular and pathological characteristics of 41 MCPyV-positive and 27 MCPyV-negative MCCs. Expression of mTOR, TSC1, and TSC2 messenger RNA was significantly higher in MCPyV-negative MCCs, and Akt (T308) phosphorylation also was significantly higher (92% vs 66%; P = .019), whereas 4E-BP1 (S65 and T70) phosphorylation was common in both MCC types (92%-100%). The expression rates of most other tested signals were high (60%-100%) and not significantly correlated with MCPyV large T antigen expression. PIK3CA mutations were observed more frequently in MCPyV-positive MCCs (6/36 [17%] vs 2/20 [10%]). These results suggest that protein expression (activation) of most Akt/mTOR/4E-BP1 pathway signals was not significantly different in MCPyV-positive and MCPyV-negative MCCs, although these 2 types may differ in tumorigenesis, and MCPyV-negative MCCs showed significantly more frequent p-Akt (T308) activation. Therefore, certain Akt/mTOR/4E-BP1 pathway signals could be novel therapeutic targets for MCC regardless of MCPyV infection status. Copyright © 2015 Elsevier Inc. All rights reserved.

Merkel cell polyomavirus IgG antibody levels are associated with progression to AIDS among HIV-infected individuals.

PubMed

Vahabpour, Rouhollah; Nasimi, Maryam; Naderi, Niloofar; Salehi-Vaziri, Mostafa; Mohajel, Nasir; Sadeghi, Farzin; Keyvani, Hossein; Monavari, Seyed Hamidreza

2017-04-01

The association of Merkel cell polyomavirus (MCP y V) with Merkel cell carcinoma (MCC) in immunocompromised individuals has been revealed in a number of surveys. The study of MCP y V specific antibody titers and viral loads in such patients has a great attraction for research groups interested in viral reactivation. In this cross-sectional study to evaluate MCP y V antibody titer, DNA prevalence and viral load in peripheral blood mononuclear cells (PBMCs), we examined 205 HIV-1 infected patients and 100 un-infected controls. The HIV-1 infected patients divided into two groups (HIV/AIDS and non-AIDS) according to their CD4 status. Total IgG antibody titer against MCP y V was analyzed by virus like particle (VLP)-based enzyme linked immunosorbent assay (ELISA). Presence of MCP y V-DNA in subject's PBMCs was examined by quantitative real-time PCR assay. Levels of anti-MCP y V IgG in HIV/AIDS patients were significantly higher than those in non-AIDS HIV-infected and control subjects (p value = <0.001). The prevalence rate of MCP y V-DNA in PBMCs of HIV/AIDS, non-AIDS HIV-infected and un-infected controls were 17%, 16%, and 14% respectively. The MCP y V viral load among the groups ranged between 0.15 to 2.9 copies/10 3 cells (median, 1.9 copies/10 3 cells), with no significant difference between the studied populations (p value = 0.3).

Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.

PubMed

Kaufman, Howard L; Russell, Jeffery S; Hamid, Omid; Bhatia, Shailender; Terheyden, Patrick; D'Angelo, Sandra P; Shih, Kent C; Lebbé, Céleste; Milella, Michele; Brownell, Isaac; Lewis, Karl D; Lorch, Jochen H; von Heydebreck, Anja; Hennessy, Meliessa; Nghiem, Paul

2018-01-19

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. Clinicaltrials.gov identifier: NCT02155647.

Avelumab: a new standard for treating metastatic Merkel cell carcinoma.

PubMed

Baker, Mairead; Cordes, Lisa; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed. Future perspectives and ongoing studies are also discussed. Expert commentary: Avelumab demonstrated rapid and durable responses and a manageable safety profile in the treatment of metastatic MCC. Patient outcomes are favorable when compared to historical responses to standard chemotherapy. Ongoing clinical trials will continue to characterize avelumab and its optimal use in MCC therapy.

Center for Cancer Research plays key role in first FDA-approved drug for treatment of Merkel cell carcinoma | Center for Cancer Research

Cancer.gov

The Center for Cancer Research’s ability to rapidly deploy integrated basic and clinical research teams at a single site facilitated the rapid FDA approval of the immunotherapy drug avelumab for metastatic Merkel cell carcinoma, a rare, aggressive form of skin cancer. Learn more...  

Strategy for eliciting antigen-specific CD8+ T cell-mediated immune response against a cryptic CTL epitope of merkel cell polyomavirus large T antigen

PubMed Central

2012-01-01

Background Merkel cell carcinoma (MCC) is a relatively new addition to the expanding category of oncovirus-induced cancers. Although still comparably rare, the number of cases has risen dramatically in recent years. Further complicating this trend is that MCC is an extremely aggressive neoplasm with poor patient prognosis and limited treatment options for advanced disease. The causative agent of MCC has been identified as the merkel cell polyomavirus (MCPyV). The MCPyV-encoded large T (LT) antigen is an oncoprotein that is theorized to be essential for virus-mediated tumorigenesis and is therefore, an excellent MCC antigen for the generation of antitumor immune responses. As a foreign antigen, the LT oncoprotein avoids the obstacle of immune tolerance, which normally impedes the development of antitumor immunity. Ergo, it is an excellent target for anti-MCC immunotherapy. Since tumor-specific CD8+ T cells lead to better prognosis for MCC and numerous other cancers, we have generated a DNA vaccine that is capable of eliciting LT-specific CD8+ T cells. The DNA vaccine (pcDNA3-CRT/LT) encodes the LT antigen linked to a damage-associated molecular pattern, calreticulin (CRT), as it has been demonstrated that the linkage of CRT to antigens promotes the induction of antigen-specific CD8+ T cells. Results The present study shows that DNA vaccine-induced generation of LT-specific CD8+ T cells is augmented by linking CRT to the LT antigen. This is relevant since the therapeutic effects of the pcDNA3-CRT/LT DNA vaccine is mediated by LT-specific CD8+ T cells. Mice vaccinated with the DNA vaccine produced demonstrably more LT-specific CD8+ T cells. The DNA vaccine was also able to confer LT-specific CD8+ T cell-mediated protective and therapeutic effects to prolong the survival of mice with LT-expressing tumors. In the interest of determining the LT epitope which most MCC-specific CD8+ T cells recognize, we identified the amino acid sequence of the immunodominant LT epitope

Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator

PubMed Central

Shuda, Masahiro; Kwun, Hyun Jin; Feng, Huichen; Chang, Yuan; Moore, Patrick S.

2011-01-01

Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although MCV is known to integrate into the tumor cell genome and to undergo mutation, the molecular mechanisms used by this virus to cause cancer are unknown. Here, we show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorage- and contact-independent growth and promoted serum-free proliferation of human cells. These effects did not involve protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E–binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT–associated 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT. Expression of a constitutively active 4E-BP1 that could not be phosphorylated antagonized the cell transformation activity of MCV sT. Taken together, these experiments showed that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an oncoprotein, and its effects on dysregulated cap-dependent translation have clinical implications for the prevention, diagnosis, and treatment of MCV-related cancers. PMID:21841310

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF.

PubMed

Rotondo, John Charles; Bononi, Ilaria; Puozzo, Andrea; Govoni, Marcello; Foschi, Valentina; Lanza, Giovanni; Gafà, Roberta; Gaboriaud, Pauline; Touzé, Françoise Antoine; Selvatici, Rita; Martini, Fernanda; Tognon, Mauro

2017-07-15

Purpose: The purpose of this investigation was to characterize Merkel cell carcinomas (MCC) arisen in patients affected by autoimmune diseases and treated with biologic drugs. Experimental Design: Serum samples from patients with MCC were analyzed for the presence and titer of antibodies against antigens of the oncogenic Merkel cell polyomavirus (MCPyV). IgG antibodies against the viral oncoproteins large T (LT) and small T (ST) antigens and the viral capsid protein-1 were analyzed by indirect ELISA. Viral antigens were recombinant LT/ST and virus-like particles (VLP), respectively. MCPyV DNA sequences were studied using PCR methods in MCC tissues and in peripheral blood mononuclear cells (PBMC). Immunohistochemical (IHC) analyses were carried out in MCC tissues to reveal MCPyV LT oncoprotein. Results: MCPyV DNA sequences identified in MCC tissues showed 100% homology with the European MKL-1 strain. PBMCs from patients tested MCPyV-negative. Viral DNA loads in the three MCC tissues were in the 0.1 to 30 copy/cell range. IgG antibodies against LT/ST were detected in patients 1 and 3, whereas patient 2 did not react to the MCPyV LT/ST antigen. Sera from the three patients with MCC contained IgG antibodies against MCPyV VP1. MCC tissues tested MCPyV LT-antigen-positive in IHC assays, with strong LT expression with diffuse nuclear localization. Normal tissues tested MCPyV LT-negative when employed as control. Conclusions: We investigated three new MCCs in patients affected by rheumatologic diseases treated with biologic drugs, including TNF. A possible cause-effect relationship between pharmacologic immunosuppressive treatment and MCC onset is suggested. Indeed, MCC is associated with MCPyV LT oncoprotein activity. Clin Cancer Res; 23(14); 3929-34. ©2017 AACR . ©2017 American Association for Cancer Research.

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

PubMed

D'Angelo, Sandra P; Russell, Jeffery; Lebbé, Céleste; Chmielowski, Bartosz; Gambichler, Thilo; Grob, Jean-Jacques; Kiecker, Felix; Rabinowits, Guilherme; Terheyden, Patrick; Zwiener, Isabella; Bajars, Marcis; Hennessy, Meliessa; Kaufman, Howard L

2018-03-22

Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC). To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC. JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing. Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred. Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability. As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at

Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals.

PubMed

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; DeBerry, Jennifer J; Gu, Jianguo G

2016-09-13

The evolution of sensory systems has let mammals develop complicated tactile end organs to enable sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. The Merkel disc, a main type of tactile end organ consisting of Merkel cells (MCs) and Aβ-afferent endings, are highly abundant in fingertips, touch domes, and whisker hair follicles of mammals. The Merkel disc has high tactile acuity for an object's physical features, such as texture, shape, and edges. Mechanisms underlying the tactile function of Merkel discs are obscured as to how MCs transmit tactile signals to Aβ-afferent endings leading to tactile sensations. Using mouse whisker hair follicles, we show herein that tactile stimuli are transduced by MCs into excitatory signals that trigger vesicular serotonin release from MCs. We identify that both ionotropic and metabotropic 5-hydroxytryptamine (5-HT) receptors are expressed on whisker Aβ-afferent endings and that their activation by serotonin released from MCs initiates Aβ-afferent impulses. Moreover, we demonstrate that these ionotropic and metabotropic 5-HT receptors have a synergistic effect that is critical to both electrophysiological and behavioral tactile responses. These findings elucidate that the Merkel disc is a unique serotonergic synapse located in the epidermis and plays a key role in tactile transmission. The epidermal serotonergic synapse may have important clinical implications in sensory dysfunctions, such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes, inflammatory diseases, and undergo chemotherapy. It may also have implications in the exaggerated tactile sensations induced by recreational drugs that act on serotoninergic synapses.

Asymmetric Assembly of Merkel Cell Polyomavirus Large T-Antigen Origin Binding Domains at the Viral Origin

DOE Office of Scientific and Technical Information (OSTI.GOV)

C Harrison; G Meinke; H Kwun

2011-12-31

The double-stranded DNA polyomavirus Merkel cell polyomavirus (MCV) causes Merkel cell carcinoma, an aggressive but rare human skin cancer that most often affects immunosuppressed and elderly persons. As in other polyomaviruses, the large T-antigen of MCV recognizes the viral origin of replication by binding repeating G(A/G)GGC pentamers. The spacing, number, orientation, and necessity of repeats for viral replication differ, however, from other family members such as SV40 and murine polyomavirus. We report here the 2.9 {angstrom} crystal structure of the MCV large T-antigen origin binding domain (OBD) in complex with a DNA fragment from the MCV origin of replication. Consistentmore » with replication data showing that three of the G(A/G)GGC-like binding sites near the center of the origin are required for replication, the crystal structure contains three copies of the OBD. This stoichiometry was verified using isothermal titration calorimetry. The affinity for G(A/G)GGC-containing double-stranded DNA was found to be {approx} 740 nM, approximately 8-fold weaker than the equivalent domain in SV40 for the analogous region of the SV40 origin. The difference in affinity is partially attributable to DNA-binding residue Lys331 (Arg154 in SV40). In contrast to SV40, a small protein-protein interface is observed between MCV OBDs when bound to the central region of the origin. This protein-protein interface is reminiscent of that seen in bovine papilloma virus E1 protein. Mutational analysis indicates, however, that this interface contributes little to DNA binding energy.« less

Merkel cell carcinoma of the eyelid. A series of 5 cases and review of the literature.

PubMed

Riesco, B; Cárdenas, N; Sáez, V; Torres, G; Gallegos, I; Dassori, J; Saldías, N

2016-02-01

Presentation of 5 clinical cases of Merkel cell carcinoma of the eyelid, highlighting the clinical, histopathological, management, and monitoring features. Review of related literature. Retrospective review of clinical records and telephone interview of the 5 patients treated for Merkel cell carcinoma between 2006 and 2013, in the Orbit and Oculoplastic Department, Clinical Hospital of the University of Chile. Five patients (2 men, 3 women); 79.2 years (range 64-94 years), with a mean onset of 10 weeks (range 5-16 weeks), tumour size reaching a mean of 2.5×2×2.1cm at the time of surgery. Described as a nodular mass, exophytic, solid, reddish coloured. With no infiltrated lymph nodes or metastases in the first match. Staging as T2N0M0, after the first surgery with oncological criteria. Two lymph node recurrences detected during monitoring. Distant metastasis was found in one patient. The histopathological diagnosis was confirmed by immunohistochemical study of the biopsy. The surgical strategy was full excision, control of surgical margins in the intraoperative period, and eyelid reconstruction with Hughes flap, Cutler/Beard flap or primary closure, depending on the case. Early diagnosis, wide excision of the tumour with intraoperative control of clear margins with conventional or Mohs surgery, and proper eyelid reconstruction are adequate for a good survival in elderly patients with this eyelid tumour. The study of sentinel lymph node biopsy in primary intervention is recommended; with subsequent radiotherapy to decrease the recurrence and increase survival. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.

PubMed

Goh, Gerald; Walradt, Trent; Markarov, Vladimir; Blom, Astrid; Riaz, Nadeem; Doumani, Ryan; Stafstrom, Krista; Moshiri, Ata; Yelistratova, Lola; Levinsohn, Jonathan; Chan, Timothy A; Nghiem, Paul; Lifton, Richard P; Choi, Jaehyuk

2016-01-19

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

PubMed

Paulson, Kelly G; Lewis, Christopher W; Redman, Mary W; Simonson, William T; Lisberg, Aaron; Ritter, Deborah; Morishima, Chihiro; Hutchinson, Kathleen; Mudgistratova, Lola; Blom, Astrid; Iyer, Jayasri; Moshiri, Ata S; Tarabadkar, Erica S; Carter, Joseph J; Bhatia, Shailender; Kawasumi, Masaoki; Galloway, Denise A; Wener, Mark H; Nghiem, Paul

2017-04-15

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society. © 2016 American Cancer Society.

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses.

PubMed

Wu, Julie H; Simonette, Rebecca A; Nguyen, Harrison P; Doan, Hung Q; Rady, Peter L; Tyring, Stephen K

2016-03-01

Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS) are two proliferative cutaneous diseases caused by the Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) respectively. Recently, studies have elucidated a key role of the small tumor (sT) antigen in the proliferative pathogenic mechanisms of MCPyV and likely TSPyV. While both sT antigens have demonstrated a capacity in regulating cellular pathways, it remains unknown whether MCPyV and TSPyV sT antigens contribute similarly or differentially to cell proliferation. The present study aims to explore the proliferative potential of MCPyV and TSPyV sT antigens by investigating their regulatory effects on the retinoblastoma protein (pRb) tumor suppressor. Inducible cell lines expressing MCPyV sT or TSPyV sT were created using a lentiviral packaging system. Cellular proteins were extracted and subjected to SDS-PAGE followed by Western blot detection and densitometric analysis. Expression of TSPyV sT markedly enhanced the phosphorylation of pRb in Western blot experiments. In contrast, expression of MCPyV sT did not alter pRb phosphorylation under the same experimental conditions. Densitometric analysis revealed that TSPyV sT antigen expression nearly doubled the ratio of phosphorylated to total pRb (P<0.001, Student's T-test), while MCPyV sT antigen expression did not cause significant change in pRb phosphorylation status. Given that hyperphosphorylation of pRb is associated with dysregulation of the cell cycle, S-phase induction, and increased cell proliferation, our findings support an important role of TSPyV-mediated pRb deactivation in the development of TS. The observation that the pRb tumor suppressor is inactivated by TSPyV sT but not MCPyV sT provides further insights into the distinct pathobiological mechanisms of MCC and TS. Copyright © 2016 Elsevier B.V. All rights reserved.

A pilot study of SPECT/CT-based mixed-reality navigation towards the sentinel node in patients with melanoma or Merkel cell carcinoma of a lower extremity.

PubMed

van den Berg, Nynke S; Engelen, Thijs; Brouwer, Oscar R; Mathéron, Hanna M; Valdés-Olmos, Renato A; Nieweg, Omgo E; van Leeuwen, Fijs W B

2016-08-01

To explore the feasibility of an intraoperative navigation technology based on preoperatively acquired single photon emission computed tomography combined with computed tomography (SPECT/CT) images during sentinel node (SN) biopsy in patients with melanoma or Merkel cell carcinoma. Patients with a melanoma (n=4) or Merkel cell carcinoma (n=1) of a lower extremity scheduled for wide re-excision of the primary lesion site and SN biopsy were studied. Following a Tc-nanocolloid injection and lymphoscintigraphy, SPECT/CT images were acquired with a reference target (ReTp) fixed on the leg or the iliac spine. Intraoperatively, a sterile ReTp was placed at the same site to enable SPECT/CT-based mixed-reality navigation of a gamma ray detection probe also containing a reference target (ReTgp).The accuracy of the navigation procedure was determined in the coronal plane (x, y-axis) by measuring the discrepancy between standard gamma probe-based SN localization and mixed-reality-based navigation to the SN. To determine the depth accuracy (z-axis), the depth estimation provided by the navigation system was compared to the skin surface-to-node distance measured in the computed tomography component of the SPECT/CT images. In four of five patients, it was possible to navigate towards the preoperatively defined SN. The average navigational error was 8.0 mm in the sagittal direction and 8.5 mm in the coronal direction. Intraoperative sterile ReTp positioning and tissue movement during surgery exerted a distinct influence on the accuracy of navigation. Intraoperative navigation during melanoma or Merkel cell carcinoma surgery is feasible and can provide the surgeon with an interactive 3D roadmap towards the SN or SNs in the groin. However, further technical optimization of the modality is required before this technology can become routine practice.

Merkel Cell Carcinoma: A Population Analysis on Survival.

PubMed

Sridharan, Vishwajith; Muralidhar, Vinayak; Margalit, Danielle N; Tishler, Roy B; DeCaprio, James A; Thakuria, Manisha; Rabinowits, Guilherme; Schoenfeld, Jonathan D

2016-10-01

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy. However, factors associated with disease presentation and outcomes remain uncertain, especially in light of recent changes in workup, such as sentinel lymph node biopsy. Therefore, this study used the SEER database to examine factors that could affect stage at presentation and treatment. We identified 4,543 patients and evaluated associations between sex, race, age, primary disease site, disease presentation, and treatment. We also used univariate and multivariate analyses to examine the effect of these factors on disease-specific survival (DSS) and overall survival (OS). We specifically conducted subgroup analyses on a more modern cohort of patients with MCC treated between 2006 and 2012. Male sex, older age, larger tumor size, and primary tumors of the scalp, neck, or trunk were associated with a higher burden of nodal disease. Multivariate predictors of worse DSS/OS in both the recent and overall cohort included age older than 75 years, number of lymph nodes involved, tumors greater than 5 cm, metastatic disease, or lack of radiation therapy. The number of involved nodes was the best predictor of DSS/OS. Associations with radiation therapy were most pronounced in patients with nodal disease and those not undergoing surgery. Sex, age, tumor size, and primary site of disease correlated with burden of nodal disease in MCC. Associations between disease presentation and treatment strategies such as radiation and DSS and OS have remained relatively constant in the modern era from 2006 to 2012 compared with findings from prior studies. Copyright © 2016 by the National Comprehensive Cancer Network.

Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma

PubMed Central

2012-01-01

Introduction Merkel cell carcinoma (MCC) is a rare tumour of skin. This study is a retrospective audit of patients with MCC from St Vincent’s and Mater Hospital, Sydney, Australia. The aim of this study was to investigate the influence of radiotherapy (RT) on the local and regional control of MCC lesions and survival of patients with MCC. Method The data bases in anatomical pathology, RT and surgery. We searched for patients having a diagnosis of MCC between 1996 and 2007. Patient, tumour and treatment characteristics were collected and analysed. Univariate survival analysis of categorical variables was conducted with the Kaplan-Meier method together with the Log-Rank test for statistical significance. Continuous variables were assessed using the Cox regression method. Multivariate analysis was performed for significant univariate results. Results Sixty seven patients were found. Sixty two who were stage I-III and were treated with radical intent were analysed. 68% were male. The median age was 74 years. Forty-two cases (68%) were stage I or II, and 20 cases (32%) were stage III. For the subset of 42 stage I and II patients, those that had RT to their primary site had a 2-year local recurrence free survival of 89% compared with 36% for patients not receiving RT (p<0.001). The cumulative 2-year regional recurrence free survival for patients having adjuvant regional RT was 84% compared with 43% for patients not receiving this treatment (p<0.001). Immune status at initial surgery was a significant predictor for OS and MCCSS. In a multivariate analysis combining macroscopic size (mm) and immune status at initial surgery, only immune status remained a significant predictor of overall survival (HR=2.096, 95% CI: 1.002-4.385, p=0.049). Conclusions RT is associated with significant improvement in local and regional control in Merkel cell carcinoma. Immunosuppression is an important factor in overall survival. PMID:23075308

Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection.

PubMed

Moshiri, Ata S; Doumani, Ryan; Yelistratova, Lola; Blom, Astrid; Lachance, Kristina; Shinohara, Michi M; Delaney, Martha; Chang, Oliver; McArdle, Susan; Thomas, Hannah; Asgari, Maryam M; Huang, Meei-Li; Schwartz, Stephen M; Nghiem, Paul

2017-04-01

Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19-2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Merkel cell carcinoma: An algorithm for multidisciplinary management and decision-making.

PubMed

Prieto, Isabel; Pérez de la Fuente, Teresa; Medina, Susana; Castelo, Beatriz; Sobrino, Beatriz; Fortes, Jose R; Esteban, David; Cassinello, Fernando; Jover, Raquel; Rodríguez, Nuria

2016-02-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Therapeutic approach is often unclear, and considerable controversy exists regarding MCC pathogenesis and optimal management. Due to its rising incidence and poor prognosis, it is imperative to establish the optimal therapy for both the tumor and the lymph node basin, and for treatment to include sentinel node biopsy. Sentinel node biopsy is currently the most consistent predictor of survival for MCC patients, although there are conflicting views and a lack of awareness regarding node management. Tumor and node management involve different specialists, and their respective decisions and interventions are interrelated. No effective systemic treatment has been made available to date, and therefore patients continue to experience distant failure, often without local failure. This review aims to improve multidisciplinary decision-making by presenting scientific evidence of the contributions of each team member implicated in MCC management. Following this review of previously published research, the authors conclude that multidisciplinary team management is beneficial for care, and propose a multidisciplinary decision algorithm for managing this tumor. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors.

PubMed

Lai, Jonathan H; Fleming, Kirsten E; Ly, Thai Yen; Pasternak, Sylvia; Godlewski, Marek; Doucette, Steve; Walsh, Noreen M

2015-09-01

Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Intraepidermal Merkel cell carcinoma: A case series of a rare entity with clinical follow up.

PubMed

Jour, George; Aung, Phyu P; Rozas-Muñoz, Eduardo; Curry, Johnathan L; Prieto, Victor; Ivan, Doina

2017-08-01

Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous carcinoma. MCC typically involves dermis and although epidermotropism has been reported, MCC strictly intraepidermal or in situ (MCCIS) is exceedingly rare. Most of the cases of MCCIS described so far have other associated lesions, such as squamous or basal cell carcinoma, actinic keratosis and so on. Herein, we describe 3 patients with MCC strictly in situ, without a dermal component. Our patients were elderly. 2 of the lesions involved the head and neck area and 1 was on a finger. All tumors were strictly intraepidermal in the diagnostic biopsies, and had histomorphologic features and an immunohistochemical profile supporting the diagnosis of MCC. Excisional biopsies were performed in 2 cases and failed to reveal dermal involvement by MCC or other associated malignancies. Our findings raise the awareness that MCC strictly in situ does exist and it should be included in the differential diagnosis of Paget's or extramammary Paget's disease, pagetoid squamous cell carcinoma, melanoma and other neoplasms that typically show histologically pagetoid extension of neoplastic cells. Considering the limited number of cases reported to date, the diagnosis of isolated MCCIS should not warrant a change in management from the typical MCC. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Multiple Primary Merkel Cell Carcinomas Presenting as Pruritic, Painful Lower Leg Tumors

PubMed Central

Blumenthal, Laura; VandenBoom, Timothy; Melian, Edward; Peterson, Anthony; Hutchens, Kelli A.

2015-01-01

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine tumor of the skin which almost exclusively presents as a solitary tumor. It is most often seen on sun-exposed regions, historically almost exclusively on the head and neck, with only rare case reports on the extremities. Although recent studies have shown increased incidence with up to 20% on the extremities, here we present one of these rare emerging presentations, with the addition of a unique treatment option. Our patient is an 80-year-old male with a 3-month history of multiple raised, rapidly enlarging tumors on the right ankle. Two separate biopsies were performed and demonstrated sheets and clusters of small blue cells filling the dermis with scant cytoplasm, dusty chromatin, and nuclear molding. Subsequent immunohistochemical stains confirmed the diagnosis of multiple primary MCC. Despite the characteristic immunohistochemical profile of primary MCC, the possibility of a metastatic neuroendocrine carcinoma from an alternate primary site was entertained, given his unusual clinical presentation. A complete clinical workup including CT scans of the chest, abdomen, and pelvis showed no evidence of disease elsewhere. Instead of amputation, the patient opted for nonsurgical treatment with radiation therapy alone, resulting in a rapid and complete response. This case represents an unusual presentation of primary MCC and demonstrates further evidence that radiation as monotherapy is an effective local treatment option for inoperable MCC. PMID:26594171

Planning study for Merkel cell carcinoma based on the relapse pattern.

PubMed

Hoeller, Ulrike; Schubert, Tina; Mueller, Thomas; Budach, Volker; Ghadjar, Pirus; Brenner, Winfried; Kuschke, Wolf

2017-04-01

To develop a technique for radiation (RT) of in-transit path ways (IT) in Merkel cell carcinoma. In the planning study, IT were ink-marked on the skin during sentinel lymphscintigraphy and wire-marked in planning-CT. Pre- and post-operative planning-CTs were acquired. The clinical target volume (CTV) included tumor bed plus safety margin, IT and draining nodes, the planning volume (PTV) the CTV plus 0.5-1cm margin. VMAT plans with 2-3 arcs were analyzed. A planning study was performed for five pts. including two pts. with primary tumor (PT) in head and neck, 1 pt. each with PT of elbow, forearm and upper leg respectively. Plans showed satisfactory PTV coverage: D mean 100%±0%, D 98% 92.4%±2.24%, homogeneity index (HI) 0.095±0.01, conformation number (CN) 0.84±0.01 and conformality index (CI) 0.95±0.01. The planning study confirms feasibility of highly conformal irradiation of IT pathways based on individualized target delineation. Currently, patients referred for non-metastatic MCC are encouraged to enroll in a prospective clinical study that evaluates the feasibility of radiation of IT pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma.

PubMed

Joseph, Jocelyn; Zobniw, Chrystia; Davis, Jennifer; Anderson, Jaime; Trinh, Van Anh

2018-04-01

To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

PubMed

Basu, Sandip; Ranade, Rohit

2016-06-01

This report illustrates an excellent partial response of Merkel cell carcinoma with multiple bilobar hepatic metastases to a single cycle of peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE. This response, coupled with minimal side effects, warrants consideration of this therapy early in the disease course (rather than at an advanced stage after failure of other therapies) if the metastatic lesions exhibit adequate tracer avidity on somatostatin receptor-based imaging. Our patient showed progression of systemic disease after having undergone a second surgery and adjuvant radiotherapy to the head and neck, as well as chemotherapy, and hence was considered a candidate for PRRT. In a pretreatment study, the metastatic lesions demonstrated avidity to both somatostatin receptors and (18)F-FDG. Three months after the first cycle of treatment, when the patient was being evaluated for a second cycle, both imaging parameters showed evidence of a partial response that included nearly complete resolution of the two previously seen lesions. In view of the relatively good tolerability, minimal side effects, and targeted nature of the treatment, PRRT may evolve to become the first-line therapy for metastatic Merkel cell carcinoma and should be examined further in a larger number of patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Epidemiological, Clinicopathological and Virological Features of Merkel Cell Carcinomas in Medical Center of University of Pécs, Hungary (2007-2012).

PubMed

Horváth, Katalin Barbara; Pankovics, Péter; Kálmán, Endre; Kádár, Zsolt; Battyáni, Zita; Lengyel, Zsuzsanna; Reuter, Gábor

2016-01-01

Merkel cell carcinoma (MCC) is a rare, highly aggressive skin tumour. In 2008, a Merkel cell polyomavirus (MC) was identified in MCCs as a potential etiological factor of MCC. The aims of this retrospective study were to investigate the epidemiological, clinicopathological and virological features of MCCs. Between 2007 and 2012, 11 patients had been diagnosed with MCC by histological methods in University of Pécs, Hungary. In eight MCC cases MC was tested by PCR (in primary skin lesions, lymph nodes/cutan metastases, MCC neighboring carcinomas). Clinicopathological characteristics (age, histological pattern, lymphovascular invasion, co-morbidities) of MC-positive and MC-negative cases were compared. MC was detected in three (37.5%) out of eight patients' primary tumour or metastasis. The average age was 73.8 (64.3 in MC-positive group). Except the youngest, 55 year-old patient (the primary tumour appeared on his leg), all tumours were found at the head and neck region. Immunosuppression (steroid therapy, chronic lymphoid leukaemia, chronic obstructive pulmonary disease) and/or old age were characteristic for all cases. Histological pattern was different in MC-positive and in MC-negative groups: MCCs with MC showed more homogeneous histological pattern, lack of lymphovascular invasion and were associated with better prognosis (mortality rate: 33% versus 80%). MCC associated with oncogenic virus is a newly recognized clinical entity. However, MC could not be detected in all histologically proven MCCs. The well-defined selection of patients/disease groups and better characterization of differences between MC-positive and negative cases is an important step towards the recognition of the etiology and pathogenesis of all MCCs.

DNA from KI, WU and Merkel Cell Polyomaviruses Is Not Detected in Childhood Central Nervous System Tumours or Neuroblastomas

PubMed Central

Giraud, Géraldine; Ramqvist, Torbjörn; Pastrana, Diana V.; Pavot, Vincent; Lindau, Cecilia; Kogner, Per; Orrego, Abiel; Buck, Christopher B.; Allander, Tobias; Holm, Stefan; Gustavsson, Bengt; Dalianis, Tina

2009-01-01

Background BK and JC polyomaviruses (BKV and JCV) are potentially oncogenic and have in the past inconclusively been associated with tumours of the central nervous system (CNS), while BKV has been hinted, but not confirmed to be associated with neuroblastomas. Recently three new polyomaviruses (KIPyV, WUPyV and MCPyV) were identified in humans. So far KIPyV and WUPyV have not been associated to human diseases, while MCPyV was discovered in Merkel Cell carcinomas and may have neuroepithelial cell tropism. However, all three viruses can be potentially oncogenic and this compelled us to investigate for their presence in childhood CNS and neuroblastomas. Methodology The presence of KI, WU and MCPyV DNA was analysed, by a joint WU and KI specific PCR (covering part of VP1) and by a MCPyV specific regular and real time quantitative PCR (covering part of Large T) in 25 CNS tumour biopsies and 31 neuroblastoma biopsies from the Karolinska University Hospital, Sweden. None of the three new human polyomaviruses were found to be associated with any of the tumours, despite the presence of PCR amplifiable DNA assayed by a S14 housekeeping gene PCR. Conclusion In this pilot study, the presence of MCPyV, KI and WU was not observed in childhood CNS tumours and neuroblastomas. Nonetheless, we suggest that additional data are warranted in tumours of the central and peripheral nervous systems and we do not exclude that other still not yet detected polyomaviruses could be present in these tumours. PMID:20011509

Gregory Merkel Tours Marshall Space Flight Center (MSFC)

NASA Technical Reports Server (NTRS)

1972-01-01

Gregory A. Merkel (left), high school student from Springfield, Massachusetts, is pictured here with Harry Coons of the Marshall Space Flight Center (MSFC) during a visit to the center. Merkel was among 25 winners of a contest in which some 3,500 high school students proposed experiments for the following year's Skylab mission. The nationwide scientific competition was sponsored by the National Science Teachers Association and the National Aeronautics and Space Administration (NASA). The winning students, along with their parents and sponsor teachers, visited MSFC where they met with scientists and engineers, participated in design reviews for their experiments, and toured MSFC facilities. Of the 25 students, 6 did not see their experiments conducted on Skylab because the experiments were not compatible with Skylab hardware and timelines. Of the 19 remaining, 11 experiments required the manufacture of additional equipment.

No detection of Merkel cell polyomavirus in oral lichen planus: Results of a preliminary study in a French cohort of patients.

PubMed

Masson Regnault, Marie; Vigarios, Emmanuelle; Projetti, Fabrice; Herbault-Barres, Beatrice; Tournier, Emilie; Lamant, Laurence; Sibaud, Vincent

2017-11-01

Oral lichen planus (OLP) is a chronic inflammatory disease considered as a CD8+ T lymphocyte-mediated autoimmune reaction, which may be triggered by undetermined virus. Recent reports have described the detection of Merkel cell polyomavirus (MCPyV) DNA in oral samples from healthy patients and in patients with different forms of oral cancers. We therefore investigated in a prospective way whether MCPyV was detectable in oral lesions of patients with active OLP. Our preliminary results do not support the hypothesis that OLP may be triggered by MCPyV infection. Further studies are needed to evaluate the involvement of other human polyomaviruses in OLP pathogenesis. © 2017 Wiley Periodicals, Inc.

An investigation of the accuracy of the Merkel equation for evaporative cooling tower calculations. Waste heat management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadigaroglu, G.; Pastor, E.J.

1974-01-01

The exact differential equations governing heat and mass transfer and air flow in an evaporative, natural-draft cooling tower are presented. The Merkel equation is then derived starting from this exact formulation and showing all the approximations involved. The Merkel formulation lumps the sensible and the latent heat transfer together and considers a single enthalpy-difference driving force for the total heat transfer. The effect of the approximations inherent in the Merkel equation is investigated and analyzed by a series of parametric numerical calculations of cooling tower performance under various ambient conditions and load conditions.

Two rare diagnoses during chronic lymphocytic leukaemia follow-up: Kaposi's sarcoma and Merkel cell carcinoma.

PubMed

Dogu, Mehmet H; Sari, Ismail; Hacioglu, Sibel; Degirmencioglu, Serkan; Şen, Nilay; Keskin, Ali

2016-02-01

Chronic lymphocytic leukaemia often has a clinical presentation characterised by increased neoplastic lymphocytes which are mostly mature looking due to B lymphocytes. Increased secondary cancer prevalence has been detected among patients with chronic lymphocytic leukaemia diagnosis. In this report, we present three chronic lymphocytic leukaemia patients who developed secondary rare cancers during their follow-up at our clinic. Case 1: A 54-year-old female patient was diagnosed with stage I chronic lymphocytic leukaemia in 2003 and was diagnosed with Merkel cell carcinoma in February 2013. Case 2: A 66-year-old male patient was diagnosed with stage II chronic lymphocytic leukaemia in 2009 and was diagnosed with Kaposi's sarcoma in March 2013. Case 3: A 77-year-old male patient was diagnosed with stage I chronic lymphocytic leukaemia in 2006 and was diagnosed with Kaposi's sarcoma in 2011. In conclusion, secondary cancers are observed in patients diagnosed with chronic lymphocytic leukaemia. Therefore, follow-up of chronic lymphocytic leukaemia requires additional attention in this context. © The Author(s) 2016.

Detection of KI WU and Merkel cell polyomavirus in respiratory tract of cystic fibrosis patients.

PubMed

Iaria, M; Caccuri, F; Apostoli, P; Giagulli, C; Pelucchi, F; Padoan, R F; Caruso, A; Fiorentini, S

2015-06-01

In the last few years, many reports have confirmed the presence of WU, KI and Merkel cell (MC) polyomaviruses (PyV) in respiratory samples wordwide, but their pathogenic role in patients with underlying conditions such as cystic fibrosis is still debated. To determine the prevalence of MCPyV, WUPyV and KIPyV, we conducted a 1-year-long microbiological testing of respiratory specimens from 93 patients with cystic fibrosis in Brescia, Italy. We detected PyV DNA in 94 out of 337 analysed specimens. KIPyV was the most common virus detected (12.1%), followed by WUPyV (8.9%) and MCPyV (6.8%). We found an intriguing association between the presence of MCPyV and the concurrent isolation of Pseudomonas aeruginosa, as well as with the patient status, classified as chronically colonized with P. aeruginosa. Our study adds perspective on the prevalence and the potential pathogenic role of PyV infections. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Intraoperative imprint cytology for evaluation of sentinel lymph nodes from Merkel cell carcinoma.

PubMed

Wong, S Lindsey; Young, Yorke D; Geisinger, Kim R; Shen, Perry; Stewart, John H; Sangueza, Omar; Pichardo-Geisinger, Rita; Levine, Edward A

2009-07-01

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy. Intraoperative imprint cytology (IIC) can potentially avoid second operations for completion lymphadenectomy when nodal metastases are found during nodal staging with sentinel lymph node biopsy (SLN). This represents the first series of IIC for MCC we are aware of and our initial experience. Patients with biopsy-proven MCC underwent SLN (at the time of wide excision) using a double indicator technique with 99technetium sulfur colloid and isosulfan blue. SLN were identified and bisected and touch imprints of each half were made. One half was air-dried and stained with Diff-Quick and the other was fixed with 95 per cent alcohol and stained with hematoxylin and eosin (H&E). Paraffin-embedded sections were examined by H&E. Eighteen patients underwent successful SLN mapping procedures. IIC was negative in 84.2 per cent (16) cases. Three false-negatives occurred with IIC, but there were no false-positives, making the sensitivity 33 per cent and the specificity 100 per cent. Two of four patients with positive pathology-confirmed SLN also had positive IIC. SLN mapping has usefulness in patients with MCC. IIC is feasible and accurate in evaluating the SLN. IIC is a practical diagnostic tool when intraoperative analysis of SLN biopsy is desired for MCC.

Basal cell carcinoma: CD56 and cytokeratin 5/6 staining patterns in the differential diagnosis with Merkel cell carcinoma.

PubMed

Panse, Gauri; McNiff, Jennifer M; Ko, Christine J

2017-06-01

Basal cell carcinoma (BCC) can resemble Merkel cell carcinoma (MCC) on histopathological examination and while CK20 is a useful marker in this differential, it is occasionally negative in MCC. CD56, a sensitive marker of neuroendocrine differentiation, is sometimes used to identify MCC, but has been reportedly variably positive in BCC as well. In contrast, CK5/6 consistently labels BCC but is not expressed in neuroendocrine tumors. We evaluated 20 cases of BCC for the pattern of CD56 and cytokeratin 5/6 (CK5/6) staining, hypothesizing that these 2 stains could differentiate BCC from MCC in difficult cases. Seventeen cases of MCC previously stained with CD56 were also examined. All BCCs showed patchy expression of CD56 except for 2 cases, which showed staining of greater than 70% of tumor. CK5/6 was diffusely positive in all cases of BCC. Fifteen of 17 MCCs were diffusely positive for CD56. The difference in the pattern of CD56 expression between MCC and BCC (diffuse vs patchy, respectively) was statistically significant (P < .05). BCC typically shows patchy CD56 expression and diffuse CK5/6 positivity. These 2 markers can be used to distinguish between BCC and MCC in challenging cases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increased expression of EZH2 in Merkel cell carcinoma is associated with disease progression and poorer prognosis.

PubMed

Harms, Kelly L; Chubb, Heather; Zhao, Lili; Fullen, Douglas R; Bichakjian, Christopher K; Johnson, Timothy M; Carskadon, Shannon; Palanisamy, Nallasivam; Harms, Paul W

2017-09-01

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that affects tumorigenesis by epigenetic gene silencing. Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that has a high risk of disease progression with nodal and distant metastases. Here, we evaluated EZH2 expression by immunohistochemistry in a cohort of 85 MCC tumors (29 primary tumors, 41 lymph node metastases, 13 in-transit metastases, and 2 distant metastases) with clinical follow-up. We show strong/moderate EZH2 expression in 54% of tumors. Importantly, weak expression of EZH2 in the primary tumor, but not nodal metastases, correlated with improved prognosis compared to moderate/strong EZH2 expression (5-year MCC-specific survival of 68% versus 22%, respectively, P=.024). In addition, EZH2 was expressed at higher levels in nodal metastases compared to primary tumors (P=.005). Our data demonstrate that EZH2 has prognostic value and may play an oncogenic role in MCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Primary cutaneous neuroendocrine carcinoma, Merkel cell carcinoma. Case series 1991-2012.

PubMed

Campillo, Ramón; Gil-Carcedo, Elisa; Alonso, David; Vallejo, Luis A; Oñate, Juan M; Gil-Carcedo, Luis M

2013-01-01

Merkel cell carcinoma was first described by Toker in 1972. It is an uncommon, primary neuroendocrine skin carcinoma which appears in the dermoepidermic area, grows fast, is very aggressive and has a poor prognosis. The aim of this work is to highlight the importance of this tumour, which develops mainly in the skin of the head and neck area, and whose prevalence has increased in recent years. We gathered data on 16 patients suffering cutaneous neuroendocrine carcinoma treated at our hospital between September 12, 1991 and July 13, 2012. We indicated the age and gender of patients. We described the area where the tumour was located, indicating the size in millimetres, according to the major axis of the lesion. Most of the patients studied were over 70 years old, except for one who was 55. The highest frequency of cases appeared among patients aged over 80 years. In the cases studied, when the tumour appeared in the head and neck region (10/16), its location could be nasal-lateronasal, cheek-malar, upper eyelid, frontal or mandibular. The major axis of the lesion ranged between 7 and 35 mm. Unlike with epidermoid or basocellular carcinomas, recurrence and ganglionar metastases were common. Immunohistochemical (CK20) tests are essential for a correct diagnosis. Treatment is usually surgical and occasionally followed by radiotherapy and chemotherapy. This carcinoma is not a very common skin tumour. It appears in old age, in the head and neck region in 50% of cases and often leads to exitus. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.

PubMed

Abraham, Karan J; Zhang, Xiao; Vidal, Ricardo; Paré, Geneviève C; Feilotter, Harriet E; Tron, Victor A

2016-04-01

Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Seroreactivity against Merkel cell polyomavirus and other polyomaviruses in chronic lymphocytic leukaemia, the MCC-Spain study.

PubMed

Robles, Claudia; Casabonne, Delphine; Benavente, Yolanda; Costas, Laura; Gonzalez-Barca, Eva; Aymerich, Marta; Campo, Elias; Tardon, Adonina; Jiménez-Moleón, José J; Castaño-Vinyals, Gemma; Dierssen-Sotos, Trinidad; Michel, Angelika; Kranz, Lena; Aragonés, Nuria; Pollan, Marina; Kogevinas, Manolis; Pawlita, Michael; de Sanjose, Silvia

2015-08-01

Merkel cell polyomavirus (MCPyV) has been suspected to cause chronic lymphocytic leukaemia (CLL) but previous data are inconsistent. We measured seroreactivities of nine polyomaviruses (MCPyV, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, HPyV-6, HPyV-7 and TSPyV) in 359 CLL cases and 370 controls using bead-based multiplex serology technology. We additionally tested two herpesviruses (HSV-1 and CMV). Associations between disease and viral seroreactivities were assessed using logistic regression. All human viruses showed high seroprevalences (69-99%) against structural proteins in controls but significantly lower viral seroprevalences in cases (58-94%; OR range = 0.21-0.70, P value < 0.05), except for MCPyV (OR = 0.79, 95% CI = 0.54-1.16). Lower seroreactivity levels were observed among CLL subjects, with significant differences already observed at early stages of disease, unrelated to treatment status. Seroreactivities against polyomavirus related oncoproteins were almost null. Our data suggest no association for MCPyV polyomavirus with CLL development and an unlikely association for other polyomaviruses tested.

Gregory A. Merkel Greeted By Astronauts and MSFC Personnel

NASA Technical Reports Server (NTRS)

1972-01-01

Springfield, Massachusetts high school student, Gregory A. Merkel, is greeted by (left to right): Astronauts Russell L. Schweickart, and Owen K. Garriott; Marshall Space Flight Center (MSFC) Skylab Program Manager, Leland Belew; and MSFC Director of Administration and Technical Services, David Newby, during a tour of MSFC. Merkel was among 25 winners of a contest in which some 3,500 high school students proposed experiments for the following year's Skylab Mission. The nationwide scientific competition was sponsored by the National Science Teachers Association and the National Aeronautics and Space Administration (NASA). The winning students, along with their parents and sponsor teachers, visited MSFC where they met with scientists and engineers, participated in design reviews for their experiments, and toured MSFC facilities. Of the 25 students, 6 did not see their experiments conducted on Skylab because the experiments were not compatible with Skylab hardware and timelines. Of the 19 remaining, 11 experiments required the manufacture of additional equipment.

Emerging and Mechanism-Based Therapies for Recurrent or Metastatic Merkel Cell Carcinoma

PubMed Central

Miller, Natalie J.; Bhatia, Shailender; Parvathaneni, Upendra; Iyer, Jayasri G.; Nghiem, Paul

2013-01-01

Opinion statement Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus-associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n=179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy. PMID:23436166

Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics.

PubMed

Paulson, Kelly G; Park, Song Youn; Vandeven, Natalie A; Lachance, Kristina; Thomas, Hannah; Chapuis, Aude G; Harms, Kelly L; Thompson, John A; Bhatia, Shailender; Stang, Andreas; Nghiem, Paul

2018-03-01

Merkel cell carcinoma (MCC) incidence rates are rising and strongly age-associated, relevant for an aging population. Determine MCC incidence in the United States and project incident cases through the year 2025. Registry data were obtained from the SEER-18 Database, containing 6600 MCC cases. Age- and sex-adjusted projections were generated using US census data. During 2000-2013, the number of reported solid cancer cases increased 15%, melanoma cases increased 57%, and MCC cases increased 95%. In 2013, the MCC incidence rate was 0.7 cases/100,000 person-years in the United States, corresponding to 2488 cases/year. MCC incidence increased exponentially with age, from 0.1 to 1.0 to 9.8 (per 100,000 person-years) among age groups 40-44 years, 60-64 years, and ≥85 years, respectively. Due to aging of the Baby Boomer generation, US MCC incident cases are predicted to climb to 2835 cases/year in 2020 and 3284 cases/year in 2025. We assumed that the age-adjusted incidence rate would stabilize, and thus, the number of incident cases we projected might be an underestimate. An aging population is driving brisk increases in the number of new MCC cases in the United States. This growing impact combined with the rapidly evolving therapeutic landscape warrants expanded awareness of MCC diagnosis and management. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Impact of total radiotherapy dose on survival for head and neck Merkel cell carcinoma after resection.

PubMed

Patel, Sagar A; Qureshi, Muhammad M; Mak, Kimberley S; Sahni, Debjani; Giacalone, Nicholas J; Ezzat, Waleed; Jalisi, Scharukh; Truong, Minh Tam

2017-07-01

Head and neck Merkel cell carcinoma (MCC) is commonly treated with surgery and adjuvant radiotherapy (RT) for high-risk features. The optimal radiation dose is unknown. One thousand six hundred twenty-five eligible patients with head and neck MCC were identified in the National Cancer Data Base (NCDB). Radiation dose was divided into 3 groups: 30 to <50 Gray (Gy), 50-55 Gy, and >55-70 Gy. Cox regression was used to compare overall survival (OS) between groups, accounting for age, sex, stage, surgery type, margin status, comorbidities, and use of chemotherapy. With a median follow-up of 33.5 months, 3-year OS was 48.9%, 70.3%, and 58.7% for 30 to <50 Gy, 50-55 Gy, and >55-70 Gy, respectively (P < .001). Compared to 50-55 Gy, doses between 30 to <50 Gy (adjusted hazard ratio [HR] 1.53; 95% confidence interval [CI] 1.17-1.99; P = .002) and >55-70 Gy (adjusted HR 1.21; 95% CI 1.0-1.46; P = .06) were associated with worse survival. Adjuvant radiation doses within 50-55 Gy may be optimal for head and neck MCC. © 2017 Wiley Periodicals, Inc.

Huntingtin interacting protein 1 as a histopathologic adjunct in the diagnosis of Merkel cell carcinoma.

PubMed

Marghalani, Siham; Feller, John Kyle; Mahalingam, Meera; Mirzabeigi, Marjan

2015-06-01

Huntington interacting protein 1 (HIP1), an antiapoptotic protein normally expressed in the brain, is highly expressed in Merkel cell carcinomas (MCCs). Given this, the aim of the current study was to ascertain the value of HIP1 as a histopathologic adjunct in the diagnosis of MCC. In this retrospective study, archival material from 26 cases with a diagnosis of MCC and/or neuroendocrine carcinoma were retrieved from the pathology files of the Skin Pathology Laboratory (Boston University School of Medicine, Boston, MA, USA). Histopathologic sections of all cases were re-reviewed and the diagnosis confirmed. All patient data were de-identified. Immunohistochemical studies were performed using antibodies to HIP1 and cytokeratins (CK) 20 and 7. A semiquantitative scoring system for immunohistochemical expression of HIP1 was utilized by deriving a cumulative score (based on percentage positivity of cells and intensity of expression). Using a cut-off total score of 3 or more as positive, the total number of positive cases was 22 for HIP1, 24 for CK20, and 11 for CK7. Comparing the results of HIP1 and CK20, there were four discordant pairs (three positive for CK20 but negative for HIP1 and one positive for HIP1 but negative for CK20). McNemar's test indicated that there was no statistical significance (P = 0.625), thereby implying a close agreement between the expression of HIP1 and CK20 in these neuroendocrine neoplasms. © 2014 The International Society of Dermatology.

Phylodynamics of Merkel-cell polyomavirus and human polyomavirus 6: A long-term history with humans.

PubMed

Torres, Carolina; Barrios, Melina Elizabeth; Cammarata, Robertina Viviana; Victoria, Matías; Fernandez-Cassi, Xavier; Bofill-Mas, Silvia; Colina, Rodney; Blanco Fernández, María Dolores; Mbayed, Viviana Andrea

2018-04-20

New human polyomaviruses have been described in the last years, including the Merkel-cell polyomavirus (MCPyV; Human polyomavirus 5) and the Human polyomavirus 6 (HPyV6). Although their infection is usually asymptomatic, in immunocompromised host can cause life-threatening pathologies, such as the Merkel cell carcinoma, an aggressive skin neoplasia associated to the MCPyV. Despite being prevalent viruses in population, epidemiological data from South America are scarce, as well as the characterization of the viral types circulating and their origin. The aims of this work were to describe MCPyV and HPyV6 from environmental samples with different geographical origin and to analyze their phylogenetic and evolutionary histories, particularly for MCPyV. Partial and complete genome sequences were obtained from sewage samples from Argentina, Uruguay and Spain. A total number of 87 sequences were obtained for MCPyV and 33 for HPyV6. Phylogenetic analysis showed that MCPyV sequences distributed according to their geographic origin in Europe/North America, Africa, Asia, South America and Oceania groups, suggesting that viral diversification might have followed human migrations across the globe. In particular, viruses from Argentina associated with Europe/North America and South America genotypes, whereas those from Uruguay and Spain also grouped with Africa genotype, reflecting the origin of the current population in each country, which could arrive not only during ancient human migration but also during recent migratory events. In addition, the South American group presented a high level of clusterization, showing internal clusters that could be related to specific locations, such as French Guiana and Brazil or the Southern region into South America, such as Argentina and Uruguay, suggesting a long term evolutionary process in the region. Additionally, in this work, we carried out the first analysis about the evolutionary history of MCPyV trough the integration of

Factors Influencing Relapse-Free Survival in Merkel Cell Carcinoma of the Lower Limb-A Review of 60 Cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulsen, Michael, E-mail: michael_poulsen@health.qld.gov.a; Round, Caroline; Keller, Jacqui

2010-02-01

Purpose: Factors affecting relapse-free survival (RFS) in patients with Merkel cell carcinoma (MCC) of the lower limb were reviewed. Methods and Materials: The records of 60 patients from 1986 to 2005 with a diagnosis of MCC of the lower limb or buttock were retrospectively reviewed. The patients were treated with curative intent with surgery, radiation, or chemotherapy. Results: The 5-year overall survival, disease-specific survival, and RFS were 53%, 61%, and 20%, respectively. Factors influencing RFS were analyzed using univariate analysis. It appeared that recurrent disease worsened RFS (p = 0.03) and the addition of any radiotherapy improved RFS (p <0.001),more » as did radiotherapy to the inguinal nodes (p = 0.01) or primary site and inguinal nodes (p = 0.003). Age, surgical margins, and stage were not statistically significant. On multivariate analysis, the only significant factor was the addition of radiotherapy (hazard ratio = 0.51 p = 0.03). Conclusion: The addition of radiotherapy improves RFS compared with surgery alone. Elective treatment should be given to the inguinal nodes to reduce the risk of relapse.« less

Localization of the rabies virus antigen in Merkel cells in the follicle-sinus complexes of muzzle skins of rabid dogs.

PubMed

Shimatsu, Taichi; Shinozaki, Harumi; Kimitsuki, Kazunori; Shiwa, Nozomi; Manalo, Daria L; Perez, Rodolfo C; Dilig, Joselito E; Yamada, Kentaro; Boonsriroj, Hassadin; Inoue, Satoshi; Park, Chun-Ho

2016-11-01

The direct fluorescent antibody test (dFAT) on fresh brain tissues is the gold standard for rabies virus antigen detection in dogs. However, this method is laborious and holds a high risk of virus exposure for the experimenter. Skin biopsies are useful for the diagnosis of humans and animals. In mammals, the tactile hair, known as the follicle-sinus complex (FSC), is a specialized touch organ that is abundant in the muzzle skin. Each tactile hair is equipped with more than 2,000 sensory nerve endings. Therefore, this organ is expected to serve as an alternative postmortem diagnostic material. However, the target cells and localization of rabies virus antigen in the FSCs remain to be defined. In the present study, muzzle skins were obtained from 60 rabid dogs diagnosed with rabies by dFAT at the Research Institute of Tropical Medicine in the Philippines. In all dogs, virus antigen was clearly detected in a part of the outer root sheath at the level of the ring sinus of the FSCs, and the majority of cells were positive for the Merkel cell (MC) markers cytokeratin 20 and CAM5.2. Our results suggest that MCs in the FSCs of the muzzle skin are a target for virus replication and could serve as a useful alternative specimen source for diagnosis of rabies. Copyright © 2016 Elsevier B.V. All rights reserved.

Expression of adhesion molecules and cytokeratin 20 in merkel cell carcinomas.

PubMed

Tanaka, Yasushi; Sano, Toshiaki; Qian, Zhi Rong; Hirokawa, Mitsuyoshi

2004-01-01

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. MCCs often show characteristic paranuclear dot-like immunopositivity for cytokeratin 20 (CK20), a globular aggregation of CK20 intermediate filaments. These aggregates typically form rhabdoid features and fibrous bodies and may be associated with a down-regulation in adhesion molecules (AMs). To date, the relationship between the expression of AMs and CK20 and clinicopathological findings in MCC has not been well examined. In this immunohistochemical study, we assessed the expression of AMs, CK20, and chromogranin A (CgA) on MCCs in 8 men and 23 women with this disease, and also characterized their clinicopathological features. This study is the largest of its kind that has been undertaken to date in Japanese patients. Compared to normal tissue, E-cadherin and alpha- and beta-catenins showed reduced membranous expression in 95.7%, 46.7%, and 45.2% of MCCs, respectively. Nuclear E-cadherin localization was seen in four tumors, all of which predominantly showed a CK20 dot pattern. However, there was no significant relationship between the membranous expression of AMs and a CK20 dot pattern. E-cadherin expression was significantly lower in tumors of > or =2 cm, and tumors negative for E-cadherin more frequently developed outside of the head and neck than within those regions. CgA was more intensely expressed in tumors with uniform nuclei and a dense lymphocytic infiltrate than in those that showed pleomorphisms and that had few, if any, infiltrating lymphocytes. These findings suggest that MCCs have a reduced expression of AMs and that down-regulation of E-cadherin expression may correlate with increased tumor aggressiveness. The fact that no significant relationship was demonstrable between the membranous expression of AMs and the CK20 expression pattern suggests that the mechanism of aggregation of intermediate filaments may be different in different types of tumors.

High-Affinity Rb Binding, p53 Inhibition, Subcellular Localization, and Transformation by Wild-Type or Tumor-Derived Shortened Merkel Cell Polyomavirus Large T Antigens

PubMed Central

Borchert, Sophie; Czech-Sioli, Manja; Neumann, Friederike; Schmidt, Claudia; Wimmer, Peter; Dobner, Thomas

2014-01-01

ABSTRACT Interference with tumor suppressor pathways by polyomavirus-encoded tumor antigens (T-Ags) can result in transformation. Consequently, it is thought that T-Ags encoded by Merkel cell polyomavirus (MCPyV), a virus integrated in ∼90% of all Merkel cell carcinoma (MCC) cases, are major contributors to tumorigenesis. The MCPyV large T-Ag (LT-Ag) has preserved the key functional domains present in all family members but has also acquired unique regions that flank the LxCxE motif. As these regions may mediate unique functions, or may modulate those shared with T-Ags of other polyomaviruses, functional studies of MCPyV T-Ags are required. Here, we have performed a comparative study of full-length or MCC-derived truncated LT-Ags with regard to their biochemical characteristics, their ability to bind to retinoblastoma (Rb) and p53 proteins, and their transforming potential. We provide evidence that full-length MCPyV LT-Ag may not directly bind to p53 but nevertheless can significantly reduce p53-dependent transcription in reporter assays. Although early region expression constructs harboring either full-length or MCC-derived truncated LT-Ag genes can transform primary baby rat kidney cells, truncated LT-Ags do not bind to p53 or reduce p53-dependent transcription. Interestingly, shortened LT-Ags exhibit a very high binding affinity for Rb, as shown by coimmunoprecipitation and in vitro binding studies. Additionally, we show that truncated MCPyV LT-Ag proteins are expressed at higher levels than those for the wild-type protein and are able to partially relocalize Rb to the cytoplasm, indicating that truncated LT proteins may have gained additional features that distinguish them from the full-length protein. IMPORTANCE MCPyV is one of the 12 known polyomaviruses that naturally infect humans. Among these, it is of particular interest since it is the only human polyomavirus known to be involved in tumorigenesis. MCPyV is thought to be causally linked to MCC, a rare

Dr. Janie Merkel is interviewed by Ryan Blum and Janice Friend.

PubMed

Merkel, Janie

2007-12-01

Dr. Janie Merkel is the director of Yale's Chemical Genomics Screening Facility, a high-throughput screening laboratory that is part of the Yale University Center for Genomics and Proteomics. The Screening Facility connects Yale researchers with industry-quality robotic machinery and a diverse group of compound libraries, which have been used successfully to link therapeutic targets with potential therapies.

Weekly Carboplatin Reduces Toxicity During Synchronous Chemoradiotherapy for Merkel Cell Carcinoma of Skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulsen, Michael; Walpole, Euan; Harvey, Jennifer

Purpose: The toxicity of radiotherapy (RT) combined with weekly carboplatin and adjuvant carboplatin and etoposide was prospectively assessed in a group of patients with high-risk Stage I and II Merkel cell carcinoma of the skin. This regimen was compared with the Trans-Tasman Radiation Oncology Group 96:07 study, which used identical eligibility criteria but carboplatin and etoposide every 3 weeks during RT. Patients and Methods: Patients were eligible if they had disease localized to the primary site and lymph nodes, with high-risk features. RT was delivered to the primary site and lymph nodes to a dose of 50 Gy and weeklymore » carboplatin (area under the curve of 2) was given during RT. This was followed by three cycles of carboplatin and etoposide. A total of 18 patients were entered into the study, and their data were compared with the data from 53 patients entered into the Trans-Tasman Radiation Oncology Group 96:07 study. Results: Involved lymph nodes (Stage II) were present in 14 patients (77%). Treatment was completed as planned in 16 patients. The weekly carboplatin dose was delivered in 17 patients, and 15 were able to complete all three cycles of adjuvant carboplatin and etoposide. Grade 3 and 4 neutrophil toxicity occurred in 7 patients, but no cases of febrile neutropenia developed. Compared with the Trans-Tasman Radiation Oncology Group 96:07 protocol (19 of 53 cases of febrile neutropenia), the reduction in the febrile neutropenia rate (p = 0.003) and decrease in Grade 3 skin toxicity (p = 0.006) were highly statistically significant. Conclusion: The results of our study have shown that weekly carboplatin at this dosage is a safe way to deliver synchronous chemotherapy during RT for MCC and results in a marked reduction of febrile neutropenia and Grade 3 skin toxicity compared with the three weekly regimen.« less

In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series.

PubMed

Xu, Melody J; Wu, Susan; Daud, Adil I; Yu, Siegrid S; Yom, Sue S

2018-05-30

Patients with metastatic Merkel cell carcinoma (mMCC) who experience disease progression on immunotherapy have limited additional standard options. Given evidence of synergism between radiation therapy (RT) and immunotherapy, two patients progressing on PD-1 inhibition were referred for short-course RT. Two patients were found to have progressive mMCC on PD-1 inhibitor therapy and were treated with single-fraction palliative RT. Both patients were observed to have local control at irradiated regions, as well as durable abscopal response at unirradiated, out-of-field, sites of metastatic disease. Short-course RT is a compelling strategy that could be a means to augment response in patients with mMCC who show progression on immune checkpoint blockade. Ongoing clinical trials are investigating the relationship between RT and immunotherapy in mMCC.

Droplet digital PCR (ddPCR) vs quantitative real-time PCR (qPCR) approach for detection and quantification of Merkel cell polyomavirus (MCPyV) DNA in formalin fixed paraffin embedded (FFPE) cutaneous biopsies.

PubMed

Arvia, Rosaria; Sollai, Mauro; Pierucci, Federica; Urso, Carmelo; Massi, Daniela; Zakrzewska, Krystyna

2017-08-01

Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma and high viral load in the skin was proposed as a risk factor for the occurrence of this tumour. MCPyV DNA was detected, with lower frequency, in different skin cancers but since the viral load was usually low, the real prevalence of viral DNA could be underestimated. To evaluate the performance of two assays (qPCR and ddPCR) for MCPyV detection and quantification in formalin fixed paraffin embedded (FFPE) tissue samples. Both assays were designed to simultaneous detection and quantification of both MCPyV as well as house-keeping DNA in clinical samples. The performance of MCPyV quantification was investigated using serial dilutions of cloned target DNA. We also evaluated the applicability of both tests for the analysis of 76 FFPE cutaneous biopsies. The two approaches resulted equivalent with regard to the reproducibility and repeatability and showed a high degree of linearity in the dynamic range tested in the present study. Moreover, qPCR was able to quantify ≥10 5 copies per reaction, while the upper limit of ddPCR was 10 4 copies. There was not significant difference between viral load measured by the two methods The detection limit of both tests was 0,15 copies per reaction, however, the number of positive samples obtained by ddPCR was higher than that obtained by qPCR (45% and 37% respectively). The ddPCR represents a better method for detection of MCPyV in FFPE biopsies, mostly these containing low copies number of viral genome. Copyright © 2017 Elsevier B.V. All rights reserved.

Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993-2010.

PubMed

Youlden, Danny R; Soyer, H Peter; Youl, Philippa H; Fritschi, Lin; Baade, Peter D

2014-08-01

Merkel cell carcinoma (MCC) is an uncommon but highly invasive form of skin cancer. The mechanisms that cause MCC are yet to be fully determined. To compare the incidence and survival rates of MCC in Queensland, Australia, known to be a high-risk area, with MCC incidence and survival elsewhere in the world. We also analyzed incidence trends and differences in survival by key demographic and clinical characteristics. Retrospective cohort study of population-based administrative data for MCC collected by the Queensland Cancer Registry and supplemented with detailed histopathologic data. Deidentified records were obtained of all Queensland residents diagnosed as having MCC during the period from 1993 to 2010. A subsample of histopathologic records were reviewed by a senior dermatopathologist to determine the potential for misclassification. A total of 879 eligible cases of MCC were included in the study. Incidence rates were directly age standardized to the 2000 United States Standard Population. Trends were examined using Joinpoint software with results expressed in terms of the annual percentage change. The period method was used to calculate 5-year relative survival, and adjusted hazard ratios were obtained from multivariate Poisson models. There were 340 cases of MCC diagnosed in Queensland between 2006 and 2010, corresponding to an incidence rate of 1.6 per 100,000 population. Men (2.5 per 100,000) had higher incidence than women (0.9 per 100,000), and rates peaked at 20.7 per 100,000 for persons 80 years or older. The overall incidence of MCC increased by an average of 2.6% per year from 1993 onwards. Relative survival was 41% after 5 years, with significantly better survival found for those younger than 70 years at diagnosis (56%-60%), those with tumors on the face or ears (51%), and those with stage I lesions (49%). Incidence rates for MCC in Queensland are at least double those of any that have been previously published elsewhere in the world. It is likely

The touch dome defines an epidermal niche specialized for mechanosensory signaling

PubMed Central

Doucet, Yanne S.; Woo, Seung-Hyun; Ruiz, Marlon E.; Owens, David M.

2013-01-01

Summary In mammalian skin, Merkel cells are mechanoreceptor cells that are required for the perception of gentle touch. Recent evidence indicates that mature Merkel cells descend from the proliferative layer of skin epidermis; however, the stem cell niche for Merkel cell homeostasis has not been reported. Here, we provide the first genetic evidence for maintenance of mature Merkel cells during homeostasis by Krt17+ stem cells located in epidermal touch domes of hairy skin and in the tips of the rete ridges of glabrous skin. Lineage tracing analysis indicated that the entire pool of mature Merkel cells is turned over every 7–8 weeks in adult epidermis and that Krt17+ stem cells also maintain squamous differentiation in the touch dome and in glabrous skin. Finally, selective genetic ablation of Krt17+ touch dome keratinocytes indicates that these cells, and not mature Merkel cells, are primarily responsible for maintaining innervation of the Merkel cell-neurite complex. PMID:23727240

Assessing Host-Virus Codivergence for Close Relatives of Merkel Cell Polyomavirus Infecting African Great Apes.

PubMed

Madinda, Nadège F; Ehlers, Bernhard; Wertheim, Joel O; Akoua-Koffi, Chantal; Bergl, Richard A; Boesch, Christophe; Akonkwa, Dieudonné Boji Mungu; Eckardt, Winnie; Fruth, Barbara; Gillespie, Thomas R; Gray, Maryke; Hohmann, Gottfried; Karhemere, Stomy; Kujirakwinja, Deo; Langergraber, Kevin; Muyembe, Jean-Jacques; Nishuli, Radar; Pauly, Maude; Petrzelkova, Klara J; Robbins, Martha M; Todd, Angelique; Schubert, Grit; Stoinski, Tara S; Wittig, Roman M; Zuberbühler, Klaus; Peeters, Martine; Leendertz, Fabian H; Calvignac-Spencer, Sébastien

2016-10-01

It has long been hypothesized that polyomaviruses (PyV; family Polyomaviridae) codiverged with their animal hosts. In contrast, recent analyses suggested that codivergence may only marginally influence the evolution of PyV. We reassess this question by focusing on a single lineage of PyV infecting hominine hosts, the Merkel cell polyomavirus (MCPyV) lineage. By characterizing the genetic diversity of these viruses in seven African great ape taxa, we show that they exhibit very strong host specificity. Reconciliation analyses identify more codivergence than noncodivergence events. In addition, we find that a number of host and PyV divergence events are synchronous. Collectively, our results support codivergence as the dominant process at play during the evolution of the MCPyV lineage. More generally, our results add to the growing body of evidence suggesting an ancient and stable association of PyV and their animal hosts. The processes involved in viral evolution and the interaction of viruses with their hosts are of great scientific interest and public health relevance. It has long been thought that the genetic diversity of double-stranded DNA viruses was generated over long periods of time, similar to typical host evolutionary timescales. This was also hypothesized for polyomaviruses (family Polyomaviridae), a group comprising several human pathogens, but this remains a point of controversy. Here, we investigate this question by focusing on a single lineage of polyomaviruses that infect both humans and their closest relatives, the African great apes. We show that these viruses exhibit considerable host specificity and that their evolution largely mirrors that of their hosts, suggesting that codivergence with their hosts played a major role in their diversification. Our results provide statistical evidence in favor of an association of polyomaviruses and their hosts over millions of years. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Effect of Radiotherapy Dose and Volume on Relapse in Merkel Cell Cancer of the Skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foote, Matthew, E-mail: matthew_foote@health.qld.gov.a; Harvey, Jennifer; Porceddu, Sandro

Purpose: To assess the effect of radiotherapy (RT) dose and volume on relapse patterns in patients with Stage I-III Merkel cell carcinoma (MCC). Patients and Methods: This was a retrospective analysis of 112 patients diagnosed with MCC between January 2000 and December 2005 and treated with curative-intent RT. Results: Of the 112 evaluable patients, 88% had RT to the site of primary disease for gross (11%) or subclinical (78%) disease. Eighty-nine percent of patients had RT to the regional lymph nodes; in most cases (71%) this was for subclinical disease in the adjuvant or elective setting, whereas 21 patients (19%)more » were treated with RT to gross nodal disease. With a median follow-up of 3.7 years, the 2-year and 5-year overall survival rates were 72% and 53%, respectively, and the 2-year locoregional control rate was 75%. The in-field relapse rate was 3% for primary disease, and relapse was significantly lower for patients receiving {>=}50Gy (hazard ratio [HR] = 0.22; 95% confidence interval [CI], 0.06-0.86). Surgical margins did not affect the local relapse rate. The in-field relapse rate was 11% for RT to the nodes, with dose being significant for nodal gross disease (HR = 0.24; 95% CI, 0.07-0.87). Patients who did not receive elective nodal RT had a much higher rate of nodal relapse compared with those who did (HR = 6.03; 95% CI, 1.34-27.10). Conclusion: This study indicates a dose-response for subclinical and gross MCC. Doses of {>=}50Gy for subclinical disease and {>=}55Gy for gross disease should be considered. The draining nodal basin should be treated in all patients.« less

Living with Merkel Cell Carcinoma (MCC): Development of a Conceptual Model of MCC Based on Patient Experiences.

PubMed

Kaufman, Howard L; Dias Barbosa, Carla; Guillemin, Isabelle; Lambert, Jérémy; Mahnke, Lisa; Bharmal, Murtuza

2018-03-06

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients' lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). In a single-arm, open-label, international, phase 2 trial in patients with stage IV, chemotherapy-refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews. These were conducted before avelumab administration. Interview transcripts were analysed qualitatively to identify concepts important to patients relating to their experience of metastatic MCC and its management. Nineteen patients were interviewed. Most reported MCC to be painless and asymptomatic. They reported being often misdiagnosed and described a long process before receiving the correct diagnosis. They also reported a feeling of "shock" after being informed of the severity and seriousness of their cancer. Overall, patients did not report impaired physical and cognitive capacities or impact on daily lives, either before or after diagnosis. However, patients and their relatives reported feelings of "worry" and "fear" about the unknown outcome of the disease. Chemotherapy and radiotherapy negatively affected patients physically and psychologically in their everyday lives. MCC disease was not perceived by the interviewed patients to result in severe functional limitations or to severely impact everyday activities, but was associated with substantial negative psychological impact. In contrast, chemotherapy and radiotherapy for MCC are highly debilitating and disrupt patients' lives. CLINICALTRIALS. NCT02155647.

Displays of emotion and citizen support for Merkel and Gysi.

PubMed

Gabriel, Oscar W; Masch, Lena

2017-01-01

Emotional appeals have always been an important instrument in the mobilization of political support in modern societies. As found in several experimental studies from the United States, the emotions displayed by leading politicians in their televised public appearances have an impact on the political attitudes and behaviors of the public. Positive emotions such as joy or happiness, pride, and amusement elicit a more positive assessment of politicians, whereas showing negative emotions such as anger or outrage often diminishes the public's support. This transfer of emotions from sender to recipient has been described as "emotional contagion." However, under specific circumstances, emotions expressed by politicians can result in counter-empathic reactions among recipients. To examine the role of emotions between political leaders and the public in an institutional and cultural setting outside the United States, this article presents experimental findings on the impact of emotions expressed by two leading German politicians on the German public. The study used emotional displays by Chancellor Angela Merkel and former parliamentary leader of the Left Party, Gregor Gysi, observing how their assessments by the German public changed in response to these displays. Consistent with existing research, we discovered positive effects on the evaluation of both politicians when they displayed positive emotions. However, the impact of negative emotions is different for Merkel and Gysi and can be described as contagion in the former and counter-contagion in the latter case. Furthermore, we found that individual recognition of the expressed emotions modified the effect they had on the evaluation of some leadership characteristics.

[Merkel cell carcinoma of the vulva - case report and the literature review].

PubMed

Jońska-Gmyrek, Joanna; Bobkiewicz, Piotr; Gmyrek, Leszek; Zółciak-Siwińska, Agnieszka; Lindner, Bogusław; Staniaszek, Jagna

2013-05-01

Merkel cell carcinoma (MCC) is a rare malignant neoplasm, mostly affecting the skin (97% of cases). It is usually found in elderly people, in the sun-exposed areas of the skin. About 50-60% of MCC cases are located on the head and the neck, less often on the extremities and the torso, and extremely rarely in the genital area. Ultraviolet radiation may be the main factor responsible for the development of the tumors but viral etiology is also debated. Due to extremely rare incidence of MCC in the area of the vulva, proper management remains a challenging task. To present a case of an aggressive MCC of the vulva and a review of the literature. A previously healthy 72-year-old patient presented at the Oncology Center of the Maria Sklodowska-Curie Institute, Warsaw, in June 2010. Four months previously the patient noticed a painless lump in the vestibular region of the vagina. She received anti-inflammatory treatment at her local gynecological clinic, with no success. In February the patient underwent removal of the vulvar tumor Histopathological examination confirmed anaplastic carcinoma. Microscopic evaluation revealed the tumor diameter to be 15mm. Surgical margins were free of neoplastic infiltration. The patient did not receive adjuvant therapy due to the results from the histopathological protocol. The disease recurred after three months. Radical vulvectomy and bilateral inguinal femoral lymphadenectomy were performed in May 2010. Histopathological examination confirmed microcellular carcinoma with no metastases to the lymph nodes and complete resection of the tumor (RO). The disease recurred in the next two months: a 50-mm tumor was found in the right inguinal lymph nodes. The decision to verify all histopathological material obtained during all procedures performed so far was made. Immunohistochemical evaluation confirmed MCC. Adjuvant radiotherapy was recommended. The area of the vulva, pelvic and inguinal lymph nodes were irradiated. One month after therapy

The Impact of Preradiation Residual Disease Volume on Time to Locoregional Failure in Cutaneous Merkel Cell Carcinoma—A TROG Substudy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Finnigan, Renee; Hruby, George; Wratten, Chris

2013-05-01

Purpose: This study evaluated the impact of margin status and gross residual disease in patients treated with chemoradiation therapy for high-risk stage I and II Merkel cell cancer (MCC). Methods and Materials: Data were pooled from 3 prospective trials in which patients were treated with 50 Gy in 25 fractions to the primary lesion and draining lymph nodes and 2 schedules of carboplatin based chemotherapy. Time to locoregional failure was analyzed according to the burden of disease at the time of radiation therapy, comparing patients with negative margins, involved margins, or macroscopic disease. Results: Analysis was performed on 88 patients,more » of whom 9 had microscopically positive resection margins and 26 had macroscopic residual disease. The majority of gross disease was confined to nodal regions. The 5-year time to locoregional failure, time to distant failure, time to progression, and disease-specific survival rates for the whole group were 73%, 69%, 62%, and 66% respectively. The hazard ratio for macroscopic disease at the primary site or the nodes was 1.25 (95% confidence interval 0.57-2.77), P=.58. Conclusions: No statistically significant differences in time to locoregional failure were identified between patients with negative margins and those with microscopic or gross residual disease. These results must, however, be interpreted with caution because of the limited sample size.« less

The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen.

PubMed

Abdul-Sada, Hussein; Müller, Marietta; Mehta, Rajni; Toth, Rachel; Arthur, J Simon C; Whitehouse, Adrian; Macdonald, Andrew

2017-04-11

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with a high metastatic potential. The majority of MCC cases are caused by the Merkel cell polyomavirus (MCPyV), through expression of the virus-encoded tumour antigens. Whilst mechanisms attributing tumour antigen expression to transformation are being uncovered, little is known of the mechanisms by which MCPyV persists in the host. We previously identified the MCPyV small T antigen (tAg) as a novel inhibitor of nuclear factor kappa B (NF-kB) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-kB activation involves a previously undocumented interaction between tAg and regulatory sub-unit 1 of protein phosphatase 4 (PP4R1). Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-kB pathway. Mutations in MCPyV tAg that fail to interact with components of this complex, or siRNA depletion of PP4R1, prevents tAg-mediated inhibition of NF-kB and pro-inflammatory cytokine production. Comparison of tAg binding partners from other human polyomavirus demonstrates that interactions with NEMO and PP4R1 are unique to MCPyV. Collectively, these data identify PP4R1 as a novel target for virus subversion of the host anti-viral response.

Demographics and Outcomes of Stage I-II Merkel Cell Carcinoma Treated with Mohs Micrographic Surgery Compared with Wide Local Excision in the National Cancer Data Base.

PubMed

Singh, Babu; Qureshi, Muhammad M; Truong, Minh Tam; Sahni, Debjani

2018-02-03

The optimal surgical approach (wide local excision (WLE) vs. Mohs micrographic surgery (MOHS)) for treating Merkel cell carcinoma (MCC) is yet to be determined. To compare survival outcomes in patients with early stage MCC treated with MOHS versus WLE. A retrospective review of all cases in the National Cancer Data Base (NCDB) of MCC of clinical Stage I-II MCC treated with WLE or MOHS was performed. 1,795 cases of Stage I-II MCC were identified who underwent WLE (N=1,685) or MOHS (N=110). There was no difference in residual tumor on surgical margins between the two treatment groups (p=0.588). On multivariate analysis, there was no difference in overall survival between the treatment modalities (adjusted HR 1.02; 95% CI 0.72-1.45, p=0.897). There was no difference in overall survival between the two groups on propensity score matched analysis. Disease specific survival was not reported as this data in not available in the NCDB. MOHS appears to be as effective as WLE in treating early stage MCC. Copyright © 2018. Published by Elsevier Inc.

Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

ClinicalTrials.gov

2017-09-26

Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

The Role of Radiotherapy Alone in Patients With Merkel Cell Carcinoma: Reporting the Australian Experience of 43 Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veness, Michael, E-mail: michael.veness@swahs.health.nsw.gov.a; Foote, Matthew; Gebski, Val

2010-11-01

Purpose: To review the role of radiotherapy (RTx) alone in patients with Merkel cell carcinoma (MCC). Methods and Materials: The records of 43 patients with MCC treated with RTx alone between 1993 and 2007 at the Westmead and Royal Brisbane/Mater Hospitals, Australia, were reviewed. Multivariate analysis was performed by use of Cox regression analysis. Results: The median age was 79 years (range, 48-91 years) in 19 women (44%) and 24 men (56%). All patients were white, and 5 (12%) had immunosuppression. A majority (56%) underwent irradiation at initial diagnosis, with the remainder (44%) treated in the relapse setting. The medianmore » duration of follow-up was 39 months. The head and neck comprised the most frequently treated site (47%). The median maximum lesion size was 30 mm (range, 5-130 mm). Relapse developed in 60% of patients, with most being out-of-field relapses. The in-field control rate was 75%. Most out-of-field relapses were to visceral organs. Relapse developed outside the irradiated field in 53% of patients. On multivariate analysis, only nodal status (negative nodes vs. nodes present) was significantly associated with relapse-free survival, with p = 0.005 (hazard ratio, 0.25; 95% confidence interval, 0.96-0.663). Overall survival at 2 and 5 years was 58% and 37%, respectively. Conclusions: Patients with MCC treated with RTx have a high likelihood of obtaining in-field control. Doses of 50 to 55 Gy in 20 to 25 fractions are recommended. A minority of patients are cured, with many dying of systemic relapse. Lower dose fractionation schedules (e.g., 25 Gy in 5 fractions) may be considered in patients with a very poor performance status.« less

Cixutumumab, Everolimus, and Octreotide Acetate in Treating Patients With Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

ClinicalTrials.gov

2016-07-14

Gastrin-Producing Neuroendocrine Tumor; Lung Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Paraganglioma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Merkel Cell Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Somatostatin-Producing Neuroendocrine Tumor; Stage III Merkel Cell Carcinoma; Stage IV Merkel Cell Carcinoma; Thyroid Gland Medullary Carcinoma

T cell therapies for human polyomavirus diseases.

PubMed

Davies, Sarah I; Muranski, Pawel

2017-11-01

Rapid restoration of virus-specific T immunity via adoptive transfer of ex vivo generated T cells has been proven as a powerful therapy for patients with advanced cancers and refractory viral infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). BK virus (BKV), John Cunningham virus (JCV), and Merkel cell carcinoma virus (MCV) are the members of the rapidly growing human polyomavirus (hPyV) family that commonly infects most healthy humans. These viruses have a clearly established potential for causing severe end-organ damage or malignant transformation, especially in individuals with weakened immunity who are unable to mount or regain endogenous T-cell responses as a result of underlying leukemia or iatrogenic immunosuppression in autoimmunity, bone marrow and solid organ transplant settings. Here we will discuss recent advances in using T-cell-based immunotherapies to save patients suffering from PyV-associated diseases including hemorrhagic cystitis, BKV virus-associated nephropathy, and JC-associated progressive multifocal leukoencephalopathy (PML). We will also review progress in the understanding of Merkel cell carcinoma (MCC) as a virally driven tumor that is amenable to immune intervention and can be targeted with adoptively transferred T cells specific for viral oncoproteins. Copyright © 2017. Published by Elsevier Inc.

77 FR 53141 - Dividend Equivalents From Sources Within the United States

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-31

.... Peter Merkel at (202) 622-3870 (not a toll-free number). SUPPLEMENTARY INFORMATION: Background On... Information The principal author of these regulations is D. Peter Merkel, the Office of Associate Chief...

The ethics of and the appropriate legislation concerning killing people and letting them die: a response to Merkel.

PubMed

McLachlan, Hugh V

2017-07-01

With regard to ethics and legislation, what is the significant difference between a doctor terminating the life-supporting treatment of a patient in the course of his job and a greedy relative of the patient doing the same thing to inherit his wealth? Merkel offers an interesting and inventive answer to this question in terms of the improper violation of personal boundaries. However, despite Merkel's claim to the contrary, his answer does not directly address the question of the relevant ethical similarities and differences between killing and letting die in general. Furthermore, it does not provide the basis a plausible rationale for legislation concerning killing and letting die. The questions of whether letting someone die is ethically the same as killing someone and whether it should be treated the same way by the criminal law are not the same as or tantamount to the question of whether or not it involves the transgression of another person's boundaries. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The Essential Role of Radiotherapy in the Treatment of Merkel Cell Carcinoma: A Study From the Rare Cancer Network

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghadjar, Pirus, E-mail: pirus.ghadjar@insel.ch; Kaanders, Johannes H.; Poortmans, Philipp

2011-11-15

Purpose: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). Methods and Materials: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. Results: Seventy-nine patients were male and 101 patients were female, and the median age was 73 yearsmore » old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). Conclusions: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.« less

Detection of mitotic figures and G2+ tumor nuclei with histone markers correlates with worse overall survival in patients with Merkel cell carcinoma.

PubMed

Henderson, Samuel A; Tetzlaff, Michael T; Pattanaprichakul, Penvadee; Fox, Patricia; Torres-Cabala, Carlos A; Bassett, Roland L; Prieto, Victor G; Richards, Hunter W; Curry, Jonathan L

2014-11-01

High mitotic figure count (MFC) correlates with low survival rate in Merkel cell carcinoma (MCC). However, the prognostic impact of histone biomarkers as surrogates of MFC in MCC is unknown. We evaluated the prognostic significance of the immunodetection of mitotic figures and of G2+ tumor nuclei with histone-associated mitotic markers H3K79me3T80ph (H3KT) and phosphohistone H3 (PHH3) in MCC. Immunohistochemical analyses of H3KT and PHH3 and proliferative marker Ki-67 were performed in a series of 21 cases of MCC. The significance of the pathologic data and immunoreactivity with these markers was evaluated with Pearson correlation and paired Student t-test. Univariate Cox proportional hazards regression models were performed to assess the relationships between these markers and survival. H3KT detected a higher number of mitotic figure (p<0.0001) and G2+ tumor nuclei (p<0.0052) than did PHH3. Furthermore, the MFC combined with G2+ tumor nuclei detected with H3KT compared to PHH3 and manual MFC was a significant predictor of impaired survival in patients with MCC (p=0.035; HR=1.0172), corresponding to a 1.72% increased risk of death for each unit increase in H3KT. Biomarker analysis of proliferative rates with histone markers may have relevance in stratifying risk in patients with MCC. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients.

PubMed

Chen, Michelle M; Roman, Sanziana A; Sosa, Julie A; Judson, Benjamin L

2015-02-01

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignant neoplasm that most commonly occurs in the head and neck and is rapidly increasing in incidence. The role of adjuvant chemoradiotherapy (CRT) in the management of head and neck MCC remains controversial. To evaluate the association between different adjuvant therapies and survival in head and neck MCC. Retrospective review of adult patients with head and neck MCC who had surgery recorded in the National Cancer Data Base from 1998 to 2011. Surgical excision, adjuvant radiation therapy (RT), or adjuvant CRT. Our main outcome was overall survival (OS). Statistical analysis included χ2, t tests, Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis. We identified 4815 patients; 92.0% underwent standard surgical excision, and 8.0% underwent Mohs surgery. On multivariate analysis, age at least 75 years (hazard ratio [HR], 2.83 [95% CI, 1.82-4.41]), larger tumor size, positive margins (HR, 1.52 [95% CI, 1.25-1.85]), and metastatic lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS. Postoperative CRT (HR, 0.62 [95% CI, 0.47-0.81]) and RT (HR, 0.80 [95% CI, 0.70-0.92]) provided a survival benefit over surgery alone. Adjuvant CRT was associated with improved OS over adjuvant RT in patients with positive margins (HR, 0.48 [95% CI, 0.25-0.93]), tumor size at least 3 cm (HR, 0.52 [95% CI, 0.30-0.90]), and male sex (HR, 0.69 [95% CI, 0.50-0.94]). To our knowledge, this the first study examining the role of adjuvant CRT in head and neck MCC. Results suggest that adjuvant CRT may help improve survival in high-risk patients, such as males and those with positive margins and larger tumors.

Intratumoral and peritumoral lymphovascular invasion detected by D2-40 immunohistochemistry correlates with metastasis in primary cutaneous Merkel cell carcinoma.

PubMed

Al-Rohil, Rami N; Milton, Denái R; Nagarajan, Priyadharsini; Curry, Jonathan L; Feldmeyer, Laurence; Torres-Cabala, Carlos A; Ivan, Doina; Prieto, Victor G; Tetzlaff, Michael T; Aung, Phyu P

2018-07-01

Primary cutaneous Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy in which lymphovascular invasion (LVI) correlates with more aggressive phenotype. The prognostic significance of LVI detected by D2-40 immunohistochemistry (IHC) in MCC remains controversial. We aimed to determine how LVI detected by D2-40 IHC compares with LVI detected by hematoxylin and eosin (H&E) staining in predicting MCC metastasis. Clinical and histopathologic features of MCCs diagnosed and treated in 2002 to 2015 were assembled and included 58 MCC tumors from 58 patients. H&E-stained tissue sections and D2-40 IHC studies were reviewed. When LVI was present, the location (peritumoral or intratumoral) and the size of the largest invaded vessel were recorded. LVI findings by H&E staining and D2-40 IHC were compared with each other and with histologic features and clinical outcomes. H&E staining showed LVI in 37 of 58 cases; D2-40 IHC confirmed LVI in 30 of these cases but failed to confirm LVI in 7. D2-40 IHC also detected 14 cases of LVI not identified on H&E staining. Histologically, D2-40-detected LVI was associated with infiltrative growth pattern and nonbrisk lymphoid infiltrate (P = .005 and P = .055, respectively). There was a statistically significant difference between the frequency of detection of peritumoral LVI by H&E in comparison to D2-40 IHC (P = .0009). MCCs in which D2-40 IHC-detected both intratumoral and peritumoral LVI were typically larger than MCCs without (mean, 24.5 mm versus 17.3 mm; P = .03) and more frequently metastasized (87% versus 51%; P = .03). D2-40 IHC detection of both intratumoral and peritumoral LVI is associated with metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of background-free tame fluorescent probes for intracellular live cell imaging

PubMed Central

Alamudi, Samira Husen; Satapathy, Rudrakanta; Kim, Jihyo; Su, Dongdong; Ren, Haiyan; Das, Rajkumar; Hu, Lingna; Alvarado-Martínez, Enrique; Lee, Jung Yeol; Hoppmann, Christian; Peña-Cabrera, Eduardo; Ha, Hyung-Ho; Park, Hee-Sung; Wang, Lei; Chang, Young-Tae

2016-01-01

Fluorescence labelling of an intracellular biomolecule in native living cells is a powerful strategy to achieve in-depth understanding of the biomolecule's roles and functions. Besides being nontoxic and specific, desirable labelling probes should be highly cell permeable without nonspecific interactions with other cellular components to warrant high signal-to-noise ratio. While it is critical, rational design for such probes is tricky. Here we report the first predictive model for cell permeable background-free probe development through optimized lipophilicity, water solubility and charged van der Waals surface area. The model was developed by utilizing high-throughput screening in combination with cheminformatics. We demonstrate its reliability by developing CO-1 and AzG-1, a cyclooctyne- and azide-containing BODIPY probe, respectively, which specifically label intracellular target organelles and engineered proteins with minimum background. The results provide an efficient strategy for development of background-free probes, referred to as ‘tame' probes, and novel tools for live cell intracellular imaging. PMID:27321135

Reduced background autofluorescence for cell imaging using nanodiamonds and lanthanide chelates.

PubMed

Cordina, Nicole M; Sayyadi, Nima; Parker, Lindsay M; Everest-Dass, Arun; Brown, Louise J; Packer, Nicolle H

2018-03-14

Bio-imaging is a key technique in tracking and monitoring important biological processes and fundamental biomolecular interactions, however the interference of background autofluorescence with targeted fluorophores is problematic for many bio-imaging applications. This study reports on two novel methods for reducing interference with cellular autofluorescence for bio-imaging. The first method uses fluorescent nanodiamonds (FNDs), containing nitrogen vacancy centers. FNDs emit at near-infrared wavelengths typically higher than most cellular autofluorescence; and when appropriately functionalized, can be used for background-free imaging of targeted biomolecules. The second method uses europium-chelating tags with long fluorescence lifetimes. These europium-chelating tags enhance background-free imaging due to the short fluorescent lifetimes of cellular autofluorescence. In this study, we used both methods to target E-selectin, a transmembrane glycoprotein that is activated by inflammation, to demonstrate background-free fluorescent staining in fixed endothelial cells. Our findings indicate that both FND and Europium based staining can improve fluorescent bio-imaging capabilities by reducing competition with cellular autofluorescence. 30 nm nanodiamonds coated with the E-selectin antibody was found to enable the most sensitive detective of E-selectin in inflamed cells, with a 40-fold increase in intensity detected.

Basaloid tumors in nevus sebaceus revisited: the follicular stem cell marker PHLDA1 (TDAG51) indicates that most are basal cell carcinomas and not trichoblastomas.

PubMed

Sellheyer, Klaus; Cribier, Bernard; Nelson, Paula; Kutzner, Heinz; Rütten, Arno

2013-05-01

Until the 1990s, basal cell carcinoma (BCC) was viewed as the most common epithelial neoplasm developing in association with nevus sebaceus (NS). Currently, trichoblastoma is thought of as the most prevalent basaloid neoplasm in NS. The follicular stem cell marker pleckstrin homology-like domain, family A, member 1 (PHLDA1) also known as T-cell death-associated gene 51 (TDAG51) labels trichoepithelioma (TE) but not BCC. Therefore, we explored its usefulness in basaloid neoplasms developing in NS. We studied immunohistochemically PHLDA1 in 10 nodular BCCs, 11 TEs, 11 trichoblastomas and 25 NS with basaloid tumors. Additionally, we examined the expression of BCC marker BerEP4 and the distribution of Merkel cells that function as surrogate markers for benign follicular neoplasms. Nineteen of the 25 basaloid tumors in NS were PHLDA1-negative comparable to BCC arising de novo and six tumors were PHLDA1-positive comparable to solitary trichoblastomas and TEs. Fewer Merkel cells were seen in BCCs associated with NS when compared with trichoblastoma. BerEP4 did not discriminate between the neoplasms. We raise concern that the unquestioned assessment that basaloid tumors developing in association with NS represent mostly trichoblastomas and not BCC may not be true. This influences clinical care, as it is paramount in the decision of whether to excise these lesions or not. Copyright © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Evolution of taste and solitary chemoreceptor cell systems.

PubMed

Finger, T E

1997-01-01

Vertebrates possess four distinct chemosensory systems distinguishable on the basis of structure, innervation and utilization: olfaction, taste, solitary chemoreceptor cells (SCC) and the common chemical sense (free nerve endings). Of these, taste and the SCC sense rely on secondary receptor cells situated in the epidermis and synapsing on sensory nerve fibers innervating them near their base. The SCC sense occurs in anamniote aquatic craniates, including hagfish, and may be used for feeding or predator avoidance. The sense of taste occurs only in vertebrates and is always utilized for feeding. The SCC system achieves a high degree of specialization in two teleosts: sea robins (Prionotus) and rocklings (Ciliata). In sea robins, SCCs are abundant on the three anterior fin rays of the pectoral fin which are free of fin webbing and are used in active exploration of the substrate. Behavioral and physiological studies show that this SCC system responds to feeding cues and drives feeding behavior. It is connected centrally like a somatosensory system. In contrast, the specialized SCC system of rocklings occurs on the anterior dorsal fin which actively samples the surrounding water. This system responds to mucus substances and may serve as a predator detector. The SCC system in rocklings is connected centrally like a gustatory system. Taste buds contain multiple receptor cell types, including a serotonergic Merkel-like cell. Taste receptor cells respond to nutritionally relevant substances. Due to similarities between SCCs and one type of taste receptor cell, the suggestion is made that taste buds may be compound sensory organs that include some cells related to SCCs and others related to cutaneous Merkel cells. The lack of taste buds in hagfish and their presence in all vertebrates may indicate that the phylogenetic development of taste buds coincided with the elaboration of head structures at the craniate-vertebrate transition.

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

PubMed Central

Sekerková, Gabriella; Zheng, Lili; Loomis, Patricia A.; Mugnaini, Enrico; Bartles, James R.

2008-01-01

The espins are novel actin-bundling proteins that are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle of hair cell stereocilia and are the target of deafness mutations in mice and humans. Espins are also enriched in the microvilli of taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells, suggesting that espins play important roles in the microvillar projections of vertebrate sensory cells. Espins are potent actin-bundling proteins that are not inhibited by Ca2+. In cells, they efficiently elongate parallel actin bundles and, thereby, help determine the steady-state length of microvilli and stereocilia. Espins bind actin monomer via their WH2 domain and can assemble actin bundles in cells. Certain espin isoforms can also bind phosphatidylinositol 4,5-bisphosphate, profilins or SH3 proteins. These biological activities distinguish espins from other actin-bundling proteins and may make them well-suited to sensory cells. PMID:16909209

Merkel Cell Carcinoma

MedlinePlus

... Us Media contacts Advertising contacts AAD logo Advertising, marketing and sponsorships Legal notice Copyright © 2018 American Academy ... prohibited without prior written permission. AAD logo Advertising, marketing and sponsorships Legal notice Copyright © 2017 American Academy ...

Understanding the influence of patient demographics on disease severity, treatment strategy, and survival outcomes in merkel cell carcinoma: a surveillance, epidemiology, and end-results study.

PubMed

Ezaldein, Harib H; Ventura, Alessandra; DeRuyter, Nicolaas P; Yin, Emily S; Giunta, Alessandro

2017-07-01

To identify trends in patient presentation and outcomes data that may guide the development of clinical algorithms on Merkel Cell Carcinoma (MCC). We performed a retrospective cohort study searching in the National Cancer Institute's SEER registry for documented MCC cases from 1986-2013. No exclusion criteria were applied. We hereby identified 7,831 original MCC entries. Demographics, staging, and socioeconomic characteristics were identified and treatment modality likelihoods and survival data were calculated via logistic regression and Kaplan-Meier statistical modeling. Concerning tumor localization, 44.5% (n= 3,485) were located on the head and neck, and 47.8% were located on the trunk and extremities (n= 3,742). Male and younger patients are more likely to receive radiation than surgery with no differences seen among patient race. Caucasians and "Other" races both showed higher overall survival than African American patients. States with higher median household income levels demonstrated survival advantage. Income quartiles yielded no differences in surgical or radiotherapy interventions. Moreover, patients who forego radiotherapy had a poorer overall survival. Generalizability of SEER data, potential intrinsic coding inconsistencies, and limited information on patient comorbidities, sentinel lymph node and surgical margin status are major limitations. There is no information regarding medical intervention such as systemic chemotherapy or immunotherapy. Recoding efforts are inconclusive regarding variables such as tumor infiltrating lymphocytes, mutations, or immunosuppression status, which are well-documented for other cancers within the database. MCC lesions of the head and neck region, lower income quartiles, and African American race are associated with higher mortality. MCC patients have a median household income that is significantly higher than national values with no significant difference in subsequent treatment modalities (surgery or radiotherapy

Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

PubMed Central

Cook, Matthew S.; Munger, Steven C.; Nadeau, Joseph H.; Capel, Blanche

2011-01-01

Human germ cell tumors show a strong sensitivity to genetic background similar to Dnd1Ter/Ter mutant mice, where testicular teratomas arise only on the 129/SvJ genetic background. The introduction of the Bax mutation onto mixed background Dnd1Ter/Ter mutants, where teratomas do not typically develop, resulted in a high incidence of teratomas. However, when Dnd1Ter/Ter; Bax–/– double mutants were backcrossed to C57BL/6J, no tumors arose. Dnd1Ter/Ter germ cells show a strong downregulation of male differentiation genes including Nanos2. In susceptible strains, where teratomas initiate around E15.5-E17.5, many mutant germ cells fail to enter mitotic arrest in G0 and do not downregulate the pluripotency markers NANOG, SOX2 and OCT4. We show that DND1 directly binds a group of transcripts that encode negative regulators of the cell cycle, including p27Kip1 and p21Cip1. P27Kip1 and P21Cip1 protein are both significantly decreased in Dnd1Ter/Ter germ cells on all strain backgrounds tested, strongly suggesting that DND1 regulates mitotic arrest in male germ cells through translational regulation of cell cycle genes. Nonetheless, in C57BL/6J mutants, germ cells arrest prior to M-phase of the cell cycle and downregulate NANOG, SOX2 and OCT4. Consistent with their ability to rescue cell cycle arrest, C57BL/6J germ cells overexpress negative regulators of the cell cycle relative to 129/SvJ. This work suggests that reprogramming of pluripotency in germ cells and prevention of tumor formation requires cell cycle arrest, and that differences in the balance of cell cycle regulators between 129/SvJ and C57BL/6 might underlie differences in tumor susceptibility. PMID:21115610

Genetic backgrounds and redox conditions influence morphological characteristics and cell differentiation of osteoclasts in mice.

PubMed

Narahara, Shun; Matsushima, Haruna; Sakai, Eiko; Fukuma, Yutaka; Nishishita, Kazuhisa; Okamoto, Kuniaki; Tsukuba, Takayuki

2012-04-01

Osteoclasts (OCLs) are multinucleated giant cells and are formed by the fusion of mononuclear progenitors of monocyte/macrophage lineage. It is known that macrophages derived from different genetic backgrounds exhibit quite distinct characteristics of immune responses. However, it is unknown whether OCLs from different genetic backgrounds show distinct characteristics. In this study, we showed that bone-marrow macrophages (BMMs) derived from C57BL/6, BALB/c and ddY mice exhibited considerably distinct morphological characteristics and cell differentiation into OCLs. The differentiation of BMMs into OCLs was comparatively quicker in the C57BL/6 and ddY mice, while that of BALB/c mice was rather slow. Morphologically, ddY OCLs showed a giant cell with a round shape, C57BL/6 OCLs were of a moderate size with many protrusions and BALB/c OCLs had the smallest size with fewer nuclei. The intracellular signaling of differentiation and expression levels of marker proteins of OCLs were different in the respective strains. Treatment of BMMs from the three different strains with the reducing agent N-acetylcysteine (NAC) or with the oxidation agent hydrogen peroxide (H(2)O(2)) induced changes in the shape and sizes of the cells and caused distinct patterns of cell differentiation and survival. Thus, genetic backgrounds and redox conditions regulate the morphological characteristics and cell differentiation of OCLs.

A cornucopia of human polyomaviruses

PubMed Central

DeCaprio, James A.; Garcea, Robert L.

2014-01-01

During the past 6 years, focused virus hunting has led to the discovery of nine new human polyomaviruses, including Merkel cell polyomavirus, which has been linked to Merkel cell carcinoma, a lethal skin cell cancer. The discovery of so many new and highly divergent human polyomaviruses raises key questions regarding their evolution, tropism, latency, reactivation, immune evasion and contribution to disease. This Review describes the similarities and differences among the new human polyomaviruses and discusses how these viruses might interact with their human host. PMID:23474680

SAP modulates B cell functions in a genetic background-dependent manner.

PubMed

Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M; Terhorst, Cox

2013-06-01

Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. Copyright © 2013 Elsevier B.V. All rights reserved.

Proteomic approach toward molecular backgrounds of drug resistance of osteosarcoma cells in spheroid culture system.

PubMed

Arai, Kazuya; Sakamoto, Ruriko; Kubota, Daisuke; Kondo, Tadashi

2013-08-01

Chemoresistance is one of the most critical prognostic factors in osteosarcoma, and elucidation of the molecular backgrounds of chemoresistance may lead to better clinical outcomes. Spheroid cells resemble in vivo cells and are considered an in vitro model for the drug discovery. We found that spheroid cells displayed more chemoresistance than conventional monolayer cells across 11 osteosarcoma cell lines. To investigate the molecular mechanisms underlying the resistance to chemotherapy, we examined the proteomic differences between the monolayer and spheroid cells by 2D-DIGE. Of the 4762 protein species observed, we further investigated 435 species with annotated mass spectra in the public proteome database, Genome Medicine Database of Japan Proteomics. Among the 435 protein species, we found that 17 species exhibited expression level differences when the cells formed spheroids in more than five cell lines and four species out of these 17 were associated with spheroid-formation associated resistance to doxorubicin. We confirmed the upregulation of cathepsin D in spheroid cells by western blotting. Cathepsin D has been implicated in chemoresistance of various malignancies but has not previously been implemented in osteosarcoma. Our study suggested that the spheroid system may be a useful tool to reveal the molecular backgrounds of chemoresistance in osteosarcoma. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A DISCRETE-EVENT SIMULATION APPROACH TO IDENTIFY RULES THAT GOVERN ARBOR REMODELING FOR BRANCHING CUTANEOUS AFFERENTS IN HAIRY SKIN

PubMed Central

Kang, Hyojung; Orlowsky, Rachel L.; Gerling, Gregory J.

2018-01-01

In mammals, touch is encoded by sensory receptors embedded in the skin. For one class of receptors in the mouse, the architecture of its Merkel cells, unmyelinated neurites, and heminodes follow particular renewal and remodeling trends over hair cycle stages from ages 4 to 10 weeks. As it is currently impossible to observe such trends across a single animal’s hair cycle, this work employs discrete event simulation to identify and evaluate policies of Merkel cell and heminode dynamics. Well matching the observed data, the results show that the baseline model replicates dynamic remodeling behaviors between stages of the hair cycle – based on particular addition and removal polices and estimated probabilities tied to constituent parts of Merkel cells, terminal branch neurites and heminodes. The analysis shows further that certain policies hold greater influence than others. This use of computation is a novel approach to understanding neuronal development. PMID:29527094

A DISCRETE-EVENT SIMULATION APPROACH TO IDENTIFY RULES THAT GOVERN ARBOR REMODELING FOR BRANCHING CUTANEOUS AFFERENTS IN HAIRY SKIN.

PubMed

Kang, Hyojung; Orlowsky, Rachel L; Gerling, Gregory J

2017-12-01

In mammals, touch is encoded by sensory receptors embedded in the skin. For one class of receptors in the mouse, the architecture of its Merkel cells, unmyelinated neurites, and heminodes follow particular renewal and remodeling trends over hair cycle stages from ages 4 to 10 weeks. As it is currently impossible to observe such trends across a single animal's hair cycle, this work employs discrete event simulation to identify and evaluate policies of Merkel cell and heminode dynamics. Well matching the observed data, the results show that the baseline model replicates dynamic remodeling behaviors between stages of the hair cycle - based on particular addition and removal polices and estimated probabilities tied to constituent parts of Merkel cells, terminal branch neurites and heminodes. The analysis shows further that certain policies hold greater influence than others. This use of computation is a novel approach to understanding neuronal development.

Controversial role of mast cells in skin cancers.

PubMed

Varricchi, Gilda; Galdiero, Maria R; Marone, Giancarlo; Granata, Francescopaolo; Borriello, Francesco; Marone, Gianni

2017-01-01

Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumor initiation and progression. The stromal microenvironment can promote tumor development. Mast cells, widely distributed throughout all tissues, are a stromal component of many solid and haematologic tumors. Mast cells can be found in human and mouse models of skin cancers such as melanoma, basal and squamous cell carcinomas, primary cutaneous lymphomas, haemangiomas and Merkel cell carcinoma. However, human and animal studies addressing potential functions of mast cells and their mediators in skin cancers have provided conflicting results. In several studies, mast cells play a pro-tumorigenic role, whereas in others, they play an anti-tumorigenic role. Other studies have failed to demonstrate a clear role for tumor-associated mast cells. Many unanswered questions need to be addressed before we understand whether tumor-associated mast cells are adversaries, allies or simply innocent bystanders in different types and subtypes of skin cancers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reducing WBC background in cancer cell separation products by negative acoustic contrast particle immuno-acoustophoresis.

PubMed

Cushing, Kevin; Undvall, Eva; Ceder, Yvonne; Lilja, Hans; Laurell, Thomas

2018-02-13

Cancer cells display acoustic properties enabling acoustophoretic separation from white blood cells (WBCs) with 2-3 log suppression of the WBC background. However, a subset of WBCs has overlapping acoustic properties with cancer cells, which is why label-free acoustophoretic cancer cell isolation needs additional purification prior to analysis. This paper reports for the first time a proof of concept for continuous flow acoustophoretic negative selection of WBCs from cancer cells using negative acoustic contrast elastomeric particles (EPs) activated with CD45-antibodies that specifically bind to WBCs. The EP/WBC complexes align at the acoustic pressure anti-nodes along the channel walls while unbound cancer cells focus to the pressure node in the channel center, enabling continuous flow based depletion of WBC background in a cancer cell product. The method does not provide a single process solution for the CTC separation challenge, but provides an elegant part to a multi-step process by further reducing the WBC background in cancer cell separation products derived from an initial step of label-free acoustophoresis. We report the recorded performance of the negative selection immuno-acoustophoretic WBC depletion and cancer cell recovery. To eliminate the negative impact of the separation due to the known problems of aggregation of negative acoustic contrast particles along the sidewalls of the acoustophoresis channel and to enable continuous separation of EP/WBC complexes from cancer cells, a new acoustic actuation method has been implemented where the ultrasound frequency is scanned (1.991MHz ± 100 kHz, scan rate 200 kHz ms -1 ). Using this frequency scanning strategy EP/WBC complexes were acoustophoretically separated from mixtures of WBCs spiked with breast and prostate cancer cells (DU145 and MCF-7). An 86-fold (MCF-7) and 52-fold (DU145) reduction of WBCs in the cancer cell fractions were recorded with separation efficiencies of 98.6% (MCF-7) and 99

Phase 1 Study of CK-301 as a Single Agent in Subjects With Advanced Cancers

ClinicalTrials.gov

2018-01-02

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Malignant Mesothelioma, Advanced; Head and Neck Cancer; Melanoma; Merkel Cell Carcinoma; Renal Cell Carcinoma; Urothelial Carcinoma; Classical Hodgkin Lymphoma

Interaction of Human Tumor Viruses with Host Cell Surface Receptors and Cell Entry

PubMed Central

Schäfer, Georgia; Blumenthal, Melissa J.; Katz, Arieh A.

2015-01-01

Currently, seven viruses, namely Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV), high-risk human papillomaviruses (HPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T cell lymphotropic virus type 1 (HTLV-1), have been described to be consistently associated with different types of human cancer. These oncogenic viruses belong to distinct viral families, display diverse cell tropism and cause different malignancies. A key to their pathogenicity is attachment to the host cell and entry in order to replicate and complete their life cycle. Interaction with the host cell during viral entry is characterized by a sequence of events, involving viral envelope and/or capsid molecules as well as cellular entry factors that are critical in target cell recognition, thereby determining cell tropism. Most oncogenic viruses initially attach to cell surface heparan sulfate proteoglycans, followed by conformational change and transfer of the viral particle to secondary high-affinity cell- and virus-specific receptors. This review summarizes the current knowledge of the host cell surface factors and molecular mechanisms underlying oncogenic virus binding and uptake by their cognate host cell(s) with the aim to provide a concise overview of potential target molecules for prevention and/or treatment of oncogenic virus infection. PMID:26008702

Videoscopic Versus Open Inguinal Lymphadenectomy for Cancer

ClinicalTrials.gov

2015-05-04

Melanoma; Merkel Cell Carcinoma; Squamous Cell Carcinoma; Penile Carcinoma; Urethral Carcinoma; Extramammary Paget's Disease; Scrotal Carcinoma; Anal Cancer; Vulvar Cancer; Skin Cancer; Lymphadenopathy

Background fluorescence estimation and vesicle segmentation in live cell imaging with conditional random fields.

PubMed

Pécot, Thierry; Bouthemy, Patrick; Boulanger, Jérôme; Chessel, Anatole; Bardin, Sabine; Salamero, Jean; Kervrann, Charles

2015-02-01

Image analysis applied to fluorescence live cell microscopy has become a key tool in molecular biology since it enables to characterize biological processes in space and time at the subcellular level. In fluorescence microscopy imaging, the moving tagged structures of interest, such as vesicles, appear as bright spots over a static or nonstatic background. In this paper, we consider the problem of vesicle segmentation and time-varying background estimation at the cellular scale. The main idea is to formulate the joint segmentation-estimation problem in the general conditional random field framework. Furthermore, segmentation of vesicles and background estimation are alternatively performed by energy minimization using a min cut-max flow algorithm. The proposed approach relies on a detection measure computed from intensity contrasts between neighboring blocks in fluorescence microscopy images. This approach permits analysis of either 2D + time or 3D + time data. We demonstrate the performance of the so-called C-CRAFT through an experimental comparison with the state-of-the-art methods in fluorescence video-microscopy. We also use this method to characterize the spatial and temporal distribution of Rab6 transport carriers at the cell periphery for two different specific adhesion geometries.

Optical Biopsy of Human Skin in Conjunction With Laser Treatment

ClinicalTrials.gov

2017-02-08

Malignant Melanoma; Merkel Cell Carcinoma; Basal Cell Carcinoma; Squamous Cell Carcinoma; Atypical Nevi; Congenital Nevi; Seborrheic Keratosis; Paget's Disease; Dermatofibroma; Kaposi's Sarcoma; Port Wine Stain; Hemangioma; Tattoos; Scleroderma; Burns

A low-background piston-cylinder-type hybrid high pressure cell for muon-spin rotation/relaxation experiments

NASA Astrophysics Data System (ADS)

Shermadini, Z.; Khasanov, R.; Elender, M.; Simutis, G.; Guguchia, Z.; Kamenev, K. V.; Amato, A.

2017-10-01

A low background double-wall piston-cylinder-type pressure cell is developed at the Paul Scherrer Institute. The cell is made from BERYLCO-25 (beryllium copper) and MP35N nonmagnetic alloys with the design and dimensions which are specifically adapted to muon-spin rotation/relaxation (μSR) measurements. The mechanical design and performance of the pressure cell are evaluated using finite-element analysis (FEA). By including the measured stress-strain characteristics of the materials into the finite-element model, the cell dimensions are optimized with the aim to reach the highest possible pressure while maintaining the sample space large (6 mm in diameter and 12 mm high). The presented unconventional design of the double-wall piston-cylinder pressure cell with a harder outer MP35N sleeve and a softer inner CuBe cylinder enables pressures of up to 2.6 GPa to be reached at ambient temperature, corresponding to 2.2 GPa at low temperatures without any irreversible damage to the pressure cell. The nature of the muon stopping distribution, mainly in the sample and in the CuBe cylinder, results in a low-background μSR signal.

Histologic Mimics of Basal Cell Carcinoma.

PubMed

Stanoszek, Lauren M; Wang, Grace Y; Harms, Paul W

2017-11-01

- Basal cell carcinoma (BCC) is the most common human malignant neoplasm and is a frequently encountered diagnosis in dermatopathology. Although BCC may be locally destructive, it rarely metastasizes. Many diagnostic entities display morphologic and immunophenotypic overlap with BCC, including nonneoplastic processes, such as follicular induction over dermatofibroma; benign follicular tumors, such as trichoblastoma, trichoepithelioma, or basaloid follicular hamartoma; and malignant tumors, such as sebaceous carcinoma or Merkel cell carcinoma. Thus, misdiagnosis has significant potential to result in overtreatment or undertreatment. - To review key features distinguishing BCC from histologic mimics, including current evidence regarding immunohistochemical markers useful for that distinction. - Review of pertinent literature on BCC immunohistochemistry and differential diagnosis. - In most cases, BCC can be reliably diagnosed by histopathologic features. Immunohistochemistry may provide useful ancillary data in certain cases. Awareness of potential mimics is critical to avoid misdiagnosis and resulting inappropriate management.

Background ELF magnetic fields in incubators: a factor of importance in cell culture work.

PubMed

Mild, Kjell Hansson; Wilén, Jonna; Mattsson, Mats-Olof; Simko, Myrtill

2009-07-01

Extremely low frequency (ELF) magnetic fields in cell culture incubators have been measured. Values of the order of tens of muT were found which is in sharp contrast to the values found in our normal environment (0.05-0.1microT). There are numerous examples of biological effects found after exposure to MF at these levels, such as changes in gene expression, blocked cell differentiation, inhibition of the effect of tamoxifen, effects on chick embryo development, etc. We therefore recommend that people working with cell culture incubators check for the background magnetic field and take this into account in performing their experiments, since this could be an unrecognised factor of importance contributing to the variability in the results from work with cell cultures.

The Regularity of Sustained Firing Reveals Two Populations of Slowly Adapting Touch Receptors in Mouse Hairy Skin

PubMed Central

Wellnitz, Scott A.; Lesniak, Daine R.; Gerling, Gregory J.

2010-01-01

Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell–neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of SAI function in mutant mice has been hindered because previous studies did not distinguish SAI responses from slowly adapting type II (SAII) responses, which are thought to arise from different end organs, such as Ruffini endings. Thus we sought methods to discriminate these afferent types. We developed an epidermis-up ex vivo skin–nerve chamber to record action potentials from afferents while imaging Merkel cells in intact receptive fields. Using model-based cluster analysis, we found that two types of slowly adapting receptors were readily distinguished based on the regularity of touch-evoked firing patterns. We identified these clusters as SAI (coefficient of variation = 0.78 ± 0.09) and SAII responses (0.21 ± 0.09). The identity of SAI afferents was confirmed by recording from transgenic mice with green fluorescent protein–expressing Merkel cells. SAI receptive fields always contained fluorescent Merkel cells (n = 10), whereas SAII receptive fields lacked these cells (n = 5). Consistent with reports from other vertebrates, mouse SAI and SAII responses arise from afferents exhibiting similar conduction velocities, receptive field sizes, mechanical thresholds, and firing rates. These results demonstrate that mice, like other vertebrates, have two classes of slowly adapting light-touch receptors, identify a simple method to distinguish these populations, and extend the utility of skin–nerve recordings for genetic dissection of touch receptor mechanisms. PMID:20393068

Highly sensitive low-background fluorescent probes for imaging of nitric oxide in cells and tissues.

PubMed

Zhang, Hui-Xian; Chen, Jian-Bo; Guo, Xiao-Feng; Wang, Hong; Zhang, Hua-Shan

2014-03-18

Small-molecule fluorescent probes in combination with fluorescent microscopy can be a powerful tool to provide real-time detection and high spatiotemporal resolution of transient molecules in cells and bodies. For the design of fluorescent probes for transient molecule imaging, high detection sensitivity is crucial. In this report, two new fluorescent probes, 8-(3,4-diaminophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-di(1,2-dihydro)naphtho[b,g]-s-indacene (DANPBO-H) and 8-(3,4-diaminophenyl)-1,7-dimethyl-4,4-difluoro-4-bora-3a,4a-diaza-di(1,2-dihydro)naphtho[b,g]-s-indacene (DANPBO-M), have been developed for nitric oxide (NO) imaging. The detection sensitivity has been efficiently improved by use of these probes through increasing NO detection signals and decreasing background fluorescence. Fluorescence in the far-red region is enhanced by 400- and 550-fold after reaction with NO is achieved and remains stable for at least 24 h under the irradiation of xenon lamp. Excitation and emission wavelengths longer than 600 nm and excellent intracellular retention of these probes and their NO products create dark background inside and outside cells and tissues. What is more, the excellent intracellular retention of these compounds is obtained by their strong lipophilicity, which is a novel design concept diametrically opposite to the traditional approaches. The high sensitivity and dark background make DANPBO-H and DANPBO-M competitive for NO imaging in cells and tissues. The lipophilicity-based intracellular retention mechanism as a design strategy has great potential in the development of fluorescent probes for bioimaging.

Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells

PubMed Central

Chan, Chu-Fang; Kuo, Tzu-Wei; Weng, Ju-Yun; Lin, Yen-Chu; Chen, Ting-Yu; Cheng, Jen-Kun; Lien, Cheng-Chang

2013-01-01

Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba2+- and bupivacaine-sensitive background K+ conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K+ conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function. PMID:23940377

PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas.

PubMed

Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E; Havighurst, Thomas C; Kim, KyungMann; Oberley, Terry D; Verma, Ajit K

2010-01-01

Chronic exposure to UVR is the major etiologic factor in the development of human skin cancers including squamous-cell carcinoma (SCC). We have previously shown that protein Kinase C epsilon (PKCepsilon) transgenic mice on FVB/N background, which overexpress PKCepsilon protein approximately eightfold over endogenous levels in epidermis, exhibit about threefold more sensitivity than wild-type littermates to UVR-induced development of SCC. To determine whether it is PKCepsilon and not the mouse genetic background that determines susceptibility to UVR carcinogenesis, we cross-bred PKCepsilon FVB/N transgenic mice with SKH-1 hairless mice to generate PKCepsilon-overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCepsilon SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1-2 KJ m(-2)) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared with the wild-type hairless mice, PKCepsilon overexpression in SKH-1 hairless mice decreased the latency (12 weeks), whereas it increased the incidence (twofold) and multiplicity (fourfold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (proliferating cell nuclear antigen, signal transducers and activators of transcription 3, and extracellular signal-regulated kinase 1/2). The results indicate that PKCepsilon level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis.

77 FR 2728 - Request for Public Comment on Nominations and Call for Additional Nominations to the Report on...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-19

... pentachlorophenol shiftwork involving light at night ortho-toluidine trichloroethylene uranium (depleted) viruses (selected): Kaposi's sarcoma--associated herpesvirus, Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV), and Merkel cell polyomavirus * Nominations to...

Counter-Flow Cooling Tower Test Cell

NASA Astrophysics Data System (ADS)

Dvořák, Lukáš; Nožička, Jiří

2014-03-01

The article contains a design of a functional experimental model of a cross-flow mechanical draft cooling tower and the results and outcomes of measurements. This device is primarily used for measuring performance characteristics of cooling fills, but with a simple rebuild, it can be used for measuring other thermodynamic processes that take part in so-called wet cooling. The main advantages of the particular test cell lie in the accuracy, size, and the possibility of changing the water distribution level. This feature is very useful for measurements of fills of different heights without the influence of the spray and rain zone. The functionality of this test cell has been verified experimentally during assembly, and data from the measurement of common film cooling fills have been compared against the results taken from another experimental line. For the purpose of evaluating the data gathered, computational scripts were created in the MATLAB numerical computing environment. The first script is for exact calculation of the thermal balance of the model, and the second is for determining Merkel's number via Chebyshev's method.

A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors

PubMed Central

Jahchan, Nadine S; Dudley, Joel T; Mazur, Pawel K; Flores, Natasha; Yang, Dian; Palmerton, Alec; Zmoos, Anne-Flore; Vaka, Dedeepya; Tran, Kim QT; Zhou, Margaret; Krasinska, Karolina; Riess, Jonathan W; Neal, Joel W; Khatri, Purvesh; Park, Kwon S; Butte, Atul J; Sage, Julien

2013-01-01

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. PMID:24078773

The molecular genetics of eyelid tumors: recent advances and future directions.

PubMed

Milman, Tatyana; McCormick, Steven A

2013-02-01

Unprecedented recent advances in the molecular genetics of cutaneous malignancies have markedly improved our ability to diagnose, treat, and counsel patients with skin tumors. This review provides an update on molecular genetics of periocular cutaneous basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma, Merkel cell carcinoma, and malignant melanoma and describes how the knowledge of molecular genetics is translated into clinical practice. A literature search of peer-reviewed and indexed publications from 1965 to 2012 using the PubMed search engine was performed. Key terms included: molecular genetics, eyelid, basal cell carcinoma, squamous cell carcinoma, sebaceous adenoma, sebaceous epithelioma, sebaceoma, sebaceous carcinoma, Merkel cell carcinoma, and melanoma. Seminal articles prior to 1965 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. We reviewed the literature regarding the advances in molecular genetics of cutaneous basal cell carcinoma, squamous cell carcinoma, sebaceous neoplasia, Merkel cell carcinoma, and malignant melanoma, and possible future directions towards diagnosing and treating cutaneous tumors at the genetic level. Cell culture experiments, animal models, and molecular genetic studies on the patients' tumor tissues helped to elucidate genetic aberrations in these lesions. Cell culture experiments, animal studies and, ultimately, clinical trials provided means to test and develop novel therapeutic strategies, namely targeted therapy directed at specific molecular genetic defects. While remarkable progress has been made in this process, the complexity of the molecular genetics of skin tumors makes complete elucidation of the genetic mechanisms and the search for ideal therapies challenging. The recent studies focusing on molecular genetics of cutaneous malignancies show promising results

Pharmaceutical Approval Update.

PubMed

Choy, Mary

2017-06-01

Ribociclib (Kisqali) for HR+/HER2- advanced or metastatic breast cancer in postmenopausal women; safinamide (Xadago) as adjunctive treatment for patients with Parkinson's disease; and avelumab (Bavencio) for metastatic Merkel cell carcinoma.

Effect of whole-body irradiation of mice on the number of background plaque-forming cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, R.E.; Lefkovits, I.; Soeederberg, A.

1983-08-01

Mice were exposed in whole-body fashion to several doses of radiation and killed at various times thereafter for a determination of the number of background plaque-forming cells (PFCs) as assayed on either sheep erythrocytes or bromelain-treated autologous mouse erythrocytes. Increased numbers of both types of PFC were found in the irradiated groups. These increases were dependent on radiation dose and time after exposure. They did not appear to be caused by a disruption of normal lymphocyte traffic or a switch in immunoglobulin isotype. An increased number of PFCs on bromelain-treated mouse RBCs but not on sheep RBCs were found inmore » irradiated congenitally athymic nude mice. On the basis of this and related observations, background PFCs on bromelain-treated mouse RBCs and on sheep RBCs appear to fall under different forms of homeostatic control.« less

Fast and background-free three-dimensional (3D) live-cell imaging with lanthanide-doped upconverting nanoparticles.

PubMed

Jo, Hong Li; Song, Yo Han; Park, Jinho; Jo, Eun-Jung; Goh, Yeongchang; Shin, Kyujin; Kim, Min-Gon; Lee, Kang Taek

2015-12-14

We report on the development of a three-dimensional (3D) live-cell imaging technique with high spatiotemporal resolution using lanthanide-doped upconverting nanoparticles (UCNPs). It employs the sectioning capability of confocal microscopy except that the two-dimensional (2D) section images are acquired by wide-field epi-fluorescence microscopy. Although epi-fluorescence images are contaminated with the out-of-focus background in general, the near-infrared (NIR) excitation used for the excitation of UCNPs does not generate any autofluorescence, which helps to lower the background. Moreover, the image blurring due to defocusing was naturally eliminated in the image reconstruction process. The 3D images were used to investigate the cellular dynamics such as nuclear uptake and single-particle tracking that require 3D description.

Below-Background Ionizing Radiation as an Environmental Cue for Bacteria

DOE PAGES

Castillo, Hugo; Smith, Geoffrey B.

2017-02-14

All organisms on earth grow under the influence of a natural and relatively constant dose of ionizing radiation referred to as background radiation, and so cells have different mechanisms to prevent the accumulation of damage caused by its different components. However, current knowledge of the deleterious effects of radiation on cells is based on the exposure to acute and high or to chronic, above background doses of radiation and therefore is not appropriate to explain the cellular and biochemical mechanisms that cells employ to sense and respond to chronic below-background levels. Studies at below-background radiation doses can provide insight intomore » the biological role of radiation, as suggested by several examples of what appears to be a stress response in cells grown at doses that range from 10 to 79 times lower than background. Here, we discuss some of the technical constraints to shield cells from radiation to below-background levels, as well as different approaches used to detect and measure responses to such unusual environmental conditions. Then, we present data from Shewanella oneidensis and Deinococcus radiodurans experiments that show how two taxonomically distant bacterial species sense and respond to unnaturally low levels of radiation. Finally, in brief, we grew S. oneidensis and D. radiodurans in liquid culture at dose rates of 72.05 (control) and 0.91 (treatment) nGy hr -1 (including radon) for up to 72 h and measured cell density and the expression of stress-related genes. Our results suggest that a stress response is triggered in the absence of normal levels of radiation.« less

Below-Background Ionizing Radiation as an Environmental Cue for Bacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Castillo, Hugo; Smith, Geoffrey B.

All organisms on earth grow under the influence of a natural and relatively constant dose of ionizing radiation referred to as background radiation, and so cells have different mechanisms to prevent the accumulation of damage caused by its different components. However, current knowledge of the deleterious effects of radiation on cells is based on the exposure to acute and high or to chronic, above background doses of radiation and therefore is not appropriate to explain the cellular and biochemical mechanisms that cells employ to sense and respond to chronic below-background levels. Studies at below-background radiation doses can provide insight intomore » the biological role of radiation, as suggested by several examples of what appears to be a stress response in cells grown at doses that range from 10 to 79 times lower than background. Here, we discuss some of the technical constraints to shield cells from radiation to below-background levels, as well as different approaches used to detect and measure responses to such unusual environmental conditions. Then, we present data from Shewanella oneidensis and Deinococcus radiodurans experiments that show how two taxonomically distant bacterial species sense and respond to unnaturally low levels of radiation. Finally, in brief, we grew S. oneidensis and D. radiodurans in liquid culture at dose rates of 72.05 (control) and 0.91 (treatment) nGy hr -1 (including radon) for up to 72 h and measured cell density and the expression of stress-related genes. Our results suggest that a stress response is triggered in the absence of normal levels of radiation.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gutierrez, O.; Schwartz, S.I.

This book describes the diagnosis of liver tumors. Topics considered include general considerations, hepatocellular carcinoma, hepatoblastoma, cholangiocarcinoma, mesenchyomoma, sarcoma, hemangioma, hepatic cell adenoma, focal nodular hyperlasia (FNH), hamartoma, echinococcus cyst, abscess, AV fistula, hepatic artery aneurysm, metastatic carcinoma-colon, metastatic cholangiocarcinoma, metastatic melanoma, metastatic merkel cell and extrahepatic tumor.

Shear Deformation of Fe Polycrystals in the Rotational Diamond Anvil Cell

NASA Astrophysics Data System (ADS)

Merkel, S.; Lincot, A.; Nisr, C.; Hanfland, M.; Zerr, A.

2014-12-01

For many years, experiments are being developed for performing deformation experiments under lower mantle conditions. They include methods such as the Deformation-DIA (Wang et al, 2003) or radial x-ray diffraction in the diamond anvil cell (Merkel et al, 2002). However, the strain applied to the sample is typically limited to about 40%. This can be an issue for studying effects of large deformation or, for the case of diamond anvil cells, applying actual plastic strain at megabar pressures. The issue can be solved using apparatus such as the Rotational-Drickamer (RDA) (e.g. Yamazaki and Karato, 2001). However, the RDA offers limited diffraction access to the sample and operating pressures do not reach those of the lower mantle.In this abstract, we investigate the potential applications of the rotational diamond anvil cell (Rot-DAC) for such studies. 300 K experiments in the Rot-DAC have been performed up to pressures exceeding 50 GPa (e.g. Serebryanaya et al, 1995) with studies focusing on the effect of shear on solid-solid phase transformation pressures. The authors did not investigate the possibility of using the Rot-DAC for studying rheological properties.Here, a sample of polycrystalline Fe is submitted to shear deformation in the Rot-DAC at pressures up to 20 GPa. Synchrotron X-ray diffraction and Rietveld refinements are then used to study the texture and stress state at multiple locations in the sample. The study shows that the Rot-DAC is efficient at producing deformation textures in a polycrystalline aggregate but that care should be taken in ensuring that the sample is actually undergoing plastic deformation and not solid rotation. Stresses, on the other hand, are difficult to extract from the x-ray diffraction data because of lack of understanding of stress distributions in the deforming aggregate.S. Merkel, H. R. Wenk, J. Shu, G. Shen, P. Gillet, H. K. Mao and R. J. Hemley, J. Geophys. Res., 107, 2271 (2002)N. Serebryanaya, V. Blank and V. Ivdenko, Phys

A Safety and Tolerability Study of INCAGN02385 in Select Advanced Malignancies

ClinicalTrials.gov

2018-05-15

Cervical Cancer; Microsatellite Instability (MSI)-High Endometrial Cancer; Gastric Cancer (Including Stomach and Gastroesophageal Junction [GEJ]); Esophageal Cancer; Hepatocellular Carcinoma; Melanoma (Uveal Melanoma Excluded); Merkel Cell Carcinoma; Mesothelioma; MSI-high Colorectal Cancer; Non-small Cell Lung Cancer (NSCLC); Ovarian Cancer; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Small Cell Lung Cancer (SCLC); Renal Cell Carcinoma (RCC); Triple-negative Breast Cancer; Urothelial Carcinoma; Diffuse Large B-cell Lymphoma

DNA from BK Virus and JC Virus and from KI, WU, and MC Polyomaviruses as Well as from Simian Virus 40 Is Not Detected in Non-UV-Light-Associated Primary Malignant Melanomas of Mucous Membranes ▿

PubMed Central

Giraud, Géraldine; Ramqvist, Torbjörn; Ragnarsson-Olding, Boel; Dalianis, Tina

2008-01-01

The single most important causative factor for malignant melanomas of the skin is UV radiation. However, this is not true for melanomas on body surfaces sheltered from the sun; thus, it is important to seek new causative factors of melanoma genesis. Human papillomaviruses and gammaherpesviruses are associated with human skin cancer; for example, human papillomavirus types 5 and 8 are associated with epidermodysplasia verruciformis, and human herpesvirus 8 is associated with Kaposi's sarcoma. Recently, a newly described human polyomavirus, Merkel cell polyomavirus (MCPyV), has been associated with Merkel cell carcinoma, an unusual form of neurotropic skin cancer. Moreover, melanocytes are of neuroepithelial origin. This background impelled us to investigate if human polyomavirus DNA could play a role in the development of extracutaneous melanomas. Sixty-four extracutaneous melanomas were initially collected and dissected. Of these, 38 could be successfully used for further testing for the presence of the five human polyomaviruses known so far—BK virus (BKV), JC virus (JCV), KI polyomavirus (KIPyV), WU polyomavirus (WUPyV), and MCPyV—and of simian virus 40 (SV40). No polyomavirus DNA could be detected in any of the samples tested by use of a nested PCR detecting BKV, JCV, and SV40; a newly designed PCR detecting KIPyV and WUPyV; or a newly designed PCR for MCPyV. We conclude that since no human polyomavirus DNA was detected in primary malignant melanomas on non-sun-exposed body surfaces, these polyomaviruses presumably are not major factors for the development of extracutaneous melanomas. PMID:18768658

Quenched substrates for live-cell labeling of SNAP-tagged fusion proteins with improved fluorescent background.

PubMed

Stöhr, Katharina; Siegberg, Daniel; Ehrhard, Tanja; Lymperopoulos, Konstantinos; Öz, Simin; Schulmeister, Sonja; Pfeifer, Andrea C; Bachmann, Julie; Klingmüller, Ursula; Sourjik, Victor; Herten, Dirk-Peter

2010-10-01

Recent developments in fluorescence microscopy raise the demands for bright and photostable fluorescent tags for specific and background free labeling in living cells. Aside from fluorescent proteins and other tagging methods, labeling of SNAP-tagged proteins has become available thereby increasing the pool of potentially applicable fluorescent dyes for specific labeling of proteins. Here, we report on novel conjugates of benzylguanine (BG) which are quenched in their fluorescence and become highly fluorescent upon labeling of the SNAP-tag, the commercial variant of the human O(6)-alkylguanosyltransferase (hAGT). We identified four conjugates showing a strong increase, i.e., >10-fold, in fluorescence intensity upon labeling of SNAP-tag in vitro. Moreover, we screened a subset of nine BG-dye conjugates in living Escherichia coli and found them all suited for labeling of the SNAP-tag. Here, quenched BG-dye conjugates yield a higher specificity due to reduced contribution from excess conjugate to the fluorescence signal. We further extended the application of these conjugates by labeling a SNAP-tag fusion of the Tar chemoreceptor in live E. coli cells and the eukaryotic transcription factor STAT5b in NIH 3T3 mouse fibroblast cells. Aside from the labeling efficiency and specificity in living cells, we discuss possible mechanisms that might be responsible for the changes in fluorescence emission upon labeling of the SNAP-tag, as well as problems we encountered with nonspecific labeling with certain conjugates in eukaryotic cells.

Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

PubMed

Pescarmona, E; Pignoloni, P; Mauro, F R; Cerretti, R; Anselmo, A P; Mandelli, F; Baroni, C D

2000-08-01

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

A Fluorogenic TMP-tag for High Signal-to-Background Intracellular Live Cell Imaging

PubMed Central

Jing, Chaoran

2013-01-01

Developed to compliment the use of fluorescent proteins in live cell imaging, chemical tags enjoy the benefit of modular incorporation of organic fluorophores, opening the possibility of high photon output and special photophysical properties. However, the theoretical challenge in using chemical tags as opposed to fluorescent proteins for high-resolution imaging is background noise from unbound and/or non-specifically bound ligand-fluorophore. We envisioned we could overcome this limit by engineering fluorogenic trimethoprim-based chemical tags (TMP-tags) in which the fluorophore is quenched until binding with E. coli dihydrofolate reductase (eDHFR) tagged protein displaces the quencher. Thus, we began by building a non-fluorogenic, covalent TMP-tag based on a proximity-induced reaction known to achieve rapid and specific labeling both in vitro and inside of living cells. Here we take the final step and render the covalent TMP-tag fluorogenic. In brief, we designed a trimeric TMP-fluorophore-quencher molecule (TMP-Q-Atto520) with the quencher attached to a leaving group that, upon TMP binding to eDHFR, would be cleaved by a cysteine residue (Cys) installed just outside the binding pocket of eDHFR. We present the in vitro experiments showing that the eDHFR:L28C nucleophile cleaves the TMP-Q-Atto520 rapidly and efficiently, resulting in covalent labeling and remarkable fluorescence enhancement. Most significantly, while only our initial design, TMP-Q-Atto520 achieved the demanding goal of not only labeling highly abundant, localized intracellular proteins, but also less abundant, more dynamic cytoplasmic proteins. These results suggest that fluorogenic TMP-tag can significantly impact highresolution live cell imaging and further establish the potential of proximity-induced reactivity and organic chemistry more broadly as part of the growing toolbox for synthetic biology and cell engineering. PMID:23745575

When the War Doesn’t End: Detainees in Legal Limbo

DTIC Science & Technology

2014-05-01

Kha led el-Masri, who was abducted from Macedonia and held in Afghanistan.17 El-Masri sued the CIA, and Angela Merkel asked then Secretary of State...34 Ex-detainee suit overshadows Rice- Merkel visit," Dec. 6, 2005. 19 Knowlton, Brian, " Merkel and Bush in ’spirited’ and friendly talks", The New

Olfactory cortical adaptation facilitates detection of odors against background.

PubMed

Kadohisa, Mikiko; Wilson, Donald A

2006-03-01

Detection and discrimination of odors generally, if not always, occurs against an odorous background. On any given inhalation, olfactory receptor neurons will be activated by features of both the target odorant and features of background stimuli. To identify a target odorant against a background therefore, the olfactory system must be capable of grouping a subset of features into an odor object distinct from the background. Our previous work has suggested that rapid homosynaptic depression of afferents to the anterior piriform cortex (aPCX) contributes to both cortical odor adaptation to prolonged stimulation and habituation of simple odor-evoked behaviors. We hypothesize here that this process may also contribute to figure-ground separation of a target odorant from background stimulation. Single-unit recordings were made from both mitral/tufted cells and aPCX neurons in urethan-anesthetized rats and mice. Single-unit responses to odorant stimuli and their binary mixtures were determined. One of the odorants was randomly selected as the background and presented for 50 s. Forty seconds after the onset of the background stimulus, the second target odorant was presented, producing a binary mixture. The results suggest that mitral/tufted cells continue to respond to the background odorant and, when the target odorant is presented, had response magnitudes similar to that evoked by the binary mixture. In contrast, aPCX neurons filter out the background stimulus while maintaining responses to the target stimulus. Thus the aPCX acts as a filter driven most strongly by changing stimuli, providing a potential mechanism for olfactory figure-ground separation and selective reading of olfactory bulb output.

CALCULATION OF COOLING TOWERS AND INJECTION COOLERS BY MEANS OF AN EVAPORATION METHOD (in German)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spangemacher, K.

1958-05-01

Calculation and evaluation of cooling towers, as recommended by Merkel, are critically examined. The usual methods of practical calculation are explained as well as a new procedure which combines great accuracy with brevity. Merkel's method is extended to injection coolers for gas and compressed air. It was discussed whether the dimensionless ''evaporation coefficient'' should be called the''Merkel coefficient.'' (tr-auth)

The Conundrum of Causality in Tumor Virology: The Cases of KSHV and MCV

PubMed Central

Moore, Patrick S.; Chang, Yuan

2014-01-01

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch’s postulates, work poorly or not at all for these viruses. Kaposi’s sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology. PMID:24304907

The conundrum of causality in tumor virology: the cases of KSHV and MCV.

PubMed

Moore, Patrick S; Chang, Yuan

2014-06-01

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch's postulates, work poorly or not at all for these viruses. Kaposi's sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Optimization of the current potential for stellarator coils

NASA Astrophysics Data System (ADS)

Boozer, Allen H.

2000-02-01

Stellarator plasma confinement devices have no continuous symmetries, which makes the design of appropriate coils far more subtle than for axisymmetric devices such as tokamaks. The modern method for designing coils for stellarators was developed by Peter Merkel [P. Merkel, Nucl. Fusion 27, 867 (1987)]. Although his method has yielded a number of successful stellarator designs, Merkel's method has a systematic tendency to give coils with a larger current than that required to produce a stellarator plasma with certain properties. In addition, Merkel's method does not naturally lead to a coil set with the flexibility to produce a number of interesting plasma configurations. The issues of coil efficiency and flexibility are addressed in this paper by a new method of optimizing the current potential, the first step in Merkel's method. The new method also allows the coil design to be based on a freer choice for the plasma-coil separation and to be constrained so space is preserved for plasma access.

German Defense Policy At A Turning Point

DTIC Science & Technology

2014-04-01

Concert of Democracies”65 German Chancellor Angela Merkel has been rather clear on this point, commenting to the Bundestag in 2009 that “I cannot see a...Whether his calls will resonate with Chancellor Angela Merkel , the Bundestag, Bundesrat, and the German electorate, is to be determined...illustrate the complexity of the German calculus regarding decisions like this, but it is also important to note that Chancellor Merkel assured

Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid.

PubMed

El Shahawy, Maha; Reibring, Claes-Göran; Neben, Cynthia L; Hallberg, Kristina; Marangoni, Pauline; Harfe, Brian D; Klein, Ophir D; Linde, Anders; Gritli-Linde, Amel

2017-07-01

The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.

Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid

PubMed Central

Neben, Cynthia L.; Harfe, Brian D.; Linde, Anders

2017-01-01

The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity. PMID:28715412

Role of genetic background in induced instability

NASA Technical Reports Server (NTRS)

Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

2003-01-01

Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

Difference in suitable mechanical properties of three-dimensional, synthetic scaffolds for self-renewing mouse embryonic stem cells of different genetic backgrounds.

PubMed

Lee, Myungook; Ahn, Jong Il; Ahn, Ji Yeon; Yang, Woo Sub; Hubbell, Jeffrey A; Lim, Jeong Mook; Lee, Seung Tae

2017-11-01

We evaluated whether the genetic background of embryonic stem cells (ESCs) affects the properties suitable for three-dimensional (3D) synthetic scaffolds for cell self-renewal. Inbred R1 and hybrid B6D2F1 mouse ESC lines were cultured for 7 days in hydrogel scaffolds with different properties derived from conjugating 7.5, 10, 12.5, or 15% (wt/vol) vinylsulfone-functionalized three-, four-, or eight-arm polyethylene glycol (PEG) with dicysteine-containing crosslinkers with an intervening matrix metalloproteinase-specific cleavage sites. Cell proliferation and expression of self-renewal-related genes and proteins by ESCs cultured in feeder-free or containing 2D culture plate or 3D hydrogel were monitored. As a preliminary experiment, the E14 ESC-customized synthetic 3D microenvironment did not maintain self-renewal of either the R1 or B6D2F1 ESCs. The best R1 cell proliferation (10.04 vs. 0.16-4.39; p < 0.0001) was observed in the four-arm 7.5% PEG-based hydrogels than those with other properties, whereas the F1 ESCs showed better proliferation when they were embedded in the three-arm 10% hydrogels. Self-renewal-related gene and protein expression by ESCs after feeder-free 3D culture was generally maintained compared with the feeder-containing 2D culture, but expression patterns and quantities differed. However, the feeder-free 3D culture yielded better expression than the feeder-free 2D culture. In conclusion, genetic background determined the suitability of hydrogel scaffolds for self-renewal of ESCs, which requires customization for the mechanical properties of each cell line. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2261-2268, 2017. © 2016 Wiley Periodicals, Inc.

Effects of Elevated Pax6 Expression and Genetic Background on Mouse Eye Development

PubMed Central

Chanas, Simon A.; Collinson, J. Martin; Ramaesh, Thaya; Dorà, Natalie; Kleinjan, Dirk A.; Hill, Robert E.; West, John D.

2009-01-01

Purpose To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. Methods Histologic features of eyes from hemizygous PAX77+/− transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77+/−↔wild-type and control wild-type↔wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77+/− mice. Results PAX77+/− mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6+/− heterozygotes (low Pax6 dose). Some previously reported PAX77+/− eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77+/−↔wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77+/− cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77+/− and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77+/− and wild-type cells to mix normally and overrepresentation of PAX77+/− in the lens epithelium and RPE. Conclusions The extent of PAX77+/− eye abnormalities depended on PAX77+/− genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77+/− genotype. Abnormal cell mixing between PAX77+/− and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77+/−↔wild-type and Pax6+/−↔wild-type chimeras may reflect differences in the levels of PAX77+/− and Pax6+/− contributions to chimeric lenses. PMID:19387074

German-Israeli Relations: Security of Israel--Reason of State?

DTIC Science & Technology

2013-03-01

the sale of submarines which the preceding government had agreed upon.23 When Chancellor Angela Merkel took office in 2005 she made the relationship...authentic conviction of the Chancellor. No Chancellor ever had as much freedom of action in dealing with Israel as Angela Merkel . Since her Knesset speech...Palestinian issue from the Iranians, and the Palestinians not to become hostages of an Iran conflict. Angela Merkel would have more leeway here, if she wanted

Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background.

PubMed

Jaramillo, Thomas C; Escamilla, Christine Ochoa; Liu, Shunan; Peca, Lauren; Birnbaum, Shari G; Powell, Craig M

2018-02-01

Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin-1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676-2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism-related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71-76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234-244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin-3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the

Background odour induces adaptation and sensitization of olfactory receptors in the antennae of houseflies.

PubMed

Kelling, F J; Ialenti, F; Den Otter, C J

2002-06-01

The presence of background odour was found to have a small but significant effect on the sensitivity of the antennal olfactory system of houseflies, Musca domestica Linnaeus (Diptera: Muscidae), to new pulses of odour. We show that cross-adaptation and cross-sensitization between a background odour of (+/-)-1-octen-3-ol and pulses of (+/-)-1-octen-3-ol, 2-pentanone and R-(+)-limonene can occur, confirming that olfactory receptor cells are sensitive to different odours. Background odour can increase the responses to low concentration odour pulses and decrease the responses to higher concentration odour pulses. It is suggested that background odour has a larger effect on olfactory receptor cells that respond with a tonic increase of spike frequency, giving information about the level of odour concentration, i.e. the 'static' environment. Cells that respond in a phasic way only provide information on the dynamics of the olfactory environment.

77 FR 3108 - Dividend Equivalents From Sources Within the United States

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-23

.... Erwin or D. Peter Merkel at (202) 622-3870 (not a toll-free number). SUPPLEMENTARY INFORMATION... is D. Peter Merkel, the Office of Associate Chief Counsel (International). Other personnel from the...

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

PubMed Central

Infante, Jeffrey R.; Taylor, Matthew H.; Patel, Manish R.; Wong, Deborah J.; Iannotti, Nicholas; Mehnert, Janice M.; Loos, Anja H.; Koch, Helga; Speit, Isabell; Gulley, James L.

2018-01-01

BACKGROUND Antibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD‐L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment‐related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune‐related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion‐related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were

Optimization of the current potential for stellarator coils

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boozer, Allen H.; Max-Planck-Institut fuer Plasmaphysik, EURATOM-Association, D-85748 Garching,

2000-02-01

Stellarator plasma confinement devices have no continuous symmetries, which makes the design of appropriate coils far more subtle than for axisymmetric devices such as tokamaks. The modern method for designing coils for stellarators was developed by Peter Merkel [P. Merkel, Nucl. Fusion 27, 867 (1987)]. Although his method has yielded a number of successful stellarator designs, Merkel's method has a systematic tendency to give coils with a larger current than that required to produce a stellarator plasma with certain properties. In addition, Merkel's method does not naturally lead to a coil set with the flexibility to produce a number ofmore » interesting plasma configurations. The issues of coil efficiency and flexibility are addressed in this paper by a new method of optimizing the current potential, the first step in Merkel's method. The new method also allows the coil design to be based on a freer choice for the plasma-coil separation and to be constrained so space is preserved for plasma access. (c) 2000 American Institute of Physics.« less

Epidemiology of non-keratinocytic skin cancers among persons with acquired immunodeficiency syndrome in the U.S.

PubMed Central

Lanoy, Emilie; Dores, Graça M.; Madeleine, Margaret M.; Toro, Jorge R.; Fraumeni, Joseph F.; Engels, Eric A.

2009-01-01

Objective Immunosuppression may increase risk for some skin cancers. We evaluated skin cancer epidemiology among persons with acquired immunodeficiency syndrome (AIDS). Design We linked data from population-based U.S. AIDS and cancer registries to evaluate risk of non-keratinocytic skin cancers (melanoma, Merkel cell carcinoma, and appendageal carcinomas, including sebaceous carcinoma) in 497,142 persons with AIDS. Methods Standardized incidence ratios (SIRs) were calculated to relate skin cancer risk to that in the general population. We used logistic regression to compare risk according to demographic factors, CD4 count, and a geographic index of ultraviolet radiation exposure. Results From 60 months before to 60 months after AIDS onset, persons with AIDS had elevated risks of melanoma (SIR=1.3, 95%CI 1.1-1.4, n=292 cases) and, more strongly, of Merkel cell carcinoma (SIR=11, 95%CI 6.3-17, n=17) and sebaceous carcinoma (SIR=8.1, 95%CI 3.2-17, n=7). Risk for appendageal carcinomas increased with progressive time relative to AIDS onset (p-trend=0.03). Risk of these skin cancers was higher in non-Hispanic whites than other racial/ethnic groups, and melanoma risk was highest among men who have sex with men. Melanoma risk was unrelated to CD4 count at AIDS onset (p=0.32). Risks for melanoma and appendageal carcinomas rose with increasing ultraviolet radiation exposure (p-trend<10-4 and p-trend=10-3, respectively). Conclusions Among persons with AIDS, there is a modest excess risk of melanoma which is not strongly related to immunosuppression and may relate to ultraviolet radiation exposure. In contrast, the greatly increased risks for Merkel cell and sebaceous carcinoma suggest an etiologic role for immunosuppression. PMID:19114864

Espins are multifunctional actin cytoskeletal regulatory proteins in the microvilli of chemosensory and mechanosensory cells

PubMed Central

Sekerková, Gabriella; Zheng, Lili; Loomis, Patricia A.; Changyaleket, Benjarat; Whitlon, Donna S.; Mugnaini, Enrico; Bartles, James R.

2010-01-01

Espins are associated with the parallel actin bundles of hair cell stereocilia and are the target of mutations that cause deafness and vestibular dysfunction in mice and humans. Here, we report that espins are also concentrated in the microvilli of a number of other sensory cells: vomeronasal organ sensory neurons, solitary chemoreceptor cells, taste cells and Merkel cells. Moreover, we show that hair cells and these other sensory cells contain novel espin isoforms that arise from a different transcriptional start site and differ significantly from other espin isoforms in their complement of ligand-binding activities and their effects on actin polymerization. The novel espin isoforms of sensory cells bundled actin filaments with high affinity in a Ca2+-resistant fashion, bound actin monomer via a WASP homology 2 domain, bound profilin via a single proline-rich peptide, and caused a dramatic elongation of microvillus-type parallel actin bundles in transfected epithelial cells. In addition, the novel espin isoforms of sensory cells differed from other espin isoforms in that they potently inhibited actin polymerization in vitro, did not bind the Src homology 3 domain of the adapter protein insulin receptor substrate p53 and did not bind the acidic, signaling phospholipid phosphatidylinositol 4,5- bisphosphate. Thus, the espins constitute a family of multifunctional actin cytoskeletal regulatory proteins with the potential to differentially influence the organization, dimensions, dynamics and signaling capabilities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in a variety of mechanosensory and chemosensory cells. PMID:15190118

Adult Palatum as a Novel Source of Neural Crest-Related Stem Cells

PubMed Central

Widera, Darius; Zander, Christin; Heidbreder, Meike; Kasperek, Yvonne; Noll, Thomas; Seitz, Oliver; Saldamli, Belma; Sudhoff, Holger; Sader, Robert; Kaltschmidt, Christian; Kaltschmidt, Barbara

2009-01-01

Somatic neural and neural crest stem cells are promising sources for cellular therapy of several neurodegenerative diseases. However, because of practical considerations such as inadequate accessibility of the source material, the application of neural crest stem cells is strictly limited. The secondary palate is a highly regenerative and heavily innervated tissue, which develops embryonically under direct contribution of neural crest cells. Here, we describe for the first time the presence of nestin-positive neural crest-related stem cells within Meissner corpuscles and Merkel cell-neurite complexes located in the hard palate of adult Wistar rats. After isolation, palatal neural crest-related stem cells (pNC-SCs) were cultivated in the presence of epidermal growth factor and fibroblast growth factor under serum-free conditions, resulting in large amounts of neurospheres. We used immunocytochemical techniques and reverse transcriptase-polymerase chain reaction to assess the expression profile of pNC-SCs. In addition to the expression of neural crest stem cell markers such as Nestin, Sox2, and p75, we detected the expression of Klf4, Oct4, and c-Myc. pNC-SCs differentiated efficiently into neuronal and glial cells. Finally, we investigated the potential expression of stemness markers within the human palate. We identified expression of stem cell markers nestin and CD133 and the transcription factors needed for reprogramming of somatic cells into pluripotent cells: Sox2, Oct4, Klf4, and c-Myc. These data show that cells isolated from palatal rugae form neurospheres, are highly plastic, and express neural crest stem cell markers. In addition, pNC-SCs may have the ability to differentiate into functional neurons and glial cells, serving as a starting point for therapeutic studies. Stem Cells 2009;27:1899–1910 PMID:19544446

Granulomatosis with polyangiitis

MedlinePlus

... ncbi.nlm.nih.gov/pubmed/21372195 . Specks U, Merkel PA, Seo P, et al. Efficacy of remission- ... PA: Elsevier Saunders; 2016:chap 270. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide ...

Plant cell technologies in space: Background, strategies and prospects

NASA Technical Reports Server (NTRS)

Kirkorian, A. D.; Scheld, H. W.

1987-01-01

An attempt is made to summarize work in plant cell technologies in space. The evolution of concepts and the general principles of plant tissue culture are discussed. The potential for production of high value secondary products by plant cells and differentiated tissue in automated, precisely controlled bioreactors is discussed. The general course of the development of the literature on plant tissue culture is highlighted.

Oblimersen in Treating Patients With Merkel Cell Carcinoma

ClinicalTrials.gov

2013-06-03

Recurrent Neuroendocrine Carcinoma of the Skin; Stage I Neuroendocrine Carcinoma of the Skin; Stage II Neuroendocrine Carcinoma of the Skin; Stage III Neuroendocrine Carcinoma of the Skin; Stage IV Neuroendocrine Carcinoma of the Skin

Temporal Dependence of Chromosomal Aberration on Radiation Quality and Cellular Genetic Background

NASA Technical Reports Server (NTRS)

Lu, Tao; Zhang, Ye; Krieger, Stephanie; Yeshitla, Samrawit; Goss, Rosalin; Bowler, Deborah; Kadhim, Munira; Wilson, Bobby; Wu, Honglu

2017-01-01

Radiation induced cancer risks are driven by genetic instability. It is not well understood how different radiation sources induce genetic instability in cells with different genetic background. Here we report our studies on genetic instability, particularly chromosome instability using fluorescence in situ hybridization (FISH), in human primary lymphocytes, normal human fibroblasts, and transformed human mammary epithelial cells in a temporal manner after exposure to high energy protons and Fe ions. The chromosome spread was prepared 48 hours, 1 week, 2 week, and 1 month after radiation exposure. Chromosome aberrations were analyzed with whole chromosome specific probes (chr. 3 and chr. 6). After exposure to protons and Fe ions of similar cumulative energy (??), Fe ions induced more chromosomal aberrations at early time point (48 hours) in all three types of cells. Over time (after 1 month), more chromosome aberrations were observed in cells exposed to Fe ions than in the same type of cells exposed to protons. While the mammary epithelial cells have higher intrinsic genetic instability and higher rate of initial chromosome aberrations than the fibroblasts, the fibroblasts retained more chromosomal aberration after long term cell culture (1 month) in comparison to their initial frequency of chromosome aberration. In lymphocytes, the chromosome aberration frequency at 1 month after exposure to Fe ions was close to unexposed background, and the chromosome aberration frequency at 1 month after exposure to proton was much higher. In addition to human cells, mouse bone marrow cells isolated from strains CBA/CaH and C57BL/6 were irradiated with proton or Fe ions and were analyzed for chromosome aberration at different time points. Cells from CBA mice showed similar frequency of chromosome aberration at early and late time points, while cells from C57 mice showed very different chromosome aberration rate at early and late time points. Our results suggest that relative

Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers

ClinicalTrials.gov

2018-06-25

Adenoid Cystic Carcinoma; Adnexal Carcinoma; Apocrine Carcinoma; Eccrine Porocarcinoma; Extraocular Cutaneous Sebaceous Carcinoma; Hidradenocarcinoma; Keratoacanthoma; Malignant Sweat Gland Neoplasm; Merkel Cell Carcinoma; Microcystic Adnexal Carcinoma; NK-Cell Lymphoma, Unclassifiable; Non-Melanomatous Lesion; Paget Disease; Papillary Adenocarcinoma; Primary Cutaneous Mucinous Carcinoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma; Sezary Syndrome; Signet Ring Cell Carcinoma; Skin Basal Cell Carcinoma; Skin Basosquamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Spiradenocarcinoma; Squamous Cell Carcinoma of Unknown Primary Origin; Stage III Skin Cancer; Stage IV Skin Cancer; Sweat Gland Carcinoma; Trichilemmocarcinoma; Vulvar Squamous Cell Carcinoma

Effects of the unintentional background concentration, indium composition and defect density on the performance of InGaN p-i-n homojunction solar cells

NASA Astrophysics Data System (ADS)

Wu, Shudong; Cheng, Liwen; Wang, Qiang

2018-07-01

We theoretically investigate the effects of the unintentional background concentration, indium composition and defect density of intrinsic layer (i-layer) on the photovoltaic performance of InGaN p-i-n homojunction solar cells by solving the Poisson and steady-state continuity equations. The built-in electric field and carrier generation rate depend on the position within the i-layer. The collection efficiency, short circuit current density, open circuit voltage, fill factor, and conversion efficiency are found to depend strongly on the background concentration, thickness, indium composition, and defect density of the i-layer. With increasing the background concentration, the maximum thickness of field-bearing i-layer decreases, and the width of depletion region may become even too small to cover the whole i-layer, resulting in a serious decrease of the carrier collection. Some oscillations as a function of indium composition are found in the short circuit current density and conversion efficiency at high indium composition and low defect density due to the interference between the absorbance and the generation rate of carriers. The defect density degrades seriously the overall photovoltaic performance, and its effect on the photovoltaic performance is roughly seven orders of magnitude higher than the previously reported values [Feng et al., J. Appl. Phys. 108 (2010) 093118]. As a result, the high crystalline quality InGaN with high indium composition is a key factor in the device performance of III-nitride based solar cells.

Interactions between genetic background, insulin resistance and β-cell function.

PubMed

Kahn, S E; Suvag, S; Wright, L A; Utzschneider, K M

2012-10-01

An interaction between genes and the environment is a critical component underlying the pathogenesis of the hyperglycaemia of type 2 diabetes. The development of more sophisticated techniques for studying gene variants and for analysing genetic data has led to the discovery of some 40 genes associated with type 2 diabetes. Most of these genes are related to changes in β-cell function, with a few associated with decreased insulin sensitivity and obesity. Interestingly, using quantitative traits based on continuous measures rather than dichotomous ones, it has become evident that not all genes associated with changes in fasting or post-prandial glucose are also associated with a diagnosis of type 2 diabetes. Identification of these gene variants has provided novel insights into the physiology and pathophysiology of the β-cell, including the identification of molecules involved in β-cell function that were not previously recognized as playing a role in this critical cell. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Determining Factors for EU Military Intervention

DTIC Science & Technology

2013-05-23

allow further debate. German Chancellor Angela Merkel ruled out ground troops citing fears for their safety.52 Germany was already committed in...Afghanistan and the Merkel government lacked the political capital needed 50Mark Regev, spokesmen for the Israeli Foreign Ministry 51Katarina Engberg, “To

Identification of a Polyomavirus microRNA Highly Expressed in Tumors

PubMed Central

Chen, Chun Jung; Cox, Jennifer E.; Azarm, Kristopher; Wylie, Karen N.; Woolard, Kevin D.; Pesavento, Patricia A.; Sullivan, Christopher S.

2014-01-01

Polyomaviruses (PyVs) are associated with tumors including Merkel cell carcinoma (MCC). Several PyVs encode microRNAs (miRNAs) but to date no abundant PyV miRNAs have been reported in tumors. To better understand the function of the Merkel cell PyV (MCPyV) miRNA, we examined phylogenetically-related viruses for miRNA expression. We show that two primate PyVs and the more distantly-related raccoon PyV (RacPyV) encode miRNAs that share genomic position and partial sequence identity with MCPyV miRNAs. Unlike MCPyV miRNA in MCC, RacPyV miRNA is highly abundant in raccoon tumors. RacPyV miRNA negatively regulates reporters of early viral (T antigen) transcripts, yet robust viral miRNA expression is tolerated in tumors. We also identify raccoon miRNAs expressed in RacPyV-associated neuroglial brain tumors, including several likely oncogenic miRNAs (oncomiRs). This work describes the first PyV miRNA abundantly expressed in tumors and is consistent with a possible role for both host and viral miRNAs in RacPyV-associated tumors. PMID:25514573

Theta frequency background tunes transmission but not summation of spiking responses.

PubMed

Parameshwaran, Dhanya; Bhalla, Upinder S

2013-01-01

Hippocampal neurons are known to fire as a function of frequency and phase of spontaneous network rhythms, associated with the animal's behaviour. This dependence is believed to give rise to precise rate and temporal codes. However, it is not well understood how these periodic membrane potential fluctuations affect the integration of synaptic inputs. Here we used sinusoidal current injection to the soma of CA1 pyramidal neurons in the rat brain slice to simulate background oscillations in the physiologically relevant theta and gamma frequency range. We used a detailed compartmental model to show that somatic current injection gave comparable results to more physiological synaptically driven theta rhythms incorporating excitatory input in the dendrites, and inhibitory input near the soma. We systematically varied the phase of synaptic inputs with respect to this background, and recorded changes in response and summation properties of CA1 neurons using whole-cell patch recordings. The response of the cell was dependent on both the phase of synaptic inputs and frequency of the background input. The probability of the cell spiking for a given synaptic input was up to 40% greater during the depolarized phases between 30-135 degrees of theta frequency current injection. Summation gain on the other hand, was not affected either by the background frequency or the phasic afferent inputs. This flat summation gain, coupled with the enhanced spiking probability during depolarized phases of the theta cycle, resulted in enhanced transmission of summed inputs during the same phase window of 30-135 degrees. Overall, our study suggests that although oscillations provide windows of opportunity to selectively boost transmission and EPSP size, summation of synaptic inputs remains unaffected during membrane oscillations.

Tumor cell membrane-targeting pH-dependent electron donor-acceptor fluorescence systems with low background signals.

PubMed

Han, Liang; Liu, Mingming; Ye, Deyong; Zhang, Ning; Lim, Ed; Lu, Jing; Jiang, Chen

2014-03-01

Minimizing the background signal is crucial for developing tumor-imaging techniques with sufficient specificity and sensitivity. Here we use pH difference between healthy tissues and tumor and tumor targeting delivery to achieve this goal. We synthesize fluorophore-dopamine conjugate as pH-dependent electron donor-acceptor fluorescence system. Fluorophores are highly sensitive to electron-transfer processes, which can alter their optical properties. The intrinsic redox properties of dopamine are oxidation of hydroquinone to quinone at basic pH and reduction of quinone to hydroquinone at acidic pH. Quinone can accept electron then quench fluorescence. We design tumor cell membrane-targeting carrier for delivery. We demonstrate quenched fluorophore-quinone can be specially transferred to tumor extracellular environment and tumor-accumulated fluorophore can be activated by acidic pH. These tumor-targeting pH-dependent electron donor-acceptor fluorescence systems may offer new opportunity for developing tumor-imaging techniques. Copyright © 2014 Elsevier Ltd. All rights reserved.

Background characterization of an ultra-low background liquid scintillation counter

DOE PAGES

Erchinger, J. L.; Orrell, John L.; Aalseth, C. E.; ...

2017-01-26

The Ultra-Low Background Liquid Scintillation Counter developed by Pacific Northwest National Laboratory will expand the application of liquid scintillation counting by enabling lower detection limits and smaller sample volumes. By reducing the overall count rate of the background environment approximately 2 orders of magnitude below that of commercially available systems, backgrounds on the order of tens of counts per day over an energy range of ~3–3600 keV can be realized. Finally, initial test results of the ULB LSC show promising results for ultra-low background detection with liquid scintillation counting.

The structure and function of cutaneous sensory receptors.

PubMed

Munger, B L; Ide, C

1988-03-01

The present review of cutaneous sensory receptors begins with a consideration of free nerve endings (FNEs) that can be considered as sensory terminals evidencing the least structural specialization of the axon and associated cells. Using the criteria established by Kruger et al (1981), FNEs of both A delta and C fibers can be identified on the basis of ultrastructural characteristics that include an intimate relationship between axons and the associated epithelium, the lack of a complete Schwann cell investment, the accumulation of numerous vesicles and other cytoplasmic organelles, and for A delta terminals a 1:1 relationship between axon and investing Schwann cell. Using these criteria, the so-called genital end bulbs of the human glans penis are merely a skein of FNEs based on the ultrastructural study of Halata and Munger (1986). Hair follicles of most species studied to date (the exception being the rabbit and to some extent the guinea pig) are multiply innervated with lanceolate, Ruffini and FNEs. The lanceolate terminals are the rapidly adapting terminals that are numerous in guard hairs. Ruffini terminals of hairs resemble those of the periodontal ligament or joint capsules and both are remarkably similar to Golgi tendon organs in terms of ultrastructural characteristics. The key ultrastructural characteristic is the encircling of collagen bundles by axons and associated Schwann and connective tissue cells. Axons frequently enter the epidermis either to terminate as FNEs or become associated with Merkel cells in glabrous skin at the base of the papillary ridges or in clusters of Merkel cells in hairy skin in touch domes or Haarscheiben. Merkel cells have clusters of apparent secretory granules polarized toward the axon and the axon is typically a slowly adapting mechanoreceptor. The function of the granules is not known. Pacinian corpuscles are the largest of the corpuscular receptors of the dermis and are characterized by an elaborate inner core of stacks

Oral squamous cell carcinoma in the background of oral submucous fibrosis is a distinct clinicopathological entity with better prognosis.

PubMed

Gadbail, Amol Ramchandra; Chaudhary, Minal; Gawande, Madhuri; Hande, Alka; Sarode, Sachin; Tekade, Satyajit Ashok; Korde, Sheetal; Zade, Prajakta; Bhowate, Rahul; Borle, Rajiv; Patil, Swati

2017-07-01

The aim of this study was to compare the clinicopathological features of oral squamous cell carcinoma in the background of oral submucous fibrosis (OSCC-OSMF) and oral squamous cell carcinoma (OSCC). A total of 217 cases of OSCC were retrieved from achieves for the analysis. OSCC-OSMF cases were segregated on the basis of history and clinicopathological parameters. The study included 217 patients of which 112 had OSCC and 105 OSCC-OSMF. OSCC-OSMFs were younger compared with OSCC. Overall oral cancer was noted predominantly in males compared to females. The number of OSCC-OSMF was more in clinical TNM stage I and stage II as compared to OSCC, whereas the number of OSCC was more in stage III and stage IV compared to OSCC-OSMF. Histological presentation of well-differentiated squamous cell carcinoma was significantly more in OSCC-OSMF compared to OSCC, whereas moderately differentiated squamous cell carcinoma was significantly more in OSCC compared to OSCC-OSMF. Regional lymph node metastasis was significantly higher in OSCC compared to OSCC-OSMF. Three-year disease-free survival rate was significantly higher in OSCC-OSMF compared to OSCC. The OSCC-OSMF was found to be a clinicopathologically distinct entity with a better grade of tumor differentiation, less incidence of nodal metastases, and early detection (early clinical TNM stage) compared to OSCC. All these factors probably contribute to a better prognosis and increased 3-year disease-free survival in OSCC-OSMF patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A unidirectional acoustic cloak for multilayered background media with homogeneous metamaterials

NASA Astrophysics Data System (ADS)

Zhu, Jian; Chen, Tianning; Liang, Qingxuan; Wang, Xiaopeng; Xiong, Jie; Jiang, Ping

2015-08-01

The acoustic cloak, which can make an object hard to detect acoustically in a homogeneous background, has attracted great attention from researchers in recent years. The inhomogeneous background media were considered in this paper. The relative constitutive parameters were derived for acoustic cloaks working in multilayered media. And a unidirectional acoustic cloak for layered background media was proposed, designed and implemented successfully in a wide frequency range. In water and NaCl aqueous solution, the acoustic cloak was designed and realized with homogeneous metamaterials which were composed of steel and porous materials. The effective parameters of the unit cells of the cloak were determined by using the effective medium theory. Numerical results demonstrated excellent cloaking performance and showed that such a device could be physically realized with natural materials which will greatly promote the real applications of an invisibility cloak in inhomogeneous backgrounds.

Background and Recent Progress in Anomalous Transport Simulation

DTIC Science & Technology

2017-07-19

NUMBER (Include area code) 19 July 2017 Briefing Charts 14 June 2017 - 19 July 2017 Background and Recent Progress in Anomalous Transport Simulation ...and Recent Progress in Anomalous Transport Simulation 19 Jul 2017 Justin Koo AFRL/RQRS Edwards AFB, CA 2DISTRIBUTION A: Approved for public release...Baalrud, S.D. and Chabert, P., “Theory for the anomalous electron transport in Hall effect thrusters. I. Insights from particle-in-cell simulations

Radioprotective Effects of Sulfur-containing Mineral Water of Ramsar Hot Spring with High Natural Background Radiation on Mouse Bone Marrow Cells.

PubMed

Heidari, A H; Shabestani Monfared, A; Mozdarani, H; Mahmoudzadeh, A; Razzaghdoust, A

2017-12-01

We intend to study the inhibitory effect of sulfur compound in Ramsar hot spring mineral on tumor-genesis ability of high natural background radiation. The radioprotective effect of sulfur compounds was previously shown on radiation-induced chromosomal aberration, micronuclei in mouse bone marrow cells and human peripheral lymphocyte. Ramsar is known for having the highest level of natural background radiation on Earth. This study was performed to show the radioprotective effect of sulfur-containing Ramsar mineral water on mouse bone marrow cells. Mice were fed three types of water (drinking water, Ramsar radioactive water containing sulfur and Ramsar radioactive water whose sulfur was removed). Ten days after feeding, mice were irradiated by gamma rays (0, 2 and 4 Gy). 48 and 72 hours after irradiating, mice were killed and femurs were removed. Frequency of micronuclei was determined in bone marrow erythrocytes. A significant reduction was shown in the rate of micronuclei polychromatic erythrocyte in sulfur-containing hot spring water compared to sulfur-free water in hot spring mineral water. Gamma irradiation induced significant increases in micronuclei polychromatic erythrocyte (MNPCE) and decreases in polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte ratio (PCEs/PCEs+NCEs) (P < 0.001) in sulfur-containing hot spring water compared to sulfur-free hot spring mineral water. Also, apparently there was a significant difference between drinking water and sulfur-containing hot spring water in micronuclei polychromatic erythrocyte and polychromatic erythrocyte/polychromatic erythrocyte+ normochromatic erythrocyte ratio. The results indicate that sulfur-containing mineral water could result in a significant reduction in radiation-induced micronuclei representing the radioprotective effect of sulfur compounds.

PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours.

PubMed

Hung, Yin P; Lee, John P; Bellizzi, Andrew M; Hornick, Jason L

2017-11-01

Neuroblastoma shows considerable histological overlap with other small round blue cell tumours. PHOX2B, a transcription factor that is essential for autonomic nervous system development, has been reported as an immunohistochemical marker for neuroblastoma. The aim of this study was to validate the specificity and diagnostic utility of PHOX2B for peripheral neuroblastic tumours. We evaluated 240 cases (133 in whole-tissue sections; 107 in tissue microarrays), including 76 peripheral neuroblastic tumours (median age 2 years; including four adults) and 164 other tumours: 44 Wilms tumours; 20 Ewing sarcomas; 10 each of CIC-rearranged round cell sarcomas, poorly differentiated synovial sarcomas, lymphoblastic lymphomas, alveolar rhabdomyosarcomas, embryonal rhabdomyosarcomas, mesenchymal chondrosarcomas, Merkel cell carcinomas, olfactory neuroblastomas, and melanomas; and five each of NUT midline carcinomas and desmoplastic small round cell tumours. Immunohistochemistry for PHOX2B was performed with a rabbit monoclonal antibody. PHOX2B positivity was defined as the presence of nuclear immunoreactivity in ≥5% of cells. PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases. Furthermore, PHOX2B was consistently negative in all non-peripheral neuroblastic tumours, with staining being absent in 160 cases and limited in four cases. PHOX2B is a highly sensitive and specific immunohistochemical marker for peripheral neuroblastic tumours, including neuroblastoma. PHOX2B reliably distinguishes neuroblastoma from histological mimics such as Wilms tumour, Ewing sarcoma, and CIC-rearranged round cell sarcoma. PHOX2B negativity in two of four adult neuroblastoma cases raises the possibility that some adult neuroblastomas are of a different lineage than paediatric cases. © 2017 John Wiley & Sons Ltd.

Ultrahigh pressure deformation of polycrystaline hcp-cobalt

NASA Astrophysics Data System (ADS)

Merkel, S.; Antonangeli, D.; Fiquet, G.; Yagi, T.

2003-12-01

During the past few years, a novel set of methods has been developed allowing direct measurements on elasticity and rheology under static ultrahigh pressures using synchrotron x-ray diffraction and the diamond anvil cell. In particular, the analysis on the development of texture and uniaxial stress in a polycrystalline sample under ultrahigh pressure and non-hydrostatic conditions yielded to very interesting results on the microscopic deformation mechanisms and strength of MgO, silicate perovskite or ɛ -Fe [eg. Merkel et al. 2002, Merkel et al. 2003]. However, our understanding of the properties of the ɛ phase of iron remains poor. There are considerable uncertainties and disagreement on the results of various experiments or first-principles calculations. In particular, the results of the radial diffraction measurement on ɛ -Fe [Mao et al. 1998] have been highly controversial. In order to address this issue, we performed investigations on polycrystalline hcp-cobalt. Its properties such as the bulk modulus and thermal expansion are very close to those of ɛ -Fe and it is readily available under ambient conditions. Thus, it is a well known material and results from the high pressure radial diffraction experiments can be compared with those from well-established techniques. In the present analysis, we performed a new set a measurements between 0 and 20 GPa under ambient temperature conditions at the ESRF synchrotron source using amorphous boron gasket, monochromatic x-ray beam, and imaging plate techniques. From such an experiment, we are able to extract information on non-hydrostatic stress, elasticity, and preferred orientations of the sample in-situ under high pressure and compare them with results obtained previously on ɛ -Fe. Documenting the evolution of stress, elasticity and texture in hcp metals is of great interest for our understanding of the bulk properties and seismic anisotropy of the Earth's inner core. S. Merkel et al., J. Geophys. Res. 107 (2002

Defeating a rare, aggressive form of skin cancer with avelumab | Center for Cancer Research

Cancer.gov

For the one-year anniversary of the FDA’s approval of avelumab, CCR Communications caught up with Richard Mulcahy to share his success story as a clinical trial patient. Mulcahy was diagnosed with Merkel cell carcinoma in September of 2016. It’s been over a year since he received his first treatment of avelumab as part of a clinical trial led by Isaac Brownell, M.D., Ph.D.,

Thresholding of auditory cortical representation by background noise

PubMed Central

Liang, Feixue; Bai, Lin; Tao, Huizhong W.; Zhang, Li I.; Xiao, Zhongju

2014-01-01

It is generally thought that background noise can mask auditory information. However, how the noise specifically transforms neuronal auditory processing in a level-dependent manner remains to be carefully determined. Here, with in vivo loose-patch cell-attached recordings in layer 4 of the rat primary auditory cortex (A1), we systematically examined how continuous wideband noise of different levels affected receptive field properties of individual neurons. We found that the background noise, when above a certain critical/effective level, resulted in an elevation of intensity threshold for tone-evoked responses. This increase of threshold was linearly dependent on the noise intensity above the critical level. As such, the tonal receptive field (TRF) of individual neurons was translated upward as an entirety toward high intensities along the intensity domain. This resulted in preserved preferred characteristic frequency (CF) and the overall shape of TRF, but reduced frequency responding range and an enhanced frequency selectivity for the same stimulus intensity. Such translational effects on intensity threshold were observed in both excitatory and fast-spiking inhibitory neurons, as well as in both monotonic and nonmonotonic (intensity-tuned) A1 neurons. Our results suggest that in a noise background, fundamental auditory representations are modulated through a background level-dependent linear shifting along intensity domain, which is equivalent to reducing stimulus intensity. PMID:25426029

Unexpected effects of different genetic backgrounds on identification of genomic rearrangements via whole-genome next generation sequencing.

PubMed

Chen, Zhangguo; Gowan, Katherine; Leach, Sonia M; Viboolsittiseri, Sawanee S; Mishra, Ameet K; Kadoishi, Tanya; Diener, Katrina; Gao, Bifeng; Jones, Kenneth; Wang, Jing H

2016-10-21

Whole genome next generation sequencing (NGS) is increasingly employed to detect genomic rearrangements in cancer genomes, especially in lymphoid malignancies. We recently established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells. This mouse model spontaneously develops mature B cell lymphomas (termed G1XP lymphomas). Here, we attempt to employ whole genome NGS to identify novel structural rearrangements, in particular inter-chromosomal translocations (CTXs), in these G1XP lymphomas. We sequenced six lymphoma samples, aligned our NGS data with mouse reference genome (in C57BL/6J (B6) background) and identified CTXs using CREST algorithm. Surprisingly, we detected widespread CTXs in both lymphomas and wildtype control samples, majority of which were false positive and attributable to different genetic backgrounds. In addition, we validated our NGS pipeline by sequencing multiple control samples from distinct tissues of different genetic backgrounds of mouse (B6 vs non-B6). Lastly, our studies showed that widespread false positive CTXs can be generated by simply aligning sequences from different genetic backgrounds of mouse. We conclude that mapping and alignment with reference genome might not be a preferred method for analyzing whole-genome NGS data obtained from a genetic background different from reference genome. Given the complex genetic background of different mouse strains or the heterogeneity of cancer genomes in human patients, in order to minimize such systematic artifacts and uncover novel CTXs, a preferred method might be de novo assembly of personalized normal control genome and cancer cell genome, instead of mapping and aligning NGS data to mouse or human reference genome. Thus, our studies have critical impact on the manner of data analysis for cancer genomics.

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

DOE PAGES

Velasquez, Celestino; Cheng, Erdong; Shuda, Masahiro; ...

2016-07-11

mTOR-directed 4E-BP1 phosphorylation promotes cap-dependent translation and tumorigen-esis. During mitosis, CDK1 substitutes for mTOR and fully phosphorylates 4E-BP1 at canoni-cal as well a non-canonical S83 site resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. While S83 phosphorylation of 4E-BP1 does not affect in vitro cap-dependent translation, nor eIF4G/4E-BP1 cap-binding, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus (MCV) small T (sT) antigen viral oncoprotein. In contrast to inhibitorymore » mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain-of-function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.« less

Cancer resistance of SR/CR mice in the genetic knockout backgrounds of leukocyte effector mechanisms: determinations for functional requirements.

PubMed

Sanders, Anne M; Stehle, John R; Blanks, Michael J; Riedlinger, Gregory; Kim-Shapiro, Jung W; Monjazeb, Arta M; Adams, Jonathan M; Willingham, Mark C; Cui, Zheng

2010-03-31

Spontaneous Regression/Complete Resistant (SR/CR) mice are a colony of cancer-resistant mice that can detect and rapidly destroy malignant cells with innate cellular immunity, predominately mediated by granulocytes. Our previous studies suggest that several effector mechanisms, such as perforin, granzymes, or complements, may be involved in the killing of cancer cells. However, none of these effector mechanisms is known as critical for granulocytes. Additionally, it is unclear which effector mechanisms are required for the cancer killing activity of specific leukocyte populations and the survival of SR/CR mice against the challenges of lethal cancer cells. We hypothesized that if any of these effector mechanisms was required for the resistance to cancer cells, its functional knockout in SR/CR mice should render them sensitive to cancer challenges. This was tested by cross breeding SR/CR mice into the individual genetic knockout backgrounds of perforin (Prf-/-), superoxide (Cybb-/), or inducible nitric oxide (Nos2-/). SR/CR mice were bred into individual Prf-/-, Cybb-/-, or Nos2-/- genetic backgrounds and then challenged with sarcoma 180 (S180). Their overall survival was compared to controls. The cancer killing efficiency of purified populations of macrophages and neutrophils from these immunodeficient mice was also examined. When these genetically engineered mice were challenged with cancer cells, the knockout backgrounds of Prf-/-, Cybb-/-, or Nos2-/- did not completely abolish the SR/CR cancer resistant phenotype. However, the Nos2-/- background did appear to weaken the resistance. Incidentally, it was also observed that the male mice in these immunocompromised backgrounds tended to be less cancer-resistant than SR/CR controls. Despite the previously known roles of perforin, superoxide or nitric oxide in the effector mechanisms of innate immune responses, these effector mechanisms were not required for cancer-resistance in SR/CR mice. The resistance was

Optimal background matching camouflage.

PubMed

Michalis, Constantine; Scott-Samuel, Nicholas E; Gibson, David P; Cuthill, Innes C

2017-07-12

Background matching is the most familiar and widespread camouflage strategy: avoiding detection by having a similar colour and pattern to the background. Optimizing background matching is straightforward in a homogeneous environment, or when the habitat has very distinct sub-types and there is divergent selection leading to polymorphism. However, most backgrounds have continuous variation in colour and texture, so what is the best solution? Not all samples of the background are likely to be equally inconspicuous, and laboratory experiments on birds and humans support this view. Theory suggests that the most probable background sample (in the statistical sense), at the size of the prey, would, on average, be the most cryptic. We present an analysis, based on realistic assumptions about low-level vision, that estimates the distribution of background colours and visual textures, and predicts the best camouflage. We present data from a field experiment that tests and supports our predictions, using artificial moth-like targets under bird predation. Additionally, we present analogous data for humans, under tightly controlled viewing conditions, searching for targets on a computer screen. These data show that, in the absence of predator learning, the best single camouflage pattern for heterogeneous backgrounds is the most probable sample. © 2017 The Authors.

Estimating background-subtracted fluorescence transients in calcium imaging experiments: a quantitative approach.

PubMed

Joucla, Sébastien; Franconville, Romain; Pippow, Andreas; Kloppenburg, Peter; Pouzat, Christophe

2013-08-01

Calcium imaging has become a routine technique in neuroscience for subcellular to network level investigations. The fast progresses in the development of new indicators and imaging techniques call for dedicated reliable analysis methods. In particular, efficient and quantitative background fluorescence subtraction routines would be beneficial to most of the calcium imaging research field. A background-subtracted fluorescence transients estimation method that does not require any independent background measurement is therefore developed. This method is based on a fluorescence model fitted to single-trial data using a classical nonlinear regression approach. The model includes an appropriate probabilistic description of the acquisition system's noise leading to accurate confidence intervals on all quantities of interest (background fluorescence, normalized background-subtracted fluorescence time course) when background fluorescence is homogeneous. An automatic procedure detecting background inhomogeneities inside the region of interest is also developed and is shown to be efficient on simulated data. The implementation and performances of the proposed method on experimental recordings from the mouse hypothalamus are presented in details. This method, which applies to both single-cell and bulk-stained tissues recordings, should help improving the statistical comparison of fluorescence calcium signals between experiments and studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Background Noise Analysis in a Few-Photon-Level Qubit Memory

NASA Astrophysics Data System (ADS)

Mittiga, Thomas; Kupchak, Connor; Jordaan, Bertus; Namazi, Mehdi; Nolleke, Christian; Figeroa, Eden

2014-05-01

We have developed an Electromagnetically Induced Transparency based polarization qubit memory. The device is composed of a dual-rail probe field polarization setup colinear with an intense control field to store and retrieve any arbitrary polarization state by addressing a Λ-type energy level scheme in a 87Rb vapor cell. To achieve a signal-to-background ratio at the few photon level sufficient for polarization tomography of the retrieved state, the intense control field is filtered out through an etalon filtrating system. We have developed an analytical model predicting the influence of the signal-to-background ratio on the fidelities and compared it to experimental data. Experimentally measured global fidelities have been found to follow closely the theoretical prediction as signal-to-background decreases. These results suggest the plausibility of employing room temperature memories to store photonic qubits at the single photon level and for future applications in long distance quantum communication schemes.

[Changes in the chromatin structure of lymphoid cells under the influence of low-intensity extremely high-frequency electromagnetic radiation against the background of inflammatory process].

PubMed

Gapeev, A B; Romanova, N A; Chemeris, N K

2011-01-01

Using the alkaline single cell gel electrophoresis technique (comet assay), changes in chromatin structure of peripheral blood leukocytes and peritoneal neutrophils have been studied in mice exposed to low-intensity extremely high-frequency electromagnetic radiation (42.2 GHz, 0.1 mW/cm2, 20 min at 1 h after induction of inflammation) against the background of the systemic inflammatory process. It was revealed that the exposure of mice with the developing inflammation leads to a pronounced decrease in the level of DNA damage to peripheral blood leukocytes and peritoneal neutrophils. It is supposed that the changes in the chromatin structure of lymphoid cells have a genoprotective character in the inflammatory process and can underlie the mechanisms of realization of antiinflammatory effects of the electromagnetic radiation.

Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor

PubMed Central

Liedtke, Wolfgang; Choe, Yong; Martí-Renom, Marc A.; Bell, Andrea M.; Denis, Charlotte S.; Šali, Andrej; Hudspeth, A. J.; Friedman, Jeffrey M.; Heller, Stefan

2008-01-01

SUMMARY The detection of osmotic stimuli is essential for all organisms, yet few osmoreceptive proteins are known, none of them in vertebrates. By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, we cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human, and chicken. This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. In the central nevous system, the channel is expressed neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. The channel also occurs in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells. PMID:11081638

Background sources at PEP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lynch, H.; Schwitters, R.F.; Toner, W.T.

Important sources of background for PEP experiments are studied. Background particles originate from high-energy electrons and positrons which have been lost from stable orbits, ..gamma..-rays emitted by the primary beams through bremsstrahlung in the residual gas, and synchrotron radiation x-rays. The effect of these processes on the beam lifetime are calculated and estimates of background rates at the interaction region are given. Recommendations for the PEP design, aimed at minimizing background are presented. 7 figs., 4 tabs.

Backgrounds in Language.

ERIC Educational Resources Information Center

Maxwell, John C.; Long, Barbara K.

"Backgrounds in Language," a field-tested inservice course designed for use by groups of 15 or 25 language arts teachers, provides the subject matter background teachers need to make informed decisions about what curriculum materials to use in what way, at what time, and with which students. The course is comprised of eight 2-hour sessions,…

Genetic background effects in quantitative genetics: gene-by-system interactions.

PubMed

Sardi, Maria; Gasch, Audrey P

2018-04-11

Proper cell function depends on networks of proteins that interact physically and functionally to carry out physiological processes. Thus, it seems logical that the impact of sequence variation in one protein could be significantly influenced by genetic variants at other loci in a genome. Nonetheless, the importance of such genetic interactions, known as epistasis, in explaining phenotypic variation remains a matter of debate in genetics. Recent work from our lab revealed that genes implicated from an association study of toxin tolerance in Saccharomyces cerevisiae show extensive interactions with the genetic background: most implicated genes, regardless of allele, are important for toxin tolerance in only one of two tested strains. The prevalence of background effects in our study adds to other reports of widespread genetic-background interactions in model organisms. We suggest that these effects represent many-way interactions with myriad features of the cellular system that vary across classes of individuals. Such gene-by-system interactions may influence diverse traits and require new modeling approaches to accurately represent genotype-phenotype relationships across individuals.

Visual signal detection in structured backgrounds. II. Effects of contrast gain control, background variations, and white noise

NASA Technical Reports Server (NTRS)

Eckstein, M. P.; Ahumada, A. J. Jr; Watson, A. B.

1997-01-01

Studies of visual detection of a signal superimposed on one of two identical backgrounds show performance degradation when the background has high contrast and is similar in spatial frequency and/or orientation to the signal. To account for this finding, models include a contrast gain control mechanism that pools activity across spatial frequency, orientation and space to inhibit (divisively) the response of the receptor sensitive to the signal. In tasks in which the observer has to detect a known signal added to one of M different backgrounds grounds due to added visual noise, the main sources of degradation are the stochastic noise in the image and the suboptimal visual processing. We investigate how these two sources of degradation (contrast gain control and variations in the background) interact in a task in which the signal is embedded in one of M locations in a complex spatially varying background (structured background). We use backgrounds extracted from patient digital medical images. To isolate effects of the fixed deterministic background (the contrast gain control) from the effects of the background variations, we conduct detection experiments with three different background conditions: (1) uniform background, (2) a repeated sample of structured background, and (3) different samples of structured background. Results show that human visual detection degrades from the uniform background condition to the repeated background condition and degrades even further in the different backgrounds condition. These results suggest that both the contrast gain control mechanism and the background random variations degrade human performance in detection of a signal in a complex, spatially varying background. A filter model and added white noise are used to generate estimates of sampling efficiencies, an equivalent internal noise, an equivalent contrast-gain-control-induced noise, and an equivalent noise due to the variations in the structured background.

Fluorescence lifetime correlation spectroscopy for precise concentration detection in vivo by background subtraction

NASA Astrophysics Data System (ADS)

Gärtner, Maria; Mütze, Jörg; Ohrt, Thomas; Schwille, Petra

2009-07-01

In vivo studies of single molecule dynamics by means of Fluorescence correlation spectroscopy can suffer from high background. Fluorescence lifetime correlation spectroscopy provides a tool to distinguish between signal and unwanted contributions via lifetime separation. By studying the motion of the RNA-induced silencing complex (RISC) within two compartments of a human cell, the nucleus and the cytoplasm, we observed clear differences in concentration as well as mobility of the protein complex between those two locations. Especially in the nucleus, where the fluorescence signal is very weak, a correction for background is crucial to provide reliable results of the particle number. Utilizing the fluorescent lifetime of the different contributions, we show that it is possible to distinguish between the fluorescent signal and the autofluorescent background in vivo in a single measurement.

Illuminating the Background: Topics in Cosmic Microwave Background Polarization Research

NASA Astrophysics Data System (ADS)

Miller, Nathan J.

The cosmic microwave background provides a wealth of information about the origin and history of the universe. The statistics of the anisotropy and the polarization of the cosmic microwave background, among other things, can tell us about the distribution of matter, the redshift of reionization, and the nature of the primordial uctuations. From the lensing of cosmic microwave background due to intervening matter, we can extract information about neutrinos and the equation of state of dark energy. A measurement of the large angular scale B-mode polarization has been called the "smoking gun" of in ation, a theory that describes a possible early rapid expansion of the universe. The focus of current experiments is to measure this B-mode polarization, while several experiments, such as POLARBEAR, are also looking to measure the lensing of the cosmic microwave background. This dissertation will discuss several different topics in cosmic microwave background polarization research. I will make predictions for future experiments and I will also show analysis for two current experiments, POLARBEAR and BICEP. I will show how beam systematics affect the measurement of cosmological parameters and how well we must limit these systematics in order to get unbiased constraints on cosmological parameters for future experiments. I will discuss a novel way of using the temperature-polarization cross correlation to constrain the amount of inflationary gravitational waves. Through Markov Chain Monte Carlo methods, I will determine how well future experiments will be able to constrain the neutrino masses and their degeneracy parameters. I will show results from current data analysis and calibration being done on the Cedar Flat deployment for the POLARBEAR experiment which is currently being constructed in the Atacama desert in Chile. Finally, I will analyze the claim of detection of cosmological birefringence in the BICEP data and show that there is reason to believe it is due to

Influence of air and water temperature on fill characteristics curve

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lefevre, M.R.

1985-01-01

In a previous paper, the author discussed approximations of the Merkel Theory, as well as other approximations included in the CTI recommended method of calculation of the Demand curves. The paper concluded that the familiar difference of enthalpies, used as a cooling potential, which is the Merkel Theory, could continue to be used by simply adding a corrective multiplying factor derived from a direct comparison of the exact theory and the Merkel Theory. At the end of the paper the author briefly showed that the corrections to the Demand curve was only one part of the picture and that theremore » was also an influence of the temperatures of the Characteristic curve side. The object of this paper is to now review the influence of the air and water temperature on the Characteristic curve. This completes the work presented last year.« less

Background Underground at WIPP

NASA Astrophysics Data System (ADS)

Esch, Ernst-Ingo; Hime, A.; Bowles, T. J.

2001-04-01

Recent interest to establish a dedicated underground laboratory in the United States prompted an experimental program at to quantify the enviromental backgrounds underground at the Waste Isolation Pilot Plant (WIPP) in Carlsbad, New Mexico. An outline of this program is provided along with recent experimental data on the cosmic ray muon flux at the 650 meter level of WIPP. The implications of the cosmic ray muon and fast neutron background at WIPP will be discussed in the context of new generation, low background experiments envisioned in the future.

Reducing the background fluorescence in mice receiving fluorophore/inhibitor DNA duplexes.

PubMed

Liang, Minmin; Liu, Xinrong; Liu, Guozheng; Dou, Shuping; Cheng, Dengfeng; Liu, Yuxia; Rusckowski, Mary; Hnatowich, Donald J

2011-02-07

In principle, a DNA duplex consisting of an antisense fluorophore-conjugated major strand hybridized to a shorter complementary inhibitor-conjugated minor strand should provide fluorescence only in the tumor after intravenous administration if designed to remain intact except in the presence in tumor of its mRNA target. While we have obtained impressive tumor images in mice using this approach, there remains some background fluorescence. In this study, tissue homogenates of selected mouse organs were incubated with a test duplex and the kinetics of duplex dissociation in normal tissues were measured. In this manner we were able to identify the liver as the likely major source responsible for the duplex dissociation providing this fluorescence background. Thereafter liver homogenates were used to screen a series of duplex candidates with variable-length minor strands, and dissociation was measured by gel electrophoresis. The selected fluorophore/inhibitor duplex with improved stability displayed an insignificant (P > 0.05) background fluorescence after administration to SKH-1 normal mice and apparently without affecting target mRNA binding in vitro in cell culture or in vivo in tumor bearing mice.

Automatic phase aberration compensation for digital holographic microscopy based on deep learning background detection.

PubMed

Nguyen, Thanh; Bui, Vy; Lam, Van; Raub, Christopher B; Chang, Lin-Ching; Nehmetallah, George

2017-06-26

We propose a fully automatic technique to obtain aberration free quantitative phase imaging in digital holographic microscopy (DHM) based on deep learning. The traditional DHM solves the phase aberration compensation problem by manually detecting the background for quantitative measurement. This would be a drawback in real time implementation and for dynamic processes such as cell migration phenomena. A recent automatic aberration compensation approach using principle component analysis (PCA) in DHM avoids human intervention regardless of the cells' motion. However, it corrects spherical/elliptical aberration only and disregards the higher order aberrations. Traditional image segmentation techniques can be employed to spatially detect cell locations. Ideally, automatic image segmentation techniques make real time measurement possible. However, existing automatic unsupervised segmentation techniques have poor performance when applied to DHM phase images because of aberrations and speckle noise. In this paper, we propose a novel method that combines a supervised deep learning technique with convolutional neural network (CNN) and Zernike polynomial fitting (ZPF). The deep learning CNN is implemented to perform automatic background region detection that allows for ZPF to compute the self-conjugated phase to compensate for most aberrations.

Substance P Depolarizes Lamprey Spinal Cord Neurons by Inhibiting Background Potassium Channels.

PubMed

Thörn Pérez, Carolina; Hill, Russell H; Grillner, Sten

2015-01-01

Substance P is endogenously released in the adult lamprey spinal cord and accelerates the burst frequency of fictive locomotion. This is achieved by multiple effects on interneurons and motoneurons, including an attenuation of calcium currents, potentiation of NMDA currents and reduction of the reciprocal inhibition. While substance P also depolarizes spinal cord neurons, the underlying mechanism has not been resolved. Here we show that effects of substance P on background K+ channels are the main source for this depolarization. Hyperpolarizing steps induced inward currents during whole-cell voltage clamp that were reduced by substance P. These background K+ channels are pH sensitive and are selectively blocked by anandamide and AVE1231. These blockers counteracted the effect of substance P on these channels and the resting membrane potential depolarization in spinal cord neurons. Thus, we have shown now that substance P inhibits background K+ channels that in turn induce depolarization, which is likely to contribute to the frequency increase observed with substance P during fictive locomotion.

Dilatonic parallelizable NS-NS backgrounds

NASA Astrophysics Data System (ADS)

Kawano, Teruhiko; Yamaguchi, Satoshi

2003-08-01

We complete the classification of parallelizable NS-NS backgrounds in type II supergravity by adding the dilatonic case to the result of Figueroa-O'Farrill on the non-dilatonic case. We also study the supersymmetry of these parallelizable backgrounds. It is shown that all the dilatonic parallelizable backgrounds have sixteen supersymmetries.

Defeating a rare, aggressive form of skin cancer with avelumab | Center for Cancer Research

Cancer.gov

For the one-year anniversary of the FDA’s approval of avelumab, CCR Communications caught up with Richard Mulcahy to share his success story as a clinical trial patient. Mulcahy was diagnosed with Merkel cell carcinoma in September of 2016. It’s been over a year since he received his first treatment of avelumab as part of a clinical trial led by Isaac Brownell, M.D., Ph.D., formerly an Investigator in the Dermatology Branch, at the National Cancer Institute (NCI) in Bethesda. Read more...

Oxidative DNA damage background estimated by a system model of base excision repair

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sokhansanj, B A; Wilson, III, D M

Human DNA can be damaged by natural metabolism through free radical production. It has been suggested that the equilibrium between innate damage and cellular DNA repair results in an oxidative DNA damage background that potentially contributes to disease and aging. Efforts to quantitatively characterize the human oxidative DNA damage background level based on measuring 8-oxoguanine lesions as a biomarker have led to estimates varying over 3-4 orders of magnitude, depending on the method of measurement. We applied a previously developed and validated quantitative pathway model of human DNA base excision repair, integrating experimentally determined endogenous damage rates and model parametersmore » from multiple sources. Our estimates of at most 100 8-oxoguanine lesions per cell are consistent with the low end of data from biochemical and cell biology experiments, a result robust to model limitations and parameter variation. Our results show the power of quantitative system modeling to interpret composite experimental data and make biologically and physiologically relevant predictions for complex human DNA repair pathway mechanisms and capacity.« less

Unsupervised background-constrained tank segmentation of infrared images in complex background based on the Otsu method.

PubMed

Zhou, Yulong; Gao, Min; Fang, Dan; Zhang, Baoquan

2016-01-01

In an effort to implement fast and effective tank segmentation from infrared images in complex background, the threshold of the maximum between-class variance method (i.e., the Otsu method) is analyzed and the working mechanism of the Otsu method is discussed. Subsequently, a fast and effective method for tank segmentation from infrared images in complex background is proposed based on the Otsu method via constraining the complex background of the image. Considering the complexity of background, the original image is firstly divided into three classes of target region, middle background and lower background via maximizing the sum of their between-class variances. Then, the unsupervised background constraint is implemented based on the within-class variance of target region and hence the original image can be simplified. Finally, the Otsu method is applied to simplified image for threshold selection. Experimental results on a variety of tank infrared images (880 × 480 pixels) in complex background demonstrate that the proposed method enjoys better segmentation performance and even could be comparative with the manual segmentation in segmented results. In addition, its average running time is only 9.22 ms, implying the new method with good performance in real time processing.

Background Oriented Schlieren Implementation in a Jet-Surface Interaction Test

NASA Technical Reports Server (NTRS)

Clem, Michelle M.; Brown, Clifford A.; Fagan, Amy

2013-01-01

Many current and future aircraft designs rely on the wing or other aircraft surfaces to shield the engine noise from observers on the ground. However the available data regarding how a planar surface interacts with a jet to shield and/or enhance the jet noise are currently limited. Therefore, the Jet-Surface Interaction Tests supported by NASA's Fundamental Aeronautics Program's Fixed Wing Project were undertaken to supply experimental data covering a wide range of surface geometries and positions interacting with high-speed jet flows in order to support the development of noise prediction methods. Phase 1 of the Test was conducted in the Aero-Acoustic Propulsion Laboratory at NASA Glenn Research Center and consisted of validating noise prediction schemes for a round nozzle interacting with a planar surface. Phased array data and far-field acoustic data were collected for both the shielded and reflected sides of the surface. Phase 1 results showed that the broadband shock noise was greatly reduced by the surface when the jet was operated at the over-expanded condition, however, it was unclear whether this reduction was due a change in the shock cell structure by the surface. In the present study, Background Oriented Schlieren is implemented in Phase 2 of the Jet-Surface Interaction Tests to investigate whether the planar surface interacts with the high-speed jet ow to change the shock cell structure. Background Oriented Schlieren data are acquired for under-expanded, ideally-expanded, and over-expanded ow regimes for multiple axial and radial positions of the surface at three different plate lengths. These data are analyzed with far-field noise measurements to relate the shock cell structure to the broadband shock noise produced by a jet near a surface.

Mammalian touch catches up

PubMed Central

Walsh, Carolyn M.; Bautista, Diana M.; Lumpkin, Ellen A.

2015-01-01

An assortment of touch receptors innervate the skin and encode different tactile features of the environment. Compared with invertebrate touch and other sensory systems, our understanding of the molecular and cellular underpinnings of mammalian touch lags behind. Two recent breakthroughs have accelerated progress. First, an arsenal of cell-type-specific molecular markers allowed the functional and anatomical properties of sensory neurons to be matched, thereby unraveling a cellular code for touch. Such markers have also revealed key roles of non-neuronal cell types, such as Merkel cells and keratinocytes, in touch reception. Second, the discovery of Piezo genes as a new family of mechanically activated channels has fueled the discovery of molecular mechanisms that mediate and mechanotransduction in mammalian touch receptors. PMID:26100741

Background staining of visualization systems in immunohistochemistry: comparison of the Avidin-Biotin Complex system and the EnVision+ system.

PubMed

Vosse, Bettine A H; Seelentag, Walter; Bachmann, Astrid; Bosman, Fred T; Yan, Pu

2007-03-01

The aim of this study was to evaluate specific immunostaining and background staining in formalin-fixed, paraffin-embedded human tissues with the 2 most frequently used immunohistochemical detection systems, Avidin-Biotin-Peroxidase (ABC) and EnVision+. A series of fixed tissues, including breast, colon, kidney, larynx, liver, lung, ovary, pancreas, prostate, stomach, and tonsil, was used in the study. Three monoclonal antibodies, 1 against a nuclear antigen (Ki-67), 1 against a cytoplasmic antigen (cytokeratin), and 1 against a cytoplasmic and membrane-associated antigen and a polyclonal antibody against a nuclear and cytoplasmic antigen (S-100) were selected for these studies. When the ABC system was applied, immunostaining was performed with and without blocking of endogenous avidin-binding activity. The intensity of specific immunostaining and the percentage of stained cells were comparable for the 2 detection systems. The use of ABC caused widespread cytoplasmic and rare nuclear background staining in a variety of normal and tumor cells. A very strong background staining was observed in colon, gastric mucosa, liver, and kidney. Blocking avidin-binding capacity reduced background staining, but complete blocking was difficult to attain. With the EnVision+ system no background staining occurred. Given the efficiency of the detection, equal for both systems or higher with EnVision+, and the significant background problem with ABC, we advocate the routine use of the EnVision+ system.

Detecting infrared luminescence and non-chemical signaling of living cells: single cell mid-IR spectroscopy in cryogenic environments

NASA Astrophysics Data System (ADS)

Pereverzev, Sergey

2017-02-01

Many life-relevant interaction energies are in IR range, and it is reasonable to believe that some biochemical reactions inside cells can results in emission of IR photons. Cells can use this emission for non-chemical and non-electrical signaling. Detecting weak infrared radiation from live cells is complicated because of strong thermal radiation background and absorption of radiation by tissues. A microfluidic device with live cells inside a vacuum cryogenic environment should suppress this background, and thereby permit observation of live cell auto-luminescence or signaling in the IR regime. One can make IR-transparent windows not emitting in this range, so only the cell and a small amount of liquid around it will emit infrared radiation. Currently mid-IR spectroscopy of single cells requires the use of a synchrotron source to measure absorption or reflection spectra. Decreasing of thermal radiation background will allow absorption and reflection spectroscopy of cells without using synchrotron light. Moreover, cell auto-luminescence can be directly measured. The complete absence of thermal background radiation for cryogenically cooled samples allows the use IR photon-sensitive detectors and obtaining single molecule sensitivity in IR photo-luminescence measurements. Due to low photon energies, photo-luminescence measurements will be non-distractive for pressures samples. The technique described here is based upon US patent 9366574.

Germline competence of mouse ES and iPS cell lines: Chimera technologies and genetic background.

PubMed

Carstea, Ana Claudia; Pirity, Melinda K; Dinnyes, Andras

2009-12-31

In mice, gene targeting by homologous recombination continues to play an essential role in the understanding of functional genomics. This strategy allows precise location of the site of transgene integration and is most commonly used to ablate gene expression ("knock-out"), or to introduce mutant or modified alleles at the locus of interest ("knock-in"). The efficacy of producing live, transgenic mice challenges our understanding of this complex process, and of the factors which influence germline competence of embryonic stem cell lines. Increasingly, evidence indicates that culture conditions and in vitro manipulation can affect the germline-competence of Embryonic Stem cell (ES cell) lines by accumulation of chromosome abnormalities and/or epigenetic alterations of the ES cell genome. The effectiveness of ES cell derivation is greatly strain-dependent and it may also influence the germline transmission capability. Recent technical improvements in the production of germline chimeras have been focused on means of generating ES cells lines with a higher germline potential. There are a number of options for generating chimeras from ES cells (ES chimera mice); however, each method has its advantages and disadvantages. Recent developments in induced pluripotent stem (iPS) cell technology have opened new avenues for generation of animals from genetically modified somatic cells by means of chimera technologies. The aim of this review is to give a brief account of how the factors mentioned above are influencing the germline transmission capacity and the developmental potential of mouse pluripotent stem cell lines. The most recent methods for generating specifically ES and iPS chimera mice, including the advantages and disadvantages of each method are also discussed.

Electron transfer to nitrogenase in different genomic and metabolic backgrounds.

PubMed

Poudel, Saroj; Colman, Daniel R; Fixen, Kathryn R; Ledbetter, Rhesa N; Zheng, Yanning; Pence, Natasha; Seefeldt, Lance C; Peters, John W; Harwood, Caroline S; Boyd, Eric S

2018-02-26

Nitrogenase catalyzes the reduction of dinitrogen (N 2 ) using low potential electrons from ferredoxin (Fd) or flavodoxin (Fld) through an ATP dependent process. Since its emergence in an anaerobic chemoautotroph, this oxygen (O 2 ) sensitive enzyme complex has evolved to operate in a variety of genomic and metabolic backgrounds including those of aerobes, anaerobes, chemotrophs, and phototrophs. However, whether pathways of electron delivery to nitrogenase are influenced by these different metabolic backgrounds is not well understood. Here, we report the distribution of homologs of Fds, Flds, and Fd/Fld-reducing enzymes in 359 genomes of putative N 2 fixers (diazotrophs). Six distinct lineages of nitrogenase were identified and their distributions largely corresponded to differences in the host cells' ability to integrate O 2 or light into energy metabolism. Predicted pathways of electron transfer to nitrogenase in aerobes, facultative anaerobes, and phototrophs varied from those in anaerobes at the level of Fds/Flds used to reduce nitrogenase, the enzymes that generate reduced Fds/Flds, and the putative substrates of these enzymes. Proteins that putatively reduce Fd with hydrogen or pyruvate were enriched in anaerobes, while those that reduce Fd with NADH/NADPH were enriched in aerobes, facultative anaerobes, and anoxygenic phototrophs. The energy metabolism of aerobic, facultatively anaerobic, and anoxygenic phototrophic diazotrophs often yields reduced NADH/NADPH that is not sufficiently reduced to drive N 2 reduction. At least two mechanisms have been acquired by these taxa to overcome this limitation and to generate electrons with potentials capable of reducing Fd. These include the bifurcation of electrons or the coupling of Fd reduction to reverse ion translocation. IMPORTANCE Nitrogen fixation supplies fixed nitrogen to cells from a variety of genomic and metabolic backgrounds including those of aerobes, facultative anaerobes, chemotrophs, and phototrophs

Low Background Counting at LBNL

DOE PAGES

Smith, A. R.; Thomas, K. J.; Norman, E. B.; ...

2015-03-24

The Low Background Facility (LBF) at Lawrence Berkeley National Laboratory in Berkeley, California provides low background gamma spectroscopy services to a wide array of experiments and projects. The analysis of samples takes place within two unique facilities; locally within a carefully-constructed, low background cave and remotely at an underground location that historically has operated underground in Oroville, CA, but has recently been relocated to the Sanford Underground Research Facility (SURF) in Lead, SD. These facilities provide a variety of gamma spectroscopy services to low background experiments primarily in the form of passive material screening for primordial radioisotopes (U, Th, K)more » or common cosmogenic/anthropogenic products, as well as active screening via Neutron Activation Analysis for specific applications. The LBF also provides hosting services for general R&D testing in low background environments on the surface or underground for background testing of detector systems or similar prototyping. A general overview of the facilities, services, and sensitivities is presented. Recent activities and upgrades will also be presented, such as the completion of a 3π anticoincidence shield at the surface station and environmental monitoring of Fukushima fallout. The LBF is open to any users for counting services or collaboration on a wide variety of experiments and projects.« less

Substance P Depolarizes Lamprey Spinal Cord Neurons by Inhibiting Background Potassium Channels

PubMed Central

Thörn Pérez, Carolina; Hill, Russell H.; Grillner, Sten

2015-01-01

Substance P is endogenously released in the adult lamprey spinal cord and accelerates the burst frequency of fictive locomotion. This is achieved by multiple effects on interneurons and motoneurons, including an attenuation of calcium currents, potentiation of NMDA currents and reduction of the reciprocal inhibition. While substance P also depolarizes spinal cord neurons, the underlying mechanism has not been resolved. Here we show that effects of substance P on background K+ channels are the main source for this depolarization. Hyperpolarizing steps induced inward currents during whole-cell voltage clamp that were reduced by substance P. These background K+ channels are pH sensitive and are selectively blocked by anandamide and AVE1231. These blockers counteracted the effect of substance P on these channels and the resting membrane potential depolarization in spinal cord neurons. Thus, we have shown now that substance P inhibits background K+ channels that in turn induce depolarization, which is likely to contribute to the frequency increase observed with substance P during fictive locomotion. PMID:26197458

Chromosome aberrations in peripheral blood lymphocytes of individuals living in high background radiation areas of Ramsar, Iran.

PubMed

Zakeri, F; Rajabpour, M R; Haeri, S A; Kanda, R; Hayata, I; Nakamura, S; Sugahara, T; Ahmadpour, M J

2011-11-01

In order to investigate the biological effects of exposure to low-dose radiation and to assess the dose-effect relationship in residents of high background radiation areas (HBRAs) of Ramsar, cytogenetic investigation of unstable-type aberrations was performed in 15 healthy elderly women in a HBRA of Ramsar, Talesh mahalle, and in 10 elderly women living in a nearby control area with normal background radiation. In total, 77,714 cells were analyzed; 48,819 cells in HBRA residents and 28,895 cells in controls. On average, 3,108 cells per subject were analyzed (range 1,475-5,007 cells). Significant differences were found in the frequency of dicentric plus centric rings in 100 cells (0.207 ± 0.103 vs. 0.047 ± 0.027, p < 0.0005), total chromosome-type aberrations per 100 cells (0.86 ± 0.44 vs. 0.23 ± 0.17, p < 0.0005), and chromatid-type aberrations per 100 cells (3.31 ± 2.01 vs. 1.66 ± 0.63, p = 0.01) by the Mann-Whitney U test between HBRA and the control, respectively. Using chromosomal aberrations as the main endpoint to assess the dose-effect relationship in residents of HBRAs in Ramsar, no positive correlation was found between the frequency of dicentric plus centric ring aberrations and the cumulative dose of the inhabitants estimated by direct individual dosimetry; however, obvious trends of increase with age appeared in the control group. Based on these results, individuals residing in HBRAs of Ramsar have an increased frequency of detectable abnormalities in unstable aberrations.

THE HIGH BACKGROUND RADIATION AREA IN RAMSAR IRAN: GEOLOGY, NORM, BIOLOGY, LNT, AND POSSIBLE REGULATORY FUN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karam, P. A.

2002-02-25

The city of Ramsar Iran hosts some of the highest natural radiation levels on earth, and over 2000 people are exposed to radiation doses ranging from 1 to 26 rem per year. Curiously, inhabitants of this region seem to have no greater incidence of cancer than those in neighboring areas of normal background radiation levels, and preliminary studies suggest their blood cells experience fewer induced chromosomal abnormalities when exposed to 150 rem ''challenge'' doses of radiation than do the blood cells of their neighbors. This paper will briefly describe the unique geology that gives Ramsar its extraordinarily high background radiationmore » levels. It will then summarize the studies performed to date and will conclude by suggesting ways to incorporate these findings (if they are borne out by further testing) into future radiation protection standards.« less

Dendritic Cells Program Non-Immunogenic Prostate-Specific T Cell Responses Beginning at Early Stages of Prostate Tumorigenesis

PubMed Central

Mihalyo, Marianne A.; Hagymasi, Adam T.; Slaiby, Aaron M.; Nevius, Erin E.; Adler, Adam J.

2010-01-01

BACKGROUND Prostate cancer promotes the development of T cell tolerance towards prostatic antigens, potentially limiting the efficacy of prostate cancer vaccines targeting these antigens. Here, we sought to determine the stage of disease progression when T cell tolerance develops, as well as the role of steady state dendritic cells (DC) and CD4+CD25+ T regulatory cells (Tregs) in programming tolerance. METHODS The response of naïve HA-specific CD4+ T cells were analyzed following adoptive transfer into Pro-HA × TRAMP transgenic mice harboring variably-staged HA-expressing prostate tumors on two genetic backgrounds that display different patterns and kinetics of tumorigenesis. The role of DC and Tregs in programming HA-specific CD4 cell responses were assessed via depletion. RESULTS HA-specific CD4 cells underwent non-immunogenic responses at all stages of tumorigenesis in both genetic backgrounds. These responses were completely dependent on DC, but not appreciably influenced by Tregs. CONCLUSIONS These results suggest that tolerogenicity is an early and general property of prostate tumors. PMID:17221844

Background Light Bluer Than Expected

NASA Image and Video Library

2014-11-06

This plot shows data from the Cosmic Infrared Background Experiment, or CIBER, rockets launched in 2010 and 2012. The experiment measures a diffuse glow of infrared light in the sky, known as the cosmic infrared background.

The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival

NASA Technical Reports Server (NTRS)

Wallis, Deeann; Hamblen, Melanie; Zhou, Yi; Venken, Koen J T.; Schumacher, Armin; Grimes, H. Leighton; Zoghbi, Huda Y.; Orkin, Stuart H.; Bellen, Hugo J.

2003-01-01

Gfi1 was first identified as causing interleukin 2-independent growth in T cells and lymphomagenesis in mice. Much work has shown that Gfi1 and Gfi1b, a second mouse homolog, play pivotal roles in blood cell lineage differentiation. However, neither Gfi1 nor Gfi1b has been implicated in nervous system development, even though their invertebrate homologues, senseless in Drosophila and pag-3 in C. elegans are expressed and required in the nervous system. We show that Gfi1 mRNA is expressed in many areas that give rise to neuronal cells during embryonic development in mouse, and that Gfi1 protein has a more restricted expression pattern. By E12.5 Gfi1 mRNA is expressed in both the CNS and PNS as well as in many sensory epithelia including the developing inner ear epithelia. At later developmental stages, Gfi1 expression in the ear is refined to the hair cells and neurons throughout the inner ear. Gfi1 protein is expressed in a more restricted pattern in specialized sensory cells of the PNS, including the eye, presumptive Merkel cells, the lung and hair cells of the inner ear. Gfi1 mutant mice display behavioral defects that are consistent with inner ear anomalies, as they are ataxic, circle, display head tilting behavior and do not respond to noise. They have a unique inner ear phenotype in that the vestibular and cochlear hair cells are differentially affected. Although Gfi1-deficient mice initially specify inner ear hair cells, these hair cells are disorganized in both the vestibule and cochlea. The outer hair cells of the cochlea are improperly innervated and express neuronal markers that are not normally expressed in these cells. Furthermore, Gfi1 mutant mice lose all cochlear hair cells just prior to and soon after birth through apoptosis. Finally, by five months of age there is also a dramatic reduction in the number of cochlear neurons. Hence, Gfi1 is expressed in the developing nervous system, is required for inner ear hair cell differentiation, and its loss

Transcriptome analysis reveals a stress response of Shewanella oneidensis deprived of background levels of ionizing radiation

PubMed Central

Li, Xiaoping; Schilkey, Faye; Smith, Geoffrey B.

2018-01-01

Natural ionizing background radiation has exerted a constant pressure on organisms since the first forms of life appeared on Earth, so that cells have developed molecular mechanisms to avoid or repair damages caused directly by radiation or indirectly by radiation-induced reactive oxygen species (ROS). In the present study, we investigated the transcriptional effect of depriving Shewanella oneidensis cultures of background levels of radiation by growing the cells in a mine 655 m underground, thus reducing the dose rate from 72.1 to 0.9 nGy h-1 from control to treatment, respectively. RNASeq transcriptome analysis showed the differential expression of 4.6 and 7.6% of the S. oneidensis genome during early- and late-exponential phases of growth, respectively. The greatest change observed in the treatment was the downregulation of ribosomal proteins (21% of all annotated ribosomal protein genes during early- and 14% during late-exponential) and tRNA genes (14% of all annotated tRNA genes in early-exponential), indicating a marked decrease in protein translation. Other significant changes were the upregulation of membrane transporters, implying an increase in the traffic of substrates across the cell membrane, as well as the up and downregulation of genes related to respiration, which could be interpreted as a response to insufficient oxidants in the cells. In other reports, there is evidence in multiple species that some ROS not just lead to oxidative stress, but act as signaling molecules to control cellular metabolism at the transcriptional level. Consistent with these reports, several genes involved in the metabolism of carbon and biosynthesis of amino acids were also regulated, lending support to the idea of a wide metabolic response. Our results indicate that S. oneidensis is sensitive to the withdrawal of background levels of ionizing radiation and suggest that a transcriptional response is required to maintain homeostasis and retain normal growth. PMID:29768440

The background in the $$0\

DOE PAGES

Agostini, M.; Allardt, M.; Andreotti, E.; ...

2014-04-04

The GERmanium Detector Array (Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta (0νββ) decay of 76 Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the Q ββ value of the decay. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around Q ββ. The main parameters needed for the 0νββ analysis are described. A background model was developed to describe the observed energy spectrum. The model contains severalmore » contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around Qββ with a background index ranging from 17.6 to 23.8 × 10 -3 cts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at Q ββ is dominated by close sources, mainly due to 42 K, 214 Bi, 228 60 Co and α emitting isotopes from the 226 Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known γ peaks, the energy spectrum can be fitted in an energy range of 200 keV around Q ββ with a constant background. This gives a background index consistent with the full model and uncertainties of the same size.« less

A Flexible Cosmic Ultraviolet Background Model

NASA Astrophysics Data System (ADS)

McQuinn, Matthew

2016-10-01

HST studies of the IGM, of the CGM, and of reionization-era galaxies are all aided by ionizing background models, which are a critical input in modeling the ionization state of diffuse, 10^4 K gas. The ionization state in turn enables the determination of densities and sizes of absorbing clouds and, when applied to the Ly-a forest, the global ionizing emissivity of sources. Unfortunately, studies that use these background models have no way of gauging the amount of uncertainty in the adopted model other than to recompute their results using previous background models with outdated observational inputs. As of yet there has been no systematic study of uncertainties in the background model and there unfortunately is no publicly available ultraviolet background code. A public code would enable users to update the calculation with the latest observational constraints, and it would allow users to experiment with varying the background model's assumptions regarding emissions and absorptions. We propose to develop a publicly available ionizing background code and, as an initial application, quantify the level of uncertainty in the ionizing background spectrum across cosmic time. As the background model improves, so does our understanding of (1) the sources that dominate ionizing emissions across cosmic time and (2) the properties of diffuse gas in the circumgalactic medium, the WHIM, and the Ly-a forest. HST is the primary telescope for studying both the highest redshift galaxies and low-redshift diffuse gas. The proposed program would benefit HST studies of the Universe at z 0 all the way up to z = 10, including of high-z galaxies observed in the HST Frontier Fields.

BiFCROS: A Low-Background Fluorescence Repressor Operator System for Labeling of Genomic Loci.

PubMed

Milbredt, Sarah; Waldminghaus, Torsten

2017-06-07

Fluorescence-based methods are widely used to analyze elementary cell processes such as DNA replication or chromosomal folding and segregation. Labeling DNA with a fluorescent protein allows the visualization of its temporal and spatial organization. One popular approach is FROS (fluorescence repressor operator system). This method specifically labels DNA in vivo through binding of a fusion of a fluorescent protein and a repressor protein to an operator array, which contains numerous copies of the repressor binding site integrated into the genomic site of interest. Bound fluorescent proteins are then visible as foci in microscopic analyses and can be distinguished from the background fluorescence caused by unbound fusion proteins. Even though this method is widely used, no attempt has been made so far to decrease the background fluorescence to facilitate analysis of the actual signal of interest. Here, we present a new method that greatly reduces the background signal of FROS. BiFCROS (Bimolecular Fluorescence Complementation and Repressor Operator System) is based on fusions of repressor proteins to halves of a split fluorescent protein. Binding to a hybrid FROS array results in fluorescence signals due to bimolecular fluorescence complementation. Only proteins bound to the hybrid FROS array fluoresce, greatly improving the signal to noise ratio compared to conventional FROS. We present the development of BiFCROS and discuss its potential to be used as a fast and single-cell readout for copy numbers of genetic loci. Copyright © 2017 Milbredt and Waldminghaus.

BiFCROS: A Low-Background Fluorescence Repressor Operator System for Labeling of Genomic Loci

PubMed Central

Milbredt, Sarah; Waldminghaus, Torsten

2017-01-01

Fluorescence-based methods are widely used to analyze elementary cell processes such as DNA replication or chromosomal folding and segregation. Labeling DNA with a fluorescent protein allows the visualization of its temporal and spatial organization. One popular approach is FROS (fluorescence repressor operator system). This method specifically labels DNA in vivo through binding of a fusion of a fluorescent protein and a repressor protein to an operator array, which contains numerous copies of the repressor binding site integrated into the genomic site of interest. Bound fluorescent proteins are then visible as foci in microscopic analyses and can be distinguished from the background fluorescence caused by unbound fusion proteins. Even though this method is widely used, no attempt has been made so far to decrease the background fluorescence to facilitate analysis of the actual signal of interest. Here, we present a new method that greatly reduces the background signal of FROS. BiFCROS (Bimolecular Fluorescence Complementation and Repressor Operator System) is based on fusions of repressor proteins to halves of a split fluorescent protein. Binding to a hybrid FROS array results in fluorescence signals due to bimolecular fluorescence complementation. Only proteins bound to the hybrid FROS array fluoresce, greatly improving the signal to noise ratio compared to conventional FROS. We present the development of BiFCROS and discuss its potential to be used as a fast and single-cell readout for copy numbers of genetic loci. PMID:28450375

47 CFR 215.1 - Background.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

40 CFR 11.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Background. 11.2 Section 11.2 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL SECURITY CLASSIFICATION REGULATIONS PURSUANT TO EXECUTIVE ORDER 11652 § 11.2 Background. While the Environmental Protection Agency does not...

Extragalactic background light measurements and applications.

PubMed

Cooray, Asantha

2016-03-01

This review covers the measurements related to the extragalactic background light intensity from γ-rays to radio in the electromagnetic spectrum over 20 decades in wavelength. The cosmic microwave background (CMB) remains the best measured spectrum with an accuracy better than 1%. The measurements related to the cosmic optical background (COB), centred at 1 μm, are impacted by the large zodiacal light associated with interplanetary dust in the inner Solar System. The best measurements of COB come from an indirect technique involving γ-ray spectra of bright blazars with an absorption feature resulting from pair-production off of COB photons. The cosmic infrared background (CIB) peaking at around 100 μm established an energetically important background with an intensity comparable to the optical background. This discovery paved the way for large aperture far-infrared and sub-millimetre observations resulting in the discovery of dusty, starbursting galaxies. Their role in galaxy formation and evolution remains an active area of research in modern-day astrophysics. The extreme UV (EUV) background remains mostly unexplored and will be a challenge to measure due to the high Galactic background and absorption of extragalactic photons by the intergalactic medium at these EUV/soft X-ray energies. We also summarize our understanding of the spatial anisotropies and angular power spectra of intensity fluctuations. We motivate a precise direct measurement of the COB between 0.1 and 5 μm using a small aperture telescope observing either from the outer Solar System, at distances of 5 AU or more, or out of the ecliptic plane. Other future applications include improving our understanding of the background at TeV energies and spectral distortions of CMB and CIB.

Extragalactic background light measurements and applications

PubMed Central

Cooray, Asantha

2016-01-01

This review covers the measurements related to the extragalactic background light intensity from γ-rays to radio in the electromagnetic spectrum over 20 decades in wavelength. The cosmic microwave background (CMB) remains the best measured spectrum with an accuracy better than 1%. The measurements related to the cosmic optical background (COB), centred at 1 μm, are impacted by the large zodiacal light associated with interplanetary dust in the inner Solar System. The best measurements of COB come from an indirect technique involving γ-ray spectra of bright blazars with an absorption feature resulting from pair-production off of COB photons. The cosmic infrared background (CIB) peaking at around 100 μm established an energetically important background with an intensity comparable to the optical background. This discovery paved the way for large aperture far-infrared and sub-millimetre observations resulting in the discovery of dusty, starbursting galaxies. Their role in galaxy formation and evolution remains an active area of research in modern-day astrophysics. The extreme UV (EUV) background remains mostly unexplored and will be a challenge to measure due to the high Galactic background and absorption of extragalactic photons by the intergalactic medium at these EUV/soft X-ray energies. We also summarize our understanding of the spatial anisotropies and angular power spectra of intensity fluctuations. We motivate a precise direct measurement of the COB between 0.1 and 5 μm using a small aperture telescope observing either from the outer Solar System, at distances of 5 AU or more, or out of the ecliptic plane. Other future applications include improving our understanding of the background at TeV energies and spectral distortions of CMB and CIB. PMID:27069645

A ‘synthetic-sickness’ screen for senescence re-engagement targets in mutant cancer backgrounds

PubMed Central

Godwin, Lauren S.; Bilsland, Alan E.; Stevenson, Katrina H.; Moore, Jon D.; Wiggins, Ceri M.; Collinson, Rebecca S.; Mudd, Clare; Sadaie, Mahito; Bennett, Dorothy C.; Torrance, Christopher J.; Keith, W. Nicol

2017-01-01

Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAβGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments. PMID:28806777

Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States.

PubMed

Lehrer, Steven; Rheinstein, Peter H; Rosenzweig, Kenneth E

2017-01-01

Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD). Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association. Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p < 0.001), age (β= 0.231, p < 0.001), hypertension (β= 0.155, p < 0.001), and diabetes (β= 0.353, p < 0.001). Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor.

47 CFR 201.0 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 28 Judicial Administration 1 2011-07-01 2011-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 1 2014-07-01 2014-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 1 2013-07-01 2013-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 1 2012-07-01 2012-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 2 2014-10-01 2014-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 2 2013-10-01 2013-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 2 2011-10-01 2011-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

Spectral characterization of natural backgrounds

NASA Astrophysics Data System (ADS)

Winkelmann, Max

2017-10-01

As the distribution and use of hyperspectral sensors is constantly increasing, the exploitation of spectral features is a threat for camouflaged objects. To improve camouflage materials at first the spectral behavior of backgrounds has to be known to adjust and optimize the spectral reflectance of camouflage materials. In an international effort, the NATO CSO working group SCI-295 "Development of Methods for Measurements and Evaluation of Natural Background EO Signatures" is developing a method how this characterization of backgrounds has to be done. It is obvious that the spectral characterization of a background will be quite an effort. To compare and exchange data internationally the measurements will have to be done in a similar way. To test and further improve this method an international field trial has been performed in Storkow, Germany. In the following we present first impressions and lessons learned from this field campaign and describe the data that has been measured.

Reducing background contributions in fluorescence fluctuation time-traces for single-molecule measurements in solution.

PubMed

Földes-Papp, Zeno; Liao, Shih-Chu Jeff; You, Tiefeng; Barbieri, Beniamino

2009-08-01

We first report on the development of new microscope means that reduce background contributions in fluorescence fluctuation methods: i) excitation shutter, ii) electronic switches, and iii) early and late time-gating. The elements allow for measuring molecules at low analyte concentrations. We first found conditions of early and late time-gating with time-correlated single-photon counting that made the fluorescence signal as bright as possible compared with the fluctuations in the background count rate in a diffraction-limited optical set-up. We measured about a 140-fold increase in the amplitude of autocorrelated fluorescence fluctuations at the lowest analyte concentration of about 15 pM, which gave a signal-to-background advantage of more than two-orders of magnitude. The results of this original article pave the way for single-molecule detection in solution and in live cells without immobilization or hydrodynamic/electrokinetic focusing at longer observation times than are currently available.

Sensitivity of complex cells in cat striate cortex to relative motion.

PubMed

Hammond, P; Smith, A T

1984-06-03

Sensitivity of 95 complex cells to relative motion between oriented bars and textured backgrounds was investigated monocularly in the striate cortex of lightly anesthetized, paralyzed cats. Cells were classified conventionally. Those in deep layers were either direction-selective, or strongly preferred one direction of motion, and responded well to background texture motion alone: backgrounds potentiated the response to the bar in the cell's preferred direction when moved in phase, or in the opposite direction when moved in antiphase; other combinations depressed the level of response compared with that for the bar alone. The majority of direction-selective or strongly direction-biased cells in superficial layers behaved similarly. The most interesting superficial-layer cells were bidirectional or weakly direction-biased, and recorded closer to the cortical surface than the direction-selective neurons. A majority showed preference for relative motion, some for antiphase, others for in-phase motion, regardless of the absolute direction of motion across the receptive field, which could not be accounted for on the basis of separate responses to bars and backgrounds alone. Three of the superficial-layer direction-selective cells also showed preference for antiphase relative motion. In a few complex cells from superficial laminae, backgrounds were either without influence on responses to oriented stimuli, or purely suppressive. Visual backgrounds against which objects are perceived are usually neither featureless nor motionless: the results suggest that most complex cells in striate cortex are sensitive to the context in which objects are seen and susceptible to relationships between objects and their backgrounds in relative motion.

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 6 2012-07-01 2012-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 6 2011-07-01 2011-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 6 2014-07-01 2014-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 3.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Background. 3.2 Section 3.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE ACQUISITION TRANSACTIONS OTHER THAN CONTRACTS, GRANTS, OR COOPERATIVE AGREEMENTS FOR PROTOTYPE PROJECTS § 3.2 Background. “Other transactions” is the...

Novel statistical framework to identify differentially expressed genes allowing transcriptomic background differences.

PubMed

Ling, Zhi-Qiang; Wang, Yi; Mukaisho, Kenichi; Hattori, Takanori; Tatsuta, Takeshi; Ge, Ming-Hua; Jin, Li; Mao, Wei-Min; Sugihara, Hiroyuki

2010-06-01

Tests of differentially expressed genes (DEGs) from microarray experiments are based on the null hypothesis that genes that are irrelevant to the phenotype/stimulus are expressed equally in the target and control samples. However, this strict hypothesis is not always true, as there can be several transcriptomic background differences between target and control samples, including different cell/tissue types, different cell cycle stages and different biological donors. These differences lead to increased false positives, which have little biological/medical significance. In this article, we propose a statistical framework to identify DEGs between target and control samples from expression microarray data allowing transcriptomic background differences between these samples by introducing a modified null hypothesis that the gene expression background difference is normally distributed. We use an iterative procedure to perform robust estimation of the null hypothesis and identify DEGs as outliers. We evaluated our method using our own triplicate microarray experiment, followed by validations with reverse transcription-polymerase chain reaction (RT-PCR) and on the MicroArray Quality Control dataset. The evaluations suggest that our technique (i) results in less false positive and false negative results, as measured by the degree of agreement with RT-PCR of the same samples, (ii) can be applied to different microarray platforms and results in better reproducibility as measured by the degree of DEG identification concordance both intra- and inter-platforms and (iii) can be applied efficiently with only a few microarray replicates. Based on these evaluations, we propose that this method not only identifies more reliable and biologically/medically significant DEG, but also reduces the power-cost tradeoff problem in the microarray field. Source code and binaries freely available for download at http://comonca.org.cn/fdca/resources/softwares/deg.zip.

32 CFR 763.3 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 763.3 Section 763.3 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY ISLANDS UNDER NAVY JURISDICTION RULES GOVERNING PUBLIC ACCESS Entry Regulations for Kaho'olawe Island, Hawaii § 763.3 Background. (a) Kaho'olawe Island...

32 CFR 735.2 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Background. 735.2 Section 735.2 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL REPORTING BIRTHS AND DEATHS IN COOPERATION WITH OTHER AGENCIES § 735.2 Background. For Armed Forces members and their dependents on duty overseas...

32 CFR 735.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 735.2 Section 735.2 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL REPORTING BIRTHS AND DEATHS IN COOPERATION WITH OTHER AGENCIES § 735.2 Background. For Armed Forces members and their dependents on duty overseas...

Aircraft and background noise annoyance effects

NASA Technical Reports Server (NTRS)

Willshire, K. F.

1984-01-01

To investigate annoyance of multiple noise sources, two experiments were conducted. The first experiment, which used 48 subjects, was designed to establish annoyance-noise level functions for three community noise sources presented individually: jet aircraft flyovers, air conditioner, and traffic. The second experiment, which used 216 subjects, investigated the effects of background noise on aircraft annoyance as a function of noise level and spectrum shape; and the differences between overall, aircraft, and background noise annoyance. In both experiments, rated annoyance was the dependent measure. Results indicate that the slope of the linear relationship between annoyance and noise level for traffic is significantly different from that of flyover and air conditioner noise and that further research was justified to determine the influence of the two background noises on overall, aircraft, and background noise annoyance (e.g., experiment two). In experiment two, total noise exposure, signal-to-noise ratio, and background source type were found to have effects on all three types of annoyance. Thus, both signal-to-noise ratio, and the background source must be considered when trying to determine community response to combined noise sources.

32 CFR 732.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 5 2013-07-01 2013-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 5 2014-07-01 2014-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 5 2012-07-01 2012-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

12 CFR 408.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Background. 408.1 Section 408.1 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED STATES PROCEDURES FOR COMPLIANCE WITH THE NATIONAL ENVIRONMENTAL POLICY ACT General § 408.1 Background. (a) The National Environmental Policy Act (NEPA) of 1969 (42 U.S.C...

Background of SAM atom-fraction profiles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ernst, Frank

Atom-fraction profiles acquired by SAM (scanning Auger microprobe) have important applications, e.g. in the context of alloy surface engineering by infusion of carbon or nitrogen through the alloy surface. However, such profiles often exhibit an artifact in form of a background with a level that anti-correlates with the local atom fraction. This article presents a theory explaining this phenomenon as a consequence of the way in which random noise in the spectrum propagates into the discretized differentiated spectrum that is used for quantification. The resulting model of “energy channel statistics” leads to a useful semi-quantitative background reduction procedure, which ismore » validated by applying it to simulated data. Subsequently, the procedure is applied to an example of experimental SAM data. The analysis leads to conclusions regarding optimum experimental acquisition conditions. The proposed method of background reduction is based on general principles and should be useful for a broad variety of applications. - Highlights: • Atom-fraction–depth profiles of carbon measured by scanning Auger microprobe • Strong background, varies with local carbon concentration. • Needs correction e.g. for quantitative comparison with simulations • Quantitative theory explains background. • Provides background removal strategy and practical advice for acquisition.« less

The background in the experiment Gerda

NASA Astrophysics Data System (ADS)

Agostini, M.; Allardt, M.; Andreotti, E.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Barnabé Heider, M.; Barros, N.; Baudis, L.; Bauer, C.; Becerici-Schmidt, N.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Brudanin, V.; Brugnera, R.; Budjáš, D.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; Cossavella, F.; Demidova, E. V.; Domula, A.; Egorov, V.; Falkenstein, R.; Ferella, A.; Freund, K.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gotti, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Guthikonda, K. K.; Hampel, W.; Hegai, A.; Heisel, M.; Hemmer, S.; Heusser, G.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Klimenko, A.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Liu, X.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Machado, A. A.; Majorovits, B.; Maneschg, W.; Nemchenok, I.; Nisi, S.; O'Shaughnessy, C.; Palioselitis, D.; Pandola, L.; Pelczar, K.; Pessina, G.; Pullia, A.; Riboldi, S.; Sada, C.; Salathe, M.; Schmitt, C.; Schreiner, J.; Schulz, O.; Schwingenheuer, B.; Schönert, S.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Strecker, H.; Tarka, M.; Ur, C. A.; Vasenko, A. A.; Volynets, O.; von Sturm, K.; Wagner, V.; Walter, M.; Wegmann, A.; Wester, T.; Wojcik, M.; Yanovich, E.; Zavarise, P.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2014-04-01

The GERmanium Detector Array ( Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta () decay of Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the value of the decay. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around . The main parameters needed for the analysis are described. A background model was developed to describe the observed energy spectrum. The model contains several contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around with a background index ranging from 17.6 to 23.8 cts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at is dominated by close sources, mainly due to K, Bi, Th, Co and emitting isotopes from the Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known peaks, the energy spectrum can be fitted in an energy range of 200 keV around with a constant background. This gives a background index consistent with the full model and uncertainties of the same size.

The cosmic microwave background

NASA Technical Reports Server (NTRS)

Silk, Joseph

1991-01-01

Recent limits on spectral distortions and angular anisotropies in the cosmic microwave background are reviewed. The various backgrounds are described, and the theoretical implications are assessed. Constraints on inflationary cosmology dominated by cold dark matter (CDM) and on open cosmological models dominated by baryonic dark matter (BDM), with, respectively, primordial random phase scale-invariant curvature fluctuations or non-gaussian isocurvature fluctuations are described. More exotic theories are addressed, and I conclude with the 'bottom line': what theorists expect experimentalists to be measuring within the next two to three years without having to abandon their most cherished theories.

Characterizing the Background Corona with SDO/AIA

NASA Technical Reports Server (NTRS)

Napier, Kate; Alexander, Caroline; Winebarger, Amy

2014-01-01

Characterizing the nature of the solar coronal background would enable scientists to more accurately determine plasma parameters, and may lead to a better understanding of the coronal heating problem. Because scientists study the 3D structure of the Sun in 2D, any line-of-sight includes both foreground and background material, and thus, the issue of background subtraction arises. By investigating the intensity values in and around an active region, using multiple wavelengths collected from the Atmospheric Imaging Assembly (AIA) on the Solar Dynamics Observatory (SDO) over an eight-hour period, this project aims to characterize the background as smooth or structured. Different methods were employed to measure the true coronal background and create minimum intensity images. These were then investigated for the presence of structure. The background images created were found to contain long-lived structures, including coronal loops, that were still present in all of the wavelengths, 131, 171, 193, 211, and 335 A. The intensity profiles across the active region indicate that the background is much more structured than previously thought.

[TNM 2010. What's new?].

PubMed

Wittekind, C

2010-10-01

In the seventh edition of the TNM Classification of Malignant Tumours there are several entirely new classifications: upper aerodigestive mucosal melanoma, gastrointestinal stromal tumour, gastrointestinal carcinoid (neuroendocrine tumour), intrahepatic cholangiocarcinoma, Merkel cell carcinoma, uterine sarcomas, and adrenal cortical carcinoma. Significant modifications concern carcinomas of the oesophagus, oesophagogastric junction, stomach, appendix, biliary tract, lung, skin, prostate and ophthalmic tumours, which will be not addressed in this article. For several tumour entities only minor changes were introduced which might be of importance in daily practice. The new classifications and changes will be commented on without going into details.

Outputs of paired Gabor filters summed across the background frame of reference predict the direction of movement

NASA Technical Reports Server (NTRS)

Lawton, Teri B.

1989-01-01

A cortical neural network that computes the visibility of shifts in the direction of movement is proposed. The network computes: (1) the magnitude of the position difference between the test and background patterns, (2) localized contrast differences at different spatial scales analyzed by computing temporal gradients of the difference and sum of the outputs of paired even- and odd-symmetric bandpass filters convolved with the input pattern, and (3) using global processes that pool the output from paired even- and odd-symmetric simple and complex cells across the spatial extent of the background frame of reference the direction a test pattern moved relative to a textured background. Evidence that magnocellular pathways are used to discriminate the direction of movement is presented. Since magnocellular pathways are used to discriminate the direction of movement, this task is not affected by small pattern changes such as jitter, short presentations, blurring, and different background contrasts that result when the veiling illumination in a scene changes.

Human polyomaviruses in disease and cancer.

PubMed

Dalianis, Tina; Hirsch, Hans H

2013-03-15

Today the human polyomavirus (HPyV) family consists of 10 members, BK virus (BKV) and JC virus (JCV) isolated 40 years ago and the more recently identified KI virus (KIPyV), WU virus (WUPyV), Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7, trichodysplasia spinulosa virus (TSPyV), HPyV9 and MWPyV. Serological studies suggest that HPyVs subclinically infect the general population with rates ranging from 35% to 90%. However, significant disease is only observed in patients with impaired immune functions. Thus, BKV has been linked to hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation and PyV-associated nephropathy (PyVAN) after kidney transplantation; JCV to progressive multifocal leukoencephalopathy (PML) in HIV-AIDS, hematological diseases and in autoimmune diseases treated with certain lymphocyte-specific antibodies. KIPyV and WUPyV have been found in the respiratory tract, HPyV6 and 7 in the skin, and HPyV9 in serum and skin, and MWPyV in stools and skin, but so far none of these PyVs have been linked to any disease. TSPyV, on the other hand, was identified in trichodysplasia spinulosa, a rare skin disease characterized by virus-induced lytic as well as proliferative tumor-like features that is observed in immune-suppressed transplant patients. In contrast to all the other HPyVs so far, MCPyV is unique in its association with a cancer, Merkel cell carcinoma, which is a rare skin cancer arising in the elderly and chronically immunosuppressed individuals. The discovery of the new HPyVs has revived interest in the Polyomaviridae and their association to human disease and cancer. In this review, we summarize knowledge about this expanding family of human pathogens. Copyright © 2013 Elsevier Inc. All rights reserved.

Discovery of a New Human Polyomavirus Associated with Trichodysplasia Spinulosa in an Immunocompromized Patient

PubMed Central

van der Meijden, Els; Janssens, René W. A.; Lauber, Chris; Bouwes Bavinck, Jan Nico; Gorbalenya, Alexander E.; Feltkamp, Mariet C. W.

2010-01-01

The Polyomaviridae constitute a family of small DNA viruses infecting a variety of hosts. In humans, polyomaviruses can cause infections of the central nervous system, urinary tract, skin, and possibly the respiratory tract. Here we report the identification of a new human polyomavirus in plucked facial spines of a heart transplant patient with trichodysplasia spinulosa, a rare skin disease exclusively seen in immunocompromized patients. The trichodysplasia spinulosa-associated polyomavirus (TSV) genome was amplified through rolling-circle amplification and consists of a 5232-nucleotide circular DNA organized similarly to known polyomaviruses. Two putative “early” (small and large T antigen) and three putative “late” (VP1, VP2, VP3) genes were identified. The TSV large T antigen contains several domains (e.g. J-domain) and motifs (e.g. HPDKGG, pRb family-binding, zinc finger) described for other polyomaviruses and potentially involved in cellular transformation. Phylogenetic analysis revealed a close relationship of TSV with the Bornean orangutan polyomavirus and, more distantly, the Merkel cell polyomavirus that is found integrated in Merkel cell carcinomas of the skin. The presence of TSV in the affected patient's skin was confirmed by newly designed quantitative TSV-specific PCR, indicative of a viral load of 105 copies per cell. After topical cidofovir treatment, the lesions largely resolved coinciding with a reduction in TSV load. PCR screening demonstrated a 4% prevalence of TSV in an unrelated group of immunosuppressed transplant recipients without apparent disease. In conclusion, a new human polyomavirus was discovered and identified as the possible cause of trichodysplasia spinulosa in immunocompromized patients. The presence of TSV also in clinically unaffected individuals suggests frequent virus transmission causing subclinical, probably latent infections. Further studies have to reveal the impact of TSV infection in relation to other populations

Cosmic Background Explorer (COBE) press kit

NASA Technical Reports Server (NTRS)

1989-01-01

COBE, the Cosmic Background Explorer spacecraft, and its mission are described. COBE was designed to study the origin and dynamics of the universe including the theory that the universe began with a cataclysmic explosion referred to as the Big Bang. To this end, earth's cosmic background - the infrared radiation that bombards earth from every direction - will be measured by three sophisticated instruments: the Differential Microwave Radiometer (DMR), the Far Infrared Absolute Spectrophotometer (FIRAS), and the Diffuse Infrared Background Experiment (DIRBE).

Characterization and Prediction of the SPI Background

NASA Technical Reports Server (NTRS)

Teegarden, B. J.; Jean, P.; Knodlseder, J.; Skinner, G. K.; Weidenspointer, G.

2003-01-01

The INTEGRAL Spectrometer, like most gamma-ray instruments, is background dominated. Signal-to-background ratios of a few percent are typical. The background is primarily due to interactions of cosmic rays in the instrument and spacecraft. It characteristically varies by +/- 5% on time scales of days. This variation is caused mainly by fluctuations in the interplanetary magnetic field that modulates the cosmic ray intensity. To achieve the maximum performance from SPI it is essential to have a high quality model of this background that can predict its value to a fraction of a percent. In this poster we characterize the background and its variability, explore various models, and evaluate the accuracy of their predictions.

Expected background in the LZ experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kudryavtsev, Vitaly A.

2015-08-17

The LZ experiment, featuring a 7-tonne active liquid xenon target, is aimed at achieving unprecedented sensitivity to WIMPs with the background expected to be dominated by astrophysical neutrinos. To reach this goal, extensive simulations are carried out to accurately calculate the electron recoil and nuclear recoil rates in the detector. Both internal (from target material) and external (from detector components and surrounding environment) backgrounds are considered. A very efficient suppression of background rate is achieved with an outer liquid scintillator veto, liquid xenon skin and fiducialisation. Based on the current measurements of radioactivity of different materials, it is shown thatmore » LZ can achieve the reduction of a total background for a WIMP search down to about 2 events in 1000 live days for 5.6 tonne fiducial mass.« less