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Sample records for kaposi sarcoma csr

  1. Kaposi's Sarcoma

    MedlinePlus

    Kaposi's sarcoma (KS) is a cancer that causes patches of abnormal tissue to grow under the skin, in the lining of ... of cancer cells, blood vessels, and blood cells. KS is caused by infection with human herpesvirus-8 ( ...

  2. Can Kaposi Sarcoma Be Prevented?

    MedlinePlus

    ... early? Can Kaposi sarcoma be prevented? Kaposi sarcoma (KS) is caused by the Kaposi sarcoma associated herpesvirus ( ... to protect people against KSHV. For now, preventing KS depends on reducing the chance of becoming infected ...

  3. Epidemic Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  4. Classic Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  5. General Information about Kaposi Sarcoma

    MedlinePlus

    ... Research Kaposi Sarcoma Treatment (PDQ®)–Patient Version General Information About Kaposi Sarcoma Go to Health Professional Version ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  6. Drugs Approved for Kaposi Sarcoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for Kaposi sarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  7. Treatment Options for Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  8. Treatment Option Overview (Kaposi Sarcoma)

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  9. Kaposi's sarcoma of the penis.

    PubMed

    Houston, W; Pontin, A; Kuhn, T; Mambo, N

    1975-06-01

    The 11th case of Kaposi's sarcoma of the glans penis is reported. Aetiology and treatment are discussed and evidence adduced to support a conservative surgical approach by local excision, supplemented if necessary by low dosage irradiation and possibly methotrexate infusion.

  10. Kaposi's sarcoma in South Africa.

    PubMed

    Sitas, F; Newton, R

    2001-01-01

    Kaposi's sarcoma was endemic in South Africa even before the advent of the human immunodeficiency virus (HIV). Between 1988 and 1996, the incidence of Kaposi's sarcoma in South Africa has risen at least threefold and continues to increase as the HIV epidemic grows. Research from South Africa has shown that infection with human herpesvirus 8 (HHV8) is associated with Kaposi's sarcoma but not with any other major cancer site or type. In addition, the risk of Kaposi's sarcoma increases with increasing antibody titer to HHV8, but, for a given titer, the risk is greater in HIV-seropositive compared with HIV-seronegative individuals. The age- and sex-standardized seroprevalence of HHV8 in black South African hospital patients was found to be slightly more than 30%; the seroprevalence of HHV8 increased with age and was similar in men and in women. The modes of transmission of HHV8 are yet to be fully elucidated. Limited evidence exists for sexual transmission in black South African adults, but mother-to-child and person-to-person transmission in childhood is also likely. Furthermore, the seroprevalence of HHV8 decreases with increasing levels of education and is lower in whites than in blacks, suggesting that factors associated with poverty may be important determinants of transmission. Future research should focus on risk factors for Kaposi's sarcoma in HHV8-infected individuals, on determinants and mode of transmission of HHV8, and on the elucidation of the effect of primary HHV8 infection in adults and in children.

  11. Kaposi's sarcoma in South Africa.

    PubMed

    Sitas, F; Newton, R

    2001-01-01

    Kaposi's sarcoma was endemic in South Africa even before the advent of the human immunodeficiency virus (HIV). Between 1988 and 1996, the incidence of Kaposi's sarcoma in South Africa has risen at least threefold and continues to increase as the HIV epidemic grows. Research from South Africa has shown that infection with human herpesvirus 8 (HHV8) is associated with Kaposi's sarcoma but not with any other major cancer site or type. In addition, the risk of Kaposi's sarcoma increases with increasing antibody titer to HHV8, but, for a given titer, the risk is greater in HIV-seropositive compared with HIV-seronegative individuals. The age- and sex-standardized seroprevalence of HHV8 in black South African hospital patients was found to be slightly more than 30%; the seroprevalence of HHV8 increased with age and was similar in men and in women. The modes of transmission of HHV8 are yet to be fully elucidated. Limited evidence exists for sexual transmission in black South African adults, but mother-to-child and person-to-person transmission in childhood is also likely. Furthermore, the seroprevalence of HHV8 decreases with increasing levels of education and is lower in whites than in blacks, suggesting that factors associated with poverty may be important determinants of transmission. Future research should focus on risk factors for Kaposi's sarcoma in HHV8-infected individuals, on determinants and mode of transmission of HHV8, and on the elucidation of the effect of primary HHV8 infection in adults and in children. PMID:11158199

  12. What Is Kaposi Sarcoma?

    MedlinePlus

    ... Endemic KS occurs in people living in Equatorial Africa and is sometimes called African KS . KSHV (Kaposi ... associated herpesvirus) infection is much more common in Africa than in other parts of the world, so ...

  13. Kaposi sarcoma in unusual locations

    PubMed Central

    Pantanowitz, Liron; Dezube, Bruce J

    2008-01-01

    Kaposi sarcoma (KS) is a multifocal, vascular lesion of low-grade malignant potential that presents most frequently in mucocutaneous sites. KS also commonly involves lymph nodes and visceral organs. This article deals with the manifestation of KS in unusual anatomic regions. Unusual locations of KS involvement include the musculoskeletal system, central and peripheral nervous system, larynx, eye, major salivary glands, endocrine organs, heart, thoracic duct, urinary system and breast. The development of KS within wounds and blood clots is also presented. KS in these atypical sites may prove difficult to diagnose, resulting in patient mismanagement. Theories to explain the rarity and development of KS in these unusual sites are discussed. PMID:18605999

  14. Immunosuppressive Therapy-Related Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  15. Thymidine phosphorylase expression in Kaposi sarcoma.

    PubMed Central

    Dada, M A; Boshoff, C H; Comley, M A; Turley, H; Schneider, J W; Chetty, R; Gatter, K C

    1996-01-01

    AIMS: To examine the immunohistochemical distribution of thymidine phosphorylase (TP) in all clinicopathological subtypes of Kaposi sarcoma. METHODS: Thirty two biopsy specimens of Kaposi sarcoma (29 patients) were studied. Six of these patients represented classic, six endemic, eight HIV associated, seven post-immunosuppression/transplant related, and two unclassified variants of Kaposi sarcoma. The average age was 49 years (range 22-83 years) and the male: female ratio 24:5. Four samples of angiosarcoma and one of spindle cell haemangio-endothelioma were stained in parallel. All specimens were fixed in formalin, embedded in paraffin wax and processed routinely. Immunohistochemistry was carried out using an antibody directed against CD31 (JC70) and the monoclonal antibody P-GF.44C against TP. RESULTS: All biopsy specimens showed immunoexpression for TP. The spindle cell component stained more strongly than newly formed endothelium lined vessels and normal, resident vessels at a distance from the lesions. CONCLUSIONS: The strong immunoexpression of TP suggests up-regulation of TP and a role for TP in angiogensis in Kaposi sarcoma. The mechanism for the up-regulation of TP remains unknown, but viral infections may trigger it. The differential staining of the various cell components of Kaposi sarcoma also suggest that TP either plays a role in the differentiation and maturation of Kaposi sarcoma or is a reflection of such changes. Images PMID:8707955

  16. Kaposi's Sarcoma Herpesvirus Genome Persistence.

    PubMed

    Juillard, Franceline; Tan, Min; Li, Shijun; Kaye, Kenneth M

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These diseases are most common in immunocompromised individuals, especially those with AIDS. Similar to all herpesviruses, KSHV infection is lifelong. KSHV infection in tumor cells is primarily latent, with only a small subset of cells undergoing lytic infection. During latency, the KSHV genome persists as a multiple copy, extrachromosomal episome in the nucleus. In order to persist in proliferating tumor cells, the viral genome replicates once per cell cycle and then segregates to daughter cell nuclei. KSHV only expresses several genes during latent infection. Prominent among these genes, is the latency-associated nuclear antigen (LANA). LANA is responsible for KSHV genome persistence and also exerts transcriptional regulatory effects. LANA mediates KSHV DNA replication and in addition, is responsible for segregation of replicated genomes to daughter nuclei. LANA serves as a molecular tether, bridging the viral genome to mitotic chromosomes to ensure that KSHV DNA reaches progeny nuclei. N-terminal LANA attaches to mitotic chromosomes by binding histones H2A/H2B at the surface of the nucleosome. C-terminal LANA binds specific KSHV DNA sequence and also has a role in chromosome attachment. In addition to the essential roles of N- and C-terminal LANA in genome persistence, internal LANA sequence is also critical for efficient episome maintenance. LANA's role as an essential mediator of virus persistence makes it an attractive target for inhibition in order to prevent or treat KSHV infection and disease. PMID:27570517

  17. Identification of HHV8 in early Kaposi's sarcoma: implications for Kaposi's sarcoma pathogenesis.

    PubMed Central

    Kennedy, M M; Cooper, K; Howells, D D; Picton, S; Biddolph, S; Lucas, S B; McGee, J O; O'Leary, J J

    1998-01-01

    AIMS: Kaposi's sarcoma is a vascular tumour of uncertain pathogenesis possibly caused by an infectious agent, identified in high risk groups. Accumulating solution phase polymerase chain reaction (PCR) and seroepidemiological data suggest that a previously undescribed herpes DNA virus (human herpesvirus 8 (HHV8)) is the causative agent. Using a unique cohort of early Kaposi's sarcoma, the precise cell type infected with HHV8 in such lesions was identified to elucidate further the role of HHV8 in the pathobiology of Kaposi's sarcoma. METHODS: Sixteen cases of early Kaposi's sarcoma (derived from skin and lymph node) were assessed for the presence of HHV8 using both standard solution phase PCR and TaqMan PCR to the KS330 Bam region of HHV8. In situ amplification was also performed on a selected group in an attempt to identify the candidate infected cells. RESULTS: Using both conventional solution phase and TaqMan PCR, 87% of cases were positive. In addition, HHV8 amplicons were localised in situ to endothelial and spindle cell proliferations in early Kaposi's sarcoma. The HHV8 viral load varied from lesion to lesion. CONCLUSIONS: The presence of HHV8 in early lesions supports a role for HHV8 in the pathogenesis of Kaposi's sarcoma. Coupled with recent seroepidemiological studies, these results suggest that HHV8 is the aetiological agent of Kaposi's sarcoma. Its precise interaction with other factors known to be involved in the development of Kaposi's sarcoma, including cytokines and anti-apoptosis genes, requires elucidation. PMID:9624414

  18. What's New in Kaposi Sarcoma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for Kaposi sarcoma What’s new in Kaposi sarcoma research and treatment? A great ... once it has developed. Treatment Researchers are studying new and different ways to treat KS. Imiquimod (Aldara) ...

  19. The epidemiology of classic, African, and immunosuppressed Kaposi's sarcoma.

    PubMed

    Wahman, A; Melnick, S L; Rhame, F S; Potter, J D

    1991-01-01

    The etiology of Kaposi's sarcoma remains somewhat obscure. While lesions of classic Kaposi's sarcoma, African Kaposi's sarcoma, and immunosuppressed Kaposi's sarcoma have been found to be indistinguishable from one another, the reasons for the variations in type and severity have not been established. The origin of the spindle cell is yet to be agreed on. Geographic variation does not seem as important as ethnic variation. The very young and the very old, perhaps two ages of weakened immunity, tend to have a higher incidence of Kaposi's sarcoma. Children and AIDS patients tend to develop more virulent disease. Males tend to get Kaposi's sarcoma at higher rates than do females. Jewish and Mediterranean males have the highest incidence of classic Kaposi's sarcoma, and African Bantu have the highest incidence of African Kaposi's sarcoma, classifications which do not apply to the Kaposi's sarcoma population in the United States. Male homosexuals have much higher incidence of Kaposi's sarcoma than do male heterosexuals, but since the early 1980s, its incidence as the presenting manifestation of AIDS has decreased dramatically. There is no unequivocal association with HLA haplotype (though DR5 carriers may be at especially high risk) or evidence of family clustering. There is an impressive but not always consistent association between Kaposi's sarcoma development and immunodeficiency. Environmental factors, such as nitrite use, immunosuppression, and repeated cytomegalovirus infection, are associated with Kaposi's sarcoma, but the exact mechanism is unclear and the associations remain inconsistent. Finally, it is still unclear if there is a causative infectious agent for Kaposi's sarcoma. While cytomegalovirus has been linked to Kaposi's sarcoma, there are weaknesses in its hypothetical role as an etiologic agent as is the case for HIV itself.(ABSTRACT TRUNCATED AT 400 WORDS)

  20. Combination Therapy for Advanced Kaposi Sarcoma

    Cancer.gov

    In this clinical trial, adult patients with any form of advanced Kaposi sarcoma will be treated with liposomal doxorubicin and bevacizumab every 3 weeks for a maximum of six treatments.  Patients who respond to this therapy or have stable disease will rec

  1. Further experience with Kaposi's sarcoma in Uganda.

    PubMed Central

    Serwadda, D.; Carswell, W.; Ayuko, W. O.; Wamukota, W.; Madda, P.; Downing, R. G.

    1986-01-01

    Four Ugandan patients (1 women, 3 men) with generalized Kaposi's sarcoma (KS) were seen in the Uganda Cancer Institute between October 1983 and December 1984. They presented with generalized lymphadenopathy, plaques/nodules on the body, general swelling of the head, oral and visceral involvement and respiratory distress. Initial responses to adriamycin as a single or a combination chemotherapy of actinomycin D, vincristine, adriamycin and imidazole carboxamide appeared to be favourable but no sustained response was obtained. Serological tests for human T-lymphotropic virus (HTLV-II) antibodies were positive in all 4 cases. Images Figure 1 Figure 2 PMID:3011052

  2. Classic Kaposi's sarcoma in Arabs--widening ethnic involvement.

    PubMed

    Kumar, Pramod

    2011-01-01

    Kaposi's sarcoma is a tumor caused by human herpes virus 8 also known as Kaposi sarcoma-associated herpes virus. Originally described by Kaposi in 1872, this tumor is recognized as an AIDS-defining illness. Classic Kaposi's sarcoma (CKS) is a relatively indolent disease affecting elderly men from the Mediterranean region or of eastern European descent, besides Jews in whom it is the most common. It has been also reported in the Arab population living in Israel. Kaposi's sarcoma has been reported in Arabs after kidney transplantation; however, there are no reports of CKS occurring in non-Israeli Arabs. This is first such article reporting two Arab patients who presented with CKS thus widening the ethnic and geographic area of involvement with this condition.

  3. Kaposi sarcoma incidence in Mozambique: national and regional estimates.

    PubMed

    Meireles, Paula; Albuquerque, Gabriela; Vieira, Mariana; Foia, Severiano; Ferro, Josefo; Carrilho, Carla; Lunet, Nuno

    2015-11-01

    Kaposi sarcoma is expressed in four clinical variants, all associated with human herpes virus type 8 infection, namely, classic, endemic, immunosuppression-related and AIDS-related. The latter currently accounts for most of the burden of Kaposi sarcoma in sub-Saharan Africa, reflecting the frequency of HIV infection and its management. We aimed to estimate the incidence of Kaposi sarcoma in Mozambique and in its provinces. We estimated the number of incident cases of Kaposi sarcoma by adding up the expected number of endemic and AIDS-related cases. The former were estimated from the rates observed in Kyandondo, Uganda (1960-1971). The latter were computed from the number of AIDS-related deaths in each region, assuming that the ratio between the AIDS-related Kaposi sarcoma incident cases and the number of AIDS-related deaths observed in the city of Beira applies to all regions. A total of 3862 Kaposi sarcoma cases were estimated to have occurred in Mozambique in 2007, mostly AIDS-related, in the age group 25-49 years, and in provinces from South/Centre. The age-standardized incidence rates were 36.1/100 000 in men and 11.5/100 000 in women, with a more than three-fold variation across provinces. We estimated a high incidence of Kaposi sarcoma in Mozambique, along with large regional differences. These results can be used to improve disease management and to sustain political decisions on health policies.

  4. Pseudo-Kaposi sarcoma (acroangiodermatitis): occurring after bullous erysipelas.

    PubMed

    Kutlubay, Zekayi; Yardimci, Gürkan; Engin, Burhan; Demirkesen, Cuyan; Aydin, Övgü; Khatib, Rashid; Tuzun, Yalçın

    2015-05-01

    Pseudo-Kaposi sarcoma is a benign reactive vascular proliferative disorder, which can be seen at any age. It occurs when the chronic venous pressure changes result in vascular proliferation in the upper and mid dermis. This disease is divided into two subtypes: the most frequent subtype is the Mali type and seen in early ages. The Mali type is seen in chronic venous insufficiency and in those patients with arteriovenous shunts. The rare subtype is the Stewart-Bluefarb type. This disease must be distinguished from Kaposi sarcoma because of their clinical resemblance. Herein, we present a patient with pseudo-Kaposi sarcoma, which developed after bullous erysipelas.

  5. Cyclin D1 expression and HHV8 in Kaposi sarcoma.

    PubMed Central

    Kennedy, M M; Biddolph, S; Lucas, S B; Howells, D D; Picton, S; McGee, J O; Silva, I; Uhlmann, V; Luttich, K; O'Leary, J J

    1999-01-01

    BACKGROUND: Human herpesvirus 8 (HHV8) appears to be the agent responsible for Kaposi sarcoma. The mechanism remains undetermined but may involve cell cycle regulating genes including D type cyclins which are pivotal in cell cycle progression. Recent HHV8 genetic analysis has revealed the presence of a v-cyclin which is homologous to D type cyclins. AIMS: First, to assess whether there is an independent relation between endogenous cyclin D1 expression in Kaposi sarcoma and HHV8 status; second to determine whether v-cyclin mRNA expression varies with Kaposi sarcoma stage. METHODS: Cyclin D1 immunohistochemistry was performed on 17 paraffin embedded Kaposi sarcoma samples from 16 patients. HHV8 status was assessed in 15 of these using nested polymerase chain reaction (PCR) to ORF 26 and the newly described technique of TaqMan PCR. An additional 10 fresh Kaposi sarcoma samples (early and nodular) were examined for HHV8 v-cyclin RNA. RESULTS: One case, which did not contain amplifiable HHV8, showed strong cyclin D1 staining. The remaining cases were negative or weakly staining; v-cyclin transcript load was higher in early Kaposi sarcoma. CONCLUSIONS: While endogenous cyclin D1 expression is independent of HHV8 status, v-cyclin transcription is higher in early lesions, supporting the "viral hit" hypothesis. Images PMID:10645225

  6. Kaposi's sarcoma in renal transplant recipients.

    PubMed

    Zmonarski, Sławomir C; Boratyńska, Maria; Puziewicz-Zmonarska, Anna; Kazimierczak, Krzysztof; Klinger, Marian

    2005-01-01

    Kaposi's sarcoma (KS) is a spindle-shaped vascular cell tumor that occurs in the skin, lymphoid, respiratory and gastrointestinal tissues. It may resemble aggressive malignant neoplasm in HIV-related or in post-transplant types but classic form may behave as benign, potentially controllable and reversible hyperplasia. KS lesions from the onset are dispersed and multicentric. KS probability increases in solid organ transplant recipients (approximately 3/1000 patients). KS occurrence is associated with: type and dose of immunosuppression, chronic stimulation by foreign allograft antigens, viral infections (Herpes virus 8), anti rejection and induction therapy, etc. 90% of KS cases appear as dark blue or purplish macular lesions that may form nodular tumors. Histological picture shows networks of spindle shaped cells and vascular spaces surrounded by an endothelial cell layer. There is no uniform schema of KS treatment in renal transplant recipients. Immunosuppression must be reduced to the lowest levels which preserve allograft function. CsA should be converted to mofetil mycophenolate or mTOR-inhibitors. After conversion to MMF regression of KS was observed, although low therapeutic MMF doses seem to be appropriate. Sirolimus seems to inhibit the growth of established vascularized tumors and this effect is best realized with relatively low immunosuppressive doses of drug. PMID:16218035

  7. Kaposi's Sarcoma in Uganda: Geographic and Ethnic Distribution

    PubMed Central

    Taylor, J. F.; Smith, P. G.; Bull, Diana; Pike, M. C.

    1972-01-01

    Over the quinquennium 1964-68 the crude annual incidence of Kaposi's sarcoma in Uganda per million of the population was 7·9 overall, 14·6 for males and 1·1 for females. Statistical analysis indicates that the disease is most prevalent in highland areas to the west and among the indigenous Bantu tribes. There was no correlation with the distribution of squamous cell carcinoma of the lower leg, and Kaposi's sarcoma was not seen in an Indian or European during the period under review. PMID:4647399

  8. Instantánea del sarcoma de Kaposi

    Cancer.gov

    Información sobre las tendencias de incidencia, mortalidad y financiamiento del NCI sobre el sarcoma de Kaposi; así como ejemplos de actividades del NCI y adelantos en la investigación de este tipo de cáncer.

  9. Differential Expression of Viral Bcl-2 Encoded by Kaposi's Sarcoma-Associated Herpesvirus and Human Bcl-2 in Primary Effusion Lymphoma Cells and Kaposi's Sarcoma Lesions

    PubMed Central

    Widmer, Isabelle; Wernli, Marion; Bachmann, Felix; Gudat, Fred; Cathomas, Gieri; Erb, Peter

    2002-01-01

    Expression of human herpesvirus 8 viral Bcl-2 protein was demonstrated in spindle cells of late-stage Kaposi's sarcoma lesions but not in primary effusion lymphoma cell lines. In contrast, strong expression of human Bcl-2 was found in stimulated primary effusion lymphoma cells, whereas in Kaposi's sarcoma lesions preferential mononuclear cells, and to a lesser extent spindle cells, stained positive. PMID:11836434

  10. Isolated Kaposi Sarcoma of the Tonsil: A Case Report and Review of the Scientific Literature

    PubMed Central

    Pittore, Barbara; Pelagatti, Carlo Loris; Deiana, Francesco; Ortu, Francesco; Maricosu, Elena; Cossu, Sergio; Sotgiu, Giovanni

    2015-01-01

    Kaposi sarcoma is a tumour caused by human herpes virus 8, also known as Kaposi sarcoma-associated herpes virus. It usually affects the skin and oral mucosa; however, it can also sometimes affect the lungs, the liver, the stomach, the bowel, and lymph nodes. Several body sites may be affected simultaneously. The involvement of the tonsils is rare. We described an isolated localization of Kaposi's sarcoma of the right tonsil in a HIV-positive patient. PMID:25755902

  11. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma.

    PubMed Central

    Zhong, W; Wang, H; Herndier, B; Ganem, D

    1996-01-01

    Kaposi sarcoma (KS) is the leading neoplasm of HIV-infected patients and is also found in several HIV-negative populations. Recently, DNA sequences from a novel herpesvirus, termed KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8) have been identified within KS tissue from both HIV-positive and HIV-negative cases; infection with this agent has been proposed as a possible factor in the etiology or pathogenesis of the tumor. Here we have examined the pattern of KSHV/HHV-8 gene expression in KS and find it to be highly restricted. We identify and characterize two small transcripts that represent the bulk of the virus-specific RNA transcribed from over 120 kb of the KSHV genome in infected cells. One transcript is predicted to encode a small membrane protein; the other is an unusual polyadenylylated RNA that accumulates in the nucleus to high copy number. This pattern of viral gene expression suggests that most infected cells in KS are latently infected, with lytic viral replication likely restricted to a much smaller subpopulation of cells. These findings have implications for the therapeutic utility of currently available antiviral drugs targeted against the lytic replication cycle. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:8692871

  12. Kaposi's sarcoma tumor cells preferentially express Bcl-xL.

    PubMed Central

    Foreman, K. E.; Wrone-Smith, T.; Boise, L. H.; Thompson, C. B.; Polverini, P. J.; Simonian, P. L.; Nunez, G.; Nickoloff, B. J.

    1996-01-01

    Several recently identified proteins such as Bcl-2 and Bcl-x have been found to regulate programmed cell death (i.e., apoptosis). In this report, we examined the levels of expression of proteins that can either prevent apoptosis (i.e., Bcl-2 or the long form of Bcl-x, designated Bcl-x1) or promote apoptosis (i.e., Bax or the short form of Bcl-x, designated Bcl-xs) in proliferating benign and malignant endothelial cells (ECs). In normal skin with quiescent ECs, no detection by immunohistochemical staining was observed for Bcl-xL, Bcl-xs, or Bcl-2. However, in diseased skin samples that feature a prominent angiogenic response such as in psoriasis or pyogenic granulomas, the proliferating ECs markedly overexpressed Bcl-xL, with little to no Bcl-2. In an acquired-immune-deficiency-syndrome-related neoplasm, Kaposi's sarcoma, the spindle-shaped tumor cells also overexpressed Bcl-xL compared with Bcl-2. These in vivo studies were extended in vitro using cultured ECs and Kaposi's sarcoma tumor cells that were examined by flow cytometry and immunoblot analysis. Both cultured ECs and Kaposi's sarcoma tumor cells express significantly higher levels of Bcl-xL than Bcl-2. Such overexpression of cell survival gene products may contribute to prolonging the longevity of EC-derived cells in several different benign and neoplastic skin disorders that are characterized by a prominent angiogenic tissue response. Images Figure 1 Figure 3 PMID:8780384

  13. AIDS-Kaposi Sarcoma and Classic Kaposi Sarcoma: are different ultrasound patterns related to different variants?

    PubMed Central

    2011-01-01

    Background Kaposi Sarcoma (KS) is a malignancy of endothelial skin cells with multifocal localization on the skin, lymph nodes and visceral organs. Although all clinical variants are associated with HHV-8 infection, specific differences in the clinical onset and in the natural history of AIDS-KS and Classic-KS have been described. The present randomised prospective-observational study aimed to investigate whether the ultrasound pattern and color Doppler flow imaging of vascularisation of skin lesions of patients with Classic KS (CKS) or AIDS-KS could provide useful information to the evaluation of clinical activity of the disease. Methods Cutaneous lesions of 24 patients with histologically confirmed KS were investigated using very high frequency ultrasound probes; 16 patients had CKS and 8 had AIDS-KS. HHV-8 infection was confirmed in all patients by investigating the specific humoral response to viral antigens. Immunological and virological parameters were also assessed to monitor HIV or HHV-8 viral infection. For each patient, a target skin lesion was selected on the basis of size (diameter from 0.4 to 2 cm). Each lesion was analyzed in terms of size, depth and color Doppler pattern. Results The B-mode ultrasound patterns of skin lesions did not differ when comparing CKS patients to AIDS-KS patients, whereas the color Doppler signal, which is associated with vascular activity, was detected in the KS lesions of 6/8 AIDS-KS patients (75.0%) and in 2/16 CKS (16,7%); the latter two patients showed a clinically progressive and extensive disease stage (IV B). Conclusions Our preliminary results suggest that small cutaneous KS lesions - in both CKS and AIDS-KS patients- display similar B-mode ultrasound patterns ( hypoechoic, well defined, superficial lesions). However, the color Doppler signal, which is associated with endothelial activity and angiogenesis, which play a substantial role in KS progression, could constitute a useful tool for evaluating disease activity

  14. Herpes virus-like sequences are specifically found in Kaposi sarcoma lesions.

    PubMed Central

    O'Neill, E; Henson, T H; Ghorbani, A J; Land, M A; Webber, B L; Garcia, J V

    1996-01-01

    AIM: To detect the prevalence of herpes virus-like DNA sequences in AIDS associated Kaposi sarcoma (KSHV) lesions and normal tissue. METHODS: KSHV detection was performed by polymerase chain reaction (PCR) using four different sets of primers. PCR products were cloned, sequenced, and analysed. RESULTS: All of four biopsies of Kaposi sarcoma lesions and all of three paraffin embedded Kaposi sarcoma tissues were positive for KSHV, while normal tissue from the same patients was negative. Sequence analysis of amplification products revealed polymorphisms that result in amino acid changes of the predicted sequence. CONCLUSIONS: KSHV is prevalent in tissues from Kaposi sarcoma, suggesting a role in the development of the tumour. On this basis, anti-herpes virus agents should be considered to control Kaposi sarcoma. Images PMID:8655706

  15. Myasthenia gravis developing in an HIV-negative patient with Kaposi's sarcoma.

    PubMed

    Mantero, Vittorio; Mascolo, Maria; Bandettini di Poggio, Monica; Caponnetto, Claudia; Pardini, Matteo

    2013-07-01

    Myasthenia gravis is a disorder of neuromuscular transmission caused by autoimmune mechanisms. We reported a possible association between seropositive myasthenia gravis and Kaposi's sarcoma in a HIV-negative subject and the observed interactions between the treatment regimen for these two conditions. A 62-year-old man came to our attention for ocular myasthenia gravis. He suffered from a classic form of Kaposi's sarcoma since about 1 year. When myasthenic symptoms worsened, the patient was started on prednisone and azathioprine. The patient had a significant worsening of Kaposi's sarcoma, so prednisone and azathioprine were reduced and he was treated with vinblastine, with improvement both in dermatologic than in neurological symptomatology. We propose some considerations: the potential correlation between Kaposi's sarcoma and myasthenia gravis through immunological mechanism; myasthenia gravis as a paraneoplastic manifestation of Kaposi's sarcoma, and the role of an antitumoral agent as a treatment for both the conditions.

  16. Oral Kaposi's sarcoma: Sole presentation in HIV seropositive patient

    PubMed Central

    Arul, A. Sri Kennath J.; Kumar, A. Ramesh; Verma, Sonika; Arul, A. Sri Sennath J.

    2015-01-01

    Acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) occurs with increased frequency in all HIV transmission groups and at a particularly high rate among homosexual men. It usually presents initially as violaceous cutaneous lesions, but oral mucosa, lymph nodes and visceral organs may be affected, sometimes without skin involvement. KS in a 20-year-old HIV-seropositive patient with oral involvement as the sole presentation of the disease is presented herewith; thus contributing a new AIDS-related KS case reported in Indian Literature. PMID:26283853

  17. Kaposi Sarcoma Incidence and Survival Among HIV-Infected Homosexual Men After HIV Seroconversion

    PubMed Central

    Guiguet, Marguerite; Costagliola, Dominique; Fisher, Martin; de Luca, Andrea; Porter, Kholoud

    2010-01-01

    Background Despite the success of combination antiretroviral therapy (cART) in reducing the incidence of Kaposi sarcoma, HIV-infected individuals who have responded to treatment continue to be diagnosed with Kaposi sarcoma. We examine factors associated with the incidence of Kaposi sarcoma among cART-treated HIV-infected homosexual men and changes in their survival after its diagnosis over calendar time. Methods Data were from HIV-infected homosexual men with well-estimated dates of HIV seroconversion (ie, change in status from being HIV negative to having HIV antibodies detected). Incidence of Kaposi sarcoma was calculated. We used Kaplan–Meier methods to determine survival after Kaposi sarcoma diagnosis in three calendar periods: before 1996, 1996–2000, and 2001–2006. Poisson models were used to examine the effect of risk factors such as current and nadir CD4 cell count (ie, the lowest CD4 cell count ever recorded for a person), duration of infection, and age at diagnosis for Kaposi sarcoma incidence in cART-treated men. All statistical tests were two-sided. Results Among the 9473 men, 555 were diagnosed with Kaposi sarcoma in the period 1986–2006, of whom 319 died. The percentage surviving 24 months after Kaposi sarcoma diagnosis rose statistically significantly during the study period from 35% (95% confidence interval [CI] = 29% to 42%) before 1996 to 84% (95% CI = 76% to 90%) in 1996–2000 and to 81% (95% CI = 70% to 88%) in 2001–2006 (P < .001). Seventy men were diagnosed with Kaposi sarcoma after starting cART. Current (ie, within 6 months) CD4 cell count was associated with incidence of Kaposi sarcoma among cART-treated men (rate ratios [RRs] = 18.91, 95% CI = 8.50 to 42.09, for CD4 level category <200 cells per cubic millimeter; RR = 3.55, 95% CI = 1.40 to 9.00, for 200–349 cells per cubic millimeter; and RR = 4.11, 95% CI = 1.74 to 9.70, for 350–499 cells per cubic millimeter; all compared with ≥500 cells per cubic millimeter). After

  18. Pulmonary Kaposi's sarcoma in a female patient: Case report.

    PubMed

    Petribu, Natacha Calheiros de Lima; Cisneiros, Mayana Silva; Carvalho, Glauber Barbosa de; Baptista, Lucyana de Melo

    2016-01-01

    Kaposi's sarcoma (KS) is a multicentric lymphoproliferative malignancy. Most of the time this tumor is confined to the skin and subcutaneous tissue, but it can present with widespread visceral involvement, such as in the lung. Pulmonary KS is the most frequent form in young adult males, in a ratio of 15:1. The disease usually affects individuals with low CD4 lymphocyte counts (<150-200 cells/mm3). We report a case of a female patient aged 35 years, with the presence of skin lesions, self-limiting episodes of diarrhea and weight loss of 15 kg for nearly 9 months, progressing to persistent fever. AIDS was diagnosed and biopsy of the lesions revealed Kaposi's sarcoma. Computed tomography of the chest showed peribronchovascular thickening, areas of ground glass opacity, condensations with air bronchograms surrounded by ground glass opacity (halo sign) and bilateral pleural effusion. The diagnosis of pulmonary KS is still a challenge, especially due to the occurrence of other opportunistic diseases that may also occur concurrently. Therefore, suspecting this diagnosis based on clinical and laboratory manifestations, and even more with CT findings, is fundamental, especially in patients who already have the cutaneous form of the disease. PMID:27656847

  19. Disseminated Kaposi's Sarcoma with the Involvement of Penis in the Setting of HIV Infection

    PubMed Central

    Farshidpour, Maham; Marjani, Majid; Baghaei, Parvaneh; Tabarsi, Payam; Masjedi, Heidar; Asadi Kani, Zahra Farzaneh; Nadji, Seyed Alireza; Mansouri, Davood

    2015-01-01

    Kaposi's sarcoma (KS) is a malignant proliferation of the endothelial cells. It typically presents with several vascular nodules on the skin and other organs. The penile localization of KS, particularly on the shaft area, is exceptional. We report an HIV-positive 34-year-old man who had multiple purplish-black plaques on his extremities and several small violaceous macules on the glans and shaft of the penis. Kaposi's sarcoma was diagnosed by histopathology. PMID:25657424

  20. The chromatin landscape of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Toth, Zsolt; Brulois, Kevin; Jung, Jae U

    2013-05-01

    Kaposi's sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis. PMID:23698402

  1. Epidemiology and pathogenesis of Kaposi's sarcoma-associated herpesvirus.

    PubMed Central

    Boshoff, C; Weiss, R A

    2001-01-01

    Kaposi's sarcoma (KS) occurs in Europe and the Mediterranean countries (classic KS) and Africa (endemic KS), immunosuppressed patients (iatrogenic or post-transplant KS) and those with acquired immune deficiency syndrome (AIDS), especially among those who acquired human immunodeficiency virus sexually (AIDS-KS). KS-associated herpesvirus (KSHV or HHV-8) is unusual among herpesviruses in having a restricted geographical distribution. Like KS, which it induces in immunosuppressed or elderly people, the virus is prevalent in Africa, in Mediterranean countries, among Jews and Arabs and certain Amerindians. Distinct KSHV genotypes occur in different parts of the world, but have not been identified as having a differential pathogenesis. KSHV is aetiologically linked to three distinct neoplasms: (i) KS, (ii) primary effusion lymphoma, and (iii) plasmablastic multicentric Castleman's disease. The histogenesis, clonality and pathology of the tumours are described, together with the epidemiology and possible modes of transmission of the virus. PMID:11313009

  2. Molecular analysis of Kaposi's sarcoma occurring during haemodialysis.

    PubMed

    Metaxa-Mariatou, V; Chiras, T; Loli, A; Gazouli, M; Vallis, D; Nasioulas, G

    2004-03-01

    Human Herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). In this paper we attempted to confirm the connection between dialysis, HHV-8, and KS by examining the case of an elderly haemodialysis nonimmunosuppressed male patient with end-stage renal disease, who developed KS. By using PCR we have verified the presence of DNA from two different genomic regions (ORF 26 and ORF K1) of HHV-8. In addition, our RT-PCR results suggest active replication of HHV-8 in blood and KS lesions of the patient. Phylogenetic analysis revealed identical DNA sequence to ORF K1, and a close relation to its C1 variant. In conclusion, we document the case of KS and HHV-8 coexistence in a Greek elderly patient undergoing regular haemodialysis. Furthermore, our results indicate that factors other than immunosuppression could lead to KS development possibly due to activation of HHV-8. PMID:14987280

  3. Cannabinoid modulation of Kaposi's sarcoma-associated herpesvirus infection and transformation.

    PubMed

    Zhang, Xuefeng; Wang, Jian Feng; Kunos, George; Groopman, Jerome E

    2007-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV; also named human herpesvirus 8) is necessary but not sufficient for the development of Kaposi's sarcoma. A variety of factors may contribute to the pathogenesis of Kaposi's sarcoma in addition to KSHV. Marijuana is a widely used recreational agent, and Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major active component of marijuana, is prescribed for medicinal use. To evaluate how cannabinoids may affect the pathogenesis of Kaposi's sarcoma, we studied primary human dermal microvascular endothelial cells (HMVEC) exposed to KSHV. There was an increased efficiency of KSHV infection in the presence of low doses of Delta(9)-THC. We also found that Delta(9)-THC increased the viral load in KSHV-infected HMVEC through activation of the KSHV lytic switch gene, the open reading frame 50. Furthermore, we observed that Delta(9)-THC stimulated expression of the KSHV-encoded viral G protein-coupled receptor and Kaposi's sarcoma cell proliferation. Our results indicate that Delta(9)-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma. PMID:17671191

  4. CD40 upregulation is independent of HHV-8 in the pathogenesis of Kaposi's sarcoma.

    PubMed Central

    Kennedy, M M; Biddolph, S; Lucas, S B; Howells, D D; Picton, S; McGee, J O; O'Leary, J J

    1999-01-01

    AIMS: Human herpesvirus 8 (HHV-8) is now acknowledged as the infective cofactor in the pathogenesis of Kaposi's sarcoma. The mode by which HHV-8 causes Kaposi's sarcoma is unresolved and it is probable that it acts in conjunction with other factors including cytokines, anti-apoptosis proteins, and cell surface receptors. CD40, a cell membrane receptor belonging to the tumour necrosis factor receptor super family, promotes B cell survival and is expressed constitutively on endothelial cells. It is upregulated on cytokine treatment and has been documented recently in Kaposi's sarcoma. Because the HHV-8 genome contains cytokine homologues, this study investigated whether CD40 expression in Kaposi's sarcoma correlated with HHV-8 status, using a unique set of HHV-8 positive and negative specimens. METHODS: Twenty one paraffin wax embedded samples of Kaposi's sarcoma were selected, of which 18 were screened for the presence of HHV-8 using both conventional solution phase and TaqMan polymerase chain reaction (PCR). CD40 immunohistochemistry was assessed using a biotinylated amplification system. Staining was scored semiquantitatively. RESULTS: The results indicated that the expression of CD40 is independent of viral status, being present in both HHV-8 positive and negative specimens. CONCLUSIONS: This suggests that HHV-8 promotes Kaposi's sarcoma cell survival following infection by mechanisms other than those involving CD40. PMID:10439837

  5. Plasmacytoid dendritic cells in skin lesions of classic Kaposi's sarcoma.

    PubMed

    Karouni, Mirna; Kurban, Mazen; Abbas, Ossama

    2016-09-01

    Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), which allows them to provide anti-viral resistance and to link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer cells. pDCs are involved in the pathogenesis of several infectious [especially viral, such as Molluscum contagiosum (MC)], inflammatory/autoimmune, and neoplastic entities. Kaposi's sarcoma (KS) is a multifocal, systemic lympho-angioproliferative tumor associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Microscopy typically exhibits a chronic inflammatory lymphoplasmacytic infiltrate in addition to the vascular changes and spindle cell proliferation. Despite the extensive research done on the immune evasion strategies employed by KSHV, pDCs role in relation to KS has only rarely been investigated. Given this, we intend to investigate pDC occurrence and activity in the skin lesions of KS. Immunohistochemical staining for BDCA-2 (specific pDC marker) and MxA (surrogate marker for local type I IFN production) was performed on classic KS (n = 20) with the control group comprising inflamed MC (n = 20). As expected, BDCA-2+ pDCs were present in abundance with diffuse and intense MxA expression (indicative of local type I IFN production) in all inflamed MC cases (20 of 20, 100 %). Though present in all the KS cases, pDCs were significantly less abundant in KS than in inflamed MC cases, and MxA expression was patchy/weak in most KS cases. In summary, pDCs are part of the inflammatory host response in KS; however, they were generally low in number with decreased type I IFN production which is probably related to KSHV's ability to evade the immune system through the production of different viral proteins capable of suppressing IFN production as well as pDC function.

  6. Bacillary (epithelioid) angiomatosis and concurrent Kaposi's sarcoma in acquired immunodeficiency syndrome.

    PubMed

    Berger, T G; Tappero, J W; Kaymen, A; LeBoit, P E

    1989-11-01

    Two patients with acquired immunodeficiency syndrome developed simultaneous Kaposi's sarcoma and bacillary (epithelioid) angiomatosis. The distinguishing clinical and histologic features of these two vascular proliferations associated with human immunodeficiency virus disease are described. The lesions of bacillary (epithelioid) angiomatosis contained bacteria, while the lesions of Kaposi's sarcoma did not. With erythromycin therapy, the lesions of bacillary (epithelioid) angiomatosis cleared, while those of Kaposi's persisted. Bacillary (epithelioid) angiomatosis, a treatable but potentially fatal opportunistic infection of human immunodeficiency virus disease, should be considered in the differential diagnosis of vascular lesions in immunosuppressed patients.

  7. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma.

    PubMed

    Schalling, M; Ekman, M; Kaaya, E E; Linde, A; Biberfeld, P

    1995-07-01

    Kaposi's sarcoma (KS) is a previously rare, tumour-like lesion of controversial biological nature. KS has since the early 1980s become frequent in patients with AIDS, particularly in homosexuals. KS is also endemic in Central Africa predominantly in otherwise healthy men but also in women and children. Recently, evidence for the presence of novel, herpes virus DNA sequences in more than 90% of AIDS Kaposi lesions (AKS) was presented. This DNA was identified using representational difference analysis (RDA) generating short, unique sequences with variable homology to several herpes virus, but no intact virus was recovered. If these DNA-sequences are also present in other, non-HIV-associated forms of Kaposi's sarcoma this would strongly suggest a specific, aetiopathological involvement of this putative new herpes virus in the pathogenesis of Kaposi's sarcoma, rather than a contamination of yet another opportunistic virus in immunosuppressed AIDS patients.

  8. Morphoproteomics Identifies Etiopathogenetic Correlates of HHV-8-Associated Kaposi's Sarcoma and Provides Pathways with Therapeutic Options: A Case Study.

    PubMed

    Salihi, Suhair Al; Buryanek, Jamie; Rios, Adan A; Brown, Robert E

    2016-09-01

    A morphoproteomic analysis was performed to identify the proteins and corresponding molecular pathways activated for a case of non-HIV Kaposi's sarcoma. This analysis provides insight into the biology of the tumor and identifies etiopathogenetic correlates of HHV-8-Associated Kaposi's sarcoma that are useful in formulating therapeutic alternatives. PMID:27650622

  9. Whole-Genome Sequencing of Kaposi's Sarcoma-Associated Herpesvirus from Zambian Kaposi's Sarcoma Biopsy Specimens Reveals Unique Viral Diversity

    PubMed Central

    Olp, Landon N.; Jeanniard, Adrien; Marimo, Clemence; West, John T.

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS). Both KSHV and KS are endemic in sub-Saharan Africa where approximately 84% of global KS cases occur. Nevertheless, whole-genome sequencing of KSHV has only been completed using isolates from Western countries—where KS is not endemic. The lack of whole-genome KSHV sequence data from the most clinically important geographical region, sub-Saharan Africa, represents an important gap since it remains unclear whether genomic diversity has a role on KSHV pathogenesis. We hypothesized that distinct KSHV genotypes might be present in sub-Saharan Africa compared to Western countries. Using a KSHV-targeted enrichment protocol followed by Illumina deep-sequencing, we generated and analyzed 16 unique Zambian, KS-derived, KSHV genomes. We enriched KSHV DNA over cellular DNA 1,851 to 18,235-fold. Enrichment provided coverage levels up to 24,740-fold; therefore, supporting highly confident polymorphism analysis. Multiple alignment of the 16 newly sequenced KSHV genomes showed low level variability across the entire central conserved region. This variability resulted in distinct phylogenetic clustering between Zambian KSHV genomic sequences and those derived from Western countries. Importantly, the phylogenetic segregation of Zambian from Western sequences occurred irrespective of inclusion of the highly variable genes K1 and K15. We also show that four genes within the more conserved region of the KSHV genome contained polymorphisms that partially, but not fully, contributed to the unique Zambian KSHV whole-genome phylogenetic structure. Taken together, our data suggest that the whole KSHV genome should be taken into consideration for accurate viral characterization. IMPORTANCE Our results represent the largest number of KSHV whole-genomic sequences published to date and the first time that multiple genomes have been sequenced from sub-Saharan Africa, a geographic area

  10. Classic Kaposi's sarcoma in Italy, 1985–1998

    PubMed Central

    Dal Maso, L; Polesel, J; Ascoli, V; Zambon, P; Budroni, M; Ferretti, S; Tumino, R; Tagliabue, G; Patriarca, S; Federico, M; Vercelli, M; Giacomin, A; Vicario, G; Bellù, F; Falcini, F; Crocetti, E; De Lisi, V; Vitarelli, S; Piffer, S; Stracci, F; Serraino, D; Rezza, G; Franceschi, S

    2004-01-01

    To evaluate incidence rates (IRs) of classic Kaposi's sarcoma (CKS) in Italy after the spread of AIDS, we distinguished CKS from AIDS-related KS (AKS) using an ‘ad hoc' record linkage procedure between 15 Cancer Registries (CRs) (21% of the Italian population) and the national AIDS Registry. Between 1985 and 1998, 874 cases of CKS and 634 cases of AKS were diagnosed in the study areas. CKS accounted for 16 and 27% of KS cases below 55 years of age in men and women, respectively, but for 91 and 100% of those above age 55. The IRs for CKS were 1.0/ in men and 0.4/100 000 in women, but they varied between 0.3 in Umbria and 4.7 in Sassari in men, and between 0.1 in Parma and 1.7 in Sassari in women. IRs of CKS in both genders were stable between 1985–1987 and 1993–1998. In Northern and Central CRs the IR (adjusted for age and gender) for CKS was 0.5 in individuals born in the same area, but 1.6 in individuals born in Southern Italy or in the Islands (rate ratio=3.2) suggesting that KS-associated herpesvirus, the cause of KS, is acquired early in life. PMID:15570306

  11. Cutaneous colesional acquired immunodeficiency syndrome associated Kaposi sarcoma and cryptococcosis.

    PubMed

    Ramdial, Pratistadevi K; Sing, Yetish; Subrayan, Sumeshini; Calonje, Eduardo

    2010-12-01

    The clinicopathologic features of 4 AIDS patients with cutaneous colesional Kaposi sarcoma (KS) and cryptococcosis, a rare phenomenon, are described. Biopsies from 3 patients who were highly active antiretroviral therapy (HAART)-naive demonstrated predominant KS with a conspicuous spindle cell component and small aggregates of cryptococcal yeasts in 2 biopsies and predominant gelatinous cryptococcosis with attenuated KS spindle cells in 1 biopsy. One patient was HAART exposed. He had childhood pulmonary tuberculosis, was treated for disseminated cutaneous cryptococcosis 18 months earlier and presented with cutaneous lesions, odynophagia and massive cervical lymphadenopathy in the eighth week of HAART, after achieving viral suppression and a CD4 cell increase from 28 to 184 cells/μL. His skin biopsy demonstrated a dense lymphoplasmacytic infiltrate, neutrophils, and granulomas with admixed aggregates and single Cryptococcus neoformans and focal aggregation of human herpes virus 8-immunopositive spindle cells. Acid fast bacilli were not identified and mycobacterial molecular studies were negative. The features were compatible with cutaneous cryptococcal immune reconstitution inflammatory syndrome. His nodal and oropharyngeal biopsies demonstrated dense mixed, including granulomatous, inflammation with few cryptococcal yeasts and acid fast bacilli, confirmed to be Mycobacterium tuberculosis on polymerase chain reaction testing, without KS. These features were also compatible with immune reconstitution inflammatory syndrome, but the exact role of each infection in the extracutaneous sites was unconfirmed. Colesional KS and cryptococcosis served as the sentinel lesion of AIDS in 3 patients and of immune reconstitution inflammatory syndrome in 1 patient.

  12. Iron: a target for the management of Kaposi's sarcoma?

    PubMed Central

    Simonart, Thierry

    2004-01-01

    Background Kaposi's sarcoma (KS) is a mesenchymal tumour associated with human herpesvirus-8 infection. However, the incidence of human herpesvirus-8 infection is far higher than the prevalence of KS, suggesting that viral infection per se is not sufficient for the development of malignancy and that one or more additional cofactors are required. Discussion Epidemiological data suggest that iron may be one of the cofactors involved in the pathogenesis of KS. Iron is a well-known carcinogen and may favour KS growth through several pathways. Based on the apoptotic and antiproliferative effect of iron chelation on KS cells, it is suggested that iron withdrawal strategies could be developed for the management of KS. Studies using potent iron chelators in suitable KS animal models are critical to evaluate whether iron deprivation may be a useful anti-KS strategy. Summary It is suggested that iron may be one of non-viral co-factors involved of KS pathogenesis and that iron withdrawal strategies might interfere with tumour growth in patients with KS. PMID:14725718

  13. Expression of int-2 oncogene in Kaposi's sarcoma lesions.

    PubMed Central

    Huang, Y Q; Li, J J; Moscatelli, D; Basilico, C; Nicolaides, A; Zhang, W G; Poiesz, B J; Friedman-Kien, A E

    1993-01-01

    Fibroblast growth factors (FGFs), such as basic FGF, have been implicated in the growth of Kaposi's sarcoma (KS) cells in vitro. In the evaluation of the expression of the various genes of the different members of the FGF family and their receptors in fresh KS tissue specimens, int-2 was found to be expressed in more than half of the KS tumors examined. Using reverse transcription PCR, the expression of int-2 was detected in 21 of 38 (55.2%) fresh KS biopsy specimens. In contrast, int-2 mRNA transcripts were not found in normal appearing skin from the same patients except in one sample which was obtained from an AIDS patient with disseminated KS lesions. Sequence data confirmed that the amplified sequences were derived from int-2 mRNA with proper splicing. In addition, 12 nucleic acid alterations were identified in eight out of nine KS tumor samples sequenced. Using immunohistochemical methods, int-2 protein was detected in some of the spindle-shaped tumor cells surrounding the abnormal endothelial-lined vascular slits histologically characteristic of KS. Int-2 specific immunostaining was shown to be present in both the nuclei and cytoplasm of these spindle cells but was more pronounced in the nuclei. Neither amplification nor gross rearrangement of the int-2 gene was detected in KS lesions by Southern blot analysis. These results suggest that the expression of int-2 may play a role in the pathogenesis KS by stimulating local angiogenesis and cell proliferation. Images PMID:8450048

  14. HHV8 and Kaposi's sarcoma: a time cohort study.

    PubMed Central

    Kennedy, M M; Lucas, S B; Jones, R R; Howells, D D; Picton, S J; Hanks, E E; McGee, J O; O'Leary, J J

    1997-01-01

    AIMS: The recent finding that human herpes virus 8 (HHV8) is found in the majority of Kaposi's sarcoma (KS) cases supports the epidemiological observation that the tumour may be caused by an infectious agent. This study aimed to address when and how HHV8 evolved. METHODS: A cohort of African endemic KS (49 samples from 45 patients) and European KS (18 samples from 13 patients), spanning 27 years, was assessed for the presence of HHV8 by both standard solution phase polymerase chain reaction (PCR) and the newly described technique of TaqMan PCR. RESULTS: HHV8 was present in approximately 49% (24 of 49 tissue samples) of the African cases and in more than 90% (16 of 18 tissue samples) of the European cohort, in keeping with recent seroepidemiological data. CONCLUSIONS: HHV8 is strongly linked to the development of KS; however, in some patients, other factors may operate. The utility and flexibility of TaqMan PCR in detecting low copy viral target in human tissues was demonstrated. Images PMID:9231158

  15. CpG methylation as a tool to characterize cell-free Kaposi sarcoma herpesvirus DNA.

    PubMed

    Shamay, Meir; Hand, Nicholas; Lemas, M Victor; Koon, Henry B; Krown, Susan E; Wrangle, John; Desai, Prashant; Ramos, Juan Carlos; Ambinder, Richard F

    2012-04-01

    We studied the presence of Kaposi sarcoma herpesvirus sequences in cell-free DNA (cfDNA) isolated from the blood of patients with AIDS-related Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). The use of paramagnetic beads linked to methyl-CpG binding domain protein allowed separation of virion and cell-derived DNA. Only virion DNA was detected in the blood of KS patients, whereas cell-derived DNA was detected in a patient with AIDS-related PEL. The difference in the origins of cfDNA in these settings may in part reflect very different proliferative indices in KS and PEL tumor tissue. PMID:22357696

  16. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae.

    PubMed Central

    Moore, P S; Gao, S J; Dominguez, G; Cesarman, E; Lungu, O; Knowles, D M; Garber, R; Pellett, P E; McGeoch, D J; Chang, Y

    1996-01-01

    Detection of novel DNA sequences in Kaposi's sarcoma (KS) and AIDS-related body cavity-based, non-Hodgkin's lymphomas suggests that these neoplasms are caused by a previously unidentified human herpesvirus. We have characterized this agent using a continuously infected B-lymphocyte cell line derived from an AIDS-related lymphoma and a genomic library made from a KS lesion. In this cell line, the agent has a large episomal genome with an electrophoretic mobility similar to that of 270-kb linear DNA markers during clamped homogeneous electric field gel electrophoresis. A 20.7-kb region of the genome has been completely sequenced, and within this region, 17 partial and complete open reading frames are present; all except one have sequence and positional homology to known gammaherpesvirus genes, including the major capsid protein and thymidine kinase genes. Phylogenetic analyses using both single genes and combined gene sets demonstrated that the agent is a gamma-2 herpesvirus (genus Rhadinovirus) and is the first member of this genus known to infect humans. Evidence for transient viral transmission from infected to uninfected cells is presented, but replication-competent virions have not been identified in infected cell lines. Sera from patients with KS have specific antibodies directed against antigens of infected cell lines, and these antibodies are generally absent in sera from patients with AIDS without KS. These studies define the agent as a new human herpesvirus provisionally assigned the descriptive name KS-associated herpesvirus; its formal designation is likely to be human herpesvirus 8. PMID:8523568

  17. Human Herpesvirus 8 Genotype E in Patients with Kaposi Sarcoma, Peru

    PubMed Central

    Cassar, Olivier; Blondot, Marie-Lise; Mohanna, Salim; Jouvion, Gregory; Bravo, Francisco; Maco, Vicente; Duprez, Renan; Huerre, Michel; Gotuzzo, Eduardo

    2010-01-01

    To determine human herpesvirus 8 (HHV-8) K1 genotypes in patients with Kaposi sarcoma (KS) from Peru, we characterized HHV-8 in 25 KS biopsy samples. Our findings of 8 A, 1 B, 14 C, and 2 E subtypes showed high HHV-8 diversity in these patients and association between E genotype and KS development. PMID:20735933

  18. Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis.

    PubMed

    Cai, Qiliang; Verma, Suhbash C; Lu, Jie; Robertson, Erle S

    2010-01-01

    Kaposi's Sarcoma-associated Herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus,and is associated with the pathogenesis of Kaposi's sarcoma and two lymphoproliferative disorders known to occur frequently in AIDS patients-primary effusion lymphoma and multicentric Castleman disease. In the 15 years since its discovery, intense studies have demonstrated an etiologic role for KSHV in the development of these malignancies. Here, we review the recent advances linked to understanding KSHV latent and lytic life cycle and the molecular mechanisms of KSHV-mediated oncogenesis in terms of transformation, cell signaling, cell growth and survival, angiogenesis, immune invasion and response to microenvironmental stress, and highlight the potential therapeutic targets for blocking KSHV tumorigenesis. PMID:21040832

  19. Classic type of Kaposi's sarcoma and human herpesvirus 8 infection in Xinjiang, China.

    PubMed

    Dilnur, P; Katano, H; Wang, Z H; Osakabe, Y; Kudo, M; Sata, T; Ebihara, Y

    2001-11-01

    We report 17 cases of the classic type of Kaposi's sarcoma in Xinjiang, which is located in the north-western area of China surrounded by Mongolia in the east, Russia in the north and Kazakhstan in the west. Fifteen of the patients were of the Uygur people. All patients were male and did not have acquired immunodeficiency syndrome. Most of the lesions were found in the lower and/or upper extremities, with 16 patients showing multiple lesions. Immunohistochemical examination of the lesions revealed that human herpesvirus 8 (HHV-8)-encoded latency-associated nuclear antigen was expressed in the nuclei of spindle-shaped tumor cells. HHV-8 DNA was detected by polymerase chain reaction in all seven cases examined. Phylogenetic tree analysis revealed that DNA sequences of the HHV-8-encoded K1 gene in the seven Kaposi's sarcoma cases were classified as subtype C that was common in the Mediterranean, the Middle East and East Asian countries. In addition, using immunofluorescence we investigated the seroprevalence of HHV-8 in 73 Uygur patients with diseases other than Kaposi's sarcoma. Surprisingly, the serological study revealed that 34 of the patients (46.6%) were positive for antibodies against HHV-8, suggesting that HHV-8 infection is widespread in Xinjiang area. The occurrence of the classic type of Kaposi's sarcoma with a high seropositivity rate implies that Xinjiang is the most endemic area for HHV-8 infection in the world known to date. Considering that Xinjiang is located at the middle point of the Silk Road that used to extend from Rome to China, these data imply that the virus may have been in circulation in this area due to the migration of the people via the Silk Road.

  20. (18)F-FDG PET/CT findings in a case with HIV (-) Kaposi sarcoma.

    PubMed

    Ozdemir, E; Poyraz, N Y; Keskin, M; Kandemir, Z; Turkolmez, S

    2014-01-01

    Although mucocutaneous sites are the most frequently encountered sites of involvement, Kaposi Sarcoma (KS) may also occasionally involve the breast and the skeletal, endocrine, urinary and nervous systems.. Various imaging modalities may be used to delineate the extent of the disease by detecting unexpected sites of involvement. Herein, we report a case of classical type KS, in whom staging with (18)F-FDG PET/CT imaging disclosed widespread disease and unexpected findings of bone and salivary gland involvement.

  1. Descriptive epidemiology of Kaposi sarcoma in Europe. Report from the RARECARE project.

    PubMed

    Stiller, C A; Trama, A; Brewster, D H; Verne, J; Bouchardy, C; Navarro, C; Chirlaque, M D; Marcos-Gragera, R; Visser, O; Serraino, D; Weiderpass, E; Dei Tos, A P; Ascoli, V

    2014-12-01

    Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995-2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000-2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers.

  2. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi's sarcoma (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Schweitzer, Vanessa G.

    1992-06-01

    Since 1975, Phase I/II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy (PDT) in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, in 1981 two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts to cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of mucocutaneous Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions (endothelial cell tumors); (2) a tumor- specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; (4) the potential for retreatment without increasing side effects; and (5) porphyrin-mediated photoinactivation of enveloped viruses. Herein presented are seven cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular mucocutaneous lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

  3. Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults

    PubMed Central

    Gbabe, Oluwatoyin F; Okwundu, Charles I; Dedicoat, Martin; Freeman, Esther E

    2014-01-01

    Background Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence. However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients. Objectives To assess the added advantage of chemotherapy plusHAART compared toHAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's Clinical Trials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014. Selection criteria Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens. Data collection and analysis Two review authors assessed the studies independently and extracted outcome data. We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect. We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens. PMID:25221796

  4. Differences in Kaposi sarcoma-associated herpesvirus-specific and –nonspecific immune responses in classic Kaposi sarcoma cases and matched controls in Sicily

    PubMed Central

    Amodio, Emanuele; Goedert, James J.; Barozzi, Patrizia; Riva, Giovanni; Firenze, Alberto; Bonura, Filippa; Viviano, Enza; Romano, Nino; Luppi, Mario

    2011-01-01

    SUMMARY Kaposi sarcoma (KS) may develop because of incompetent immune responses, both nonspecifically and specifically against the KS-associated herpes virus (KSHV). Peripheral blood mononuclear cells from 15 classic (non-AIDS) KS cases, 13 KSHV seropositives (without KS), and 15 KSHV-seronegative controls were tested for interferon-γ T-cell (Elispot) responses to KSHV-LANA, KSHV-K8.1, and CMV/EBV peptide pools. The forearm and thigh of each participant also was tested for delayed-type hypersensitivity (DTH) against common recall antigens. Groups were compared with Fisher exact test and multinomial logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). KSHV Elispot response was detected in 10 (67%) classic KS cases, 11 (85%) KSHV seropositives (without KS), and 2 (13%) seronegative controls. All 4 cases with KSHV-LANA responses had current KS lesions, whereas 5 of 6 cases with KSHV-K8.1 responses had no lesions (P=0.048). No case responded to both LANA and K8.1. Compared to seronegative controls, risk for classic KS was inversely related to DTH in the thigh (OR 0.71, 95% CI 0.55–0.94, P=0.01), directly associated with DTH in the forearm (OR 1.35, 95% CI 1.02–1.80, P=0.04), and tended to be increased 5-fold per KSHV Elispot response (OR 5.13, 95% CI 0.86–30.77, P=0.07). Compared to KSHV seropositives (without KS), risk for classic KS, was reduced 5-fold (OR 0.20, CI 0.03–0.77, P=0.04) per KSHV response. CMV/EBV Elispot responses were irrelevant. Deficiency of both KSHV-specific and –nonspecific immunity is associated with classic KS. This may clarify why Kaposi sarcoma responds to immune reconstitution. PMID:21740480

  5. Treatment of recurrent Kaposi's sarcoma of an AIDS patient with weekly paclitaxel.

    PubMed

    Hsu, C H; Chen, M Y; Cheng, A L

    2000-01-01

    Paclitaxel was recently recognized as an active chemotherapeutic agent for acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the best way to administer paclitaxel in AIDS-KS patients remains unknown. Herein, we reported an AIDS-associated KS patient whose disease progressed on the first-line chemotherapy with doxorubicin and bleomycin, but later responded well to weekly 1-hour infusion of 70 mg/m2 paclitaxel. It is particular noteworthy that this weekly dosing schedule resulted in almost negligible toxicities. The authors suggested a prospective study of weekly paclitaxel for AIDS-KS should be started as soon as possible.

  6. Nodular Erythema Elevatum Diutinum Mimicking Kaposi's Sarcoma in a Human Immunodeficiency Virus Infected Patient

    PubMed Central

    Rao, G Raghurama; Joshi, Rajiv; Phaneendra Prasad, A Krishna; Amareswar, A; Sandhya, S; Sridevi, M

    2014-01-01

    Erythema elevatum diutinum (EED) has been emerging as a specific Human Immunodeficiency Virus (HIV) associated dermatosis in recent times. It is an extremely rare chronic disease of unknown origin and part of the spectrum of leukocytoclastic vasculitis. We describe a case of EED simulating Kaposi's sarcoma in a 52-year-old HIV infected female patient with no previous opportunistic infections and CD4+ count of 164/mm3. Therapy with oral dapsone (100 mg/day) for two weeks resulted in resolution of some lesions. PMID:25484391

  7. High incidence of classic Kaposi's sarcoma in Mantua, Po Valley, Northern Italy (1989–1998)

    PubMed Central

    Ascoli, V; Belli, S; Benedetti, M; Trinca, S; Ricci, P; Comba, P

    2001-01-01

    The incidence of classic Kaposi's sarcoma was estimated in the province of Mantua, Po Valley, Northern Italy, yielding age-standardized rates of 2.5/100 000 men and 0.7/100 000 women (1989–98). Elevated rates in the rural zone of Viadana/Sabbioneta (5.0/100 000 men and 2.8/100 000 women) are among the highest so far reported for Italian communities. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11487269

  8. ARID3B: a Novel Regulator of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle

    PubMed Central

    Wood, Jennifer J.; Boyne, James R.; Paulus, Christina; Jackson, Brian R.; Nevels, Michael M.

    2016-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of commonly fatal malignancies of immunocompromised individuals, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). A hallmark of all herpesviruses is their biphasic life cycle—viral latency and the productive lytic cycle—and it is well established that reactivation of the KSHV lytic cycle is associated with KS pathogenesis. Therefore, a thorough appreciation of the mechanisms that govern reactivation is required to better understand disease progression. The viral protein replication and transcription activator (RTA) is the KSHV lytic switch protein due to its ability to drive the expression of various lytic genes, leading to reactivation of the entire lytic cycle. While the mechanisms for activating lytic gene expression have received much attention, how RTA impacts cellular function is less well understood. To address this, we developed a cell line with doxycycline-inducible RTA expression and applied stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics. Using this methodology, we have identified a novel cellular protein (AT-rich interacting domain containing 3B [ARID3B]) whose expression was enhanced by RTA and that relocalized to replication compartments upon lytic reactivation. We also show that small interfering RNA (siRNA) knockdown or overexpression of ARID3B led to an enhancement or inhibition of lytic reactivation, respectively. Furthermore, DNA affinity and chromatin immunoprecipitation assays demonstrated that ARID3B specifically interacts with A/T-rich elements in the KSHV origin of lytic replication (oriLyt), and this was dependent on lytic cycle reactivation. Therefore, we have identified a novel cellular protein whose expression is enhanced by KSHV RTA with the ability to inhibit KSHV reactivation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of fatal malignancies of

  9. Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8.

    PubMed

    Jackson, Carolyn C; Dickson, Mark A; Sadjadi, Mahan; Gessain, Antoine; Abel, Laurent; Jouanguy, Emmanuelle; Casanova, Jean-Laurent

    2016-03-01

    Kaposi sarcoma (KS) is an endothelial malignancy caused by human herpes virus-8 (HHV-8) infection. The epidemic and iatrogenic forms of childhood KS result from a profound and acquired T cell deficiency. Recent studies have shown that classic KS of childhood can result from rare single-gene inborn errors of immunity, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4. The pathogenesis of the endemic form of childhood KS has remained elusive. We review childhood KS pathogenesis and its relationship to inherited and acquired immunodeficiency to oncogenic HHV-8. PMID:26469702

  10. Lichen Planus-like Keratosis: Another Differential Diagnosis for Kaposi Sarcoma

    PubMed Central

    Clavellina-Miller, Marcela; Moreno-Coutiño, Gabriela; Toussaint-Caire, Sonia; Reyes-Terán, Gustavo

    2015-01-01

    Epidemic Kaposi sarcoma is a common finding among HIV/AIDS patients that are not under antiretroviral treatment, and sometimes it is the first sign of the disease. However, it can be seen even in patients with undetectable viral load and high CD 4 cell count. Under these circumstances, the clinical presentation can be atypical in location or number. For this reason, the number of differential diagnosis is increased and biopsy of the suspicious lesions is essential for an accurate diagnosis and further apropiate treatment. PMID:26538737

  11. Kaposi's sarcoma herpesvirus and HIV-1 seroprevalences in prostitutes in Djibouti.

    PubMed

    Marcelin, Anne-Geneviève; Grandadam, Marc; Flandre, Philippe; Nicand, Elisabeth; Milliancourt, Catherine; Koeck, Jean-Louis; Philippon, Michel; Teyssou, Remy; Agut, Henri; Dupin, Nicolas; Calvez, Vincent

    2002-10-01

    Kaposi's sarcoma herpesvirus (KSHV) is linked causally to Kaposi's sarcoma. Epidemiological studies have shown that KSHV transmission can occur during sex among homosexual men, but heterosexual transmission seems to be very rare in KSHV low prevalence countries. A seroepidemiological study was conducted to determine whether KSHV is transmitted sexually between heterosexuals in an endemic country. Sera from 282 subjects of African origin living in Djibouti were tested for antibodies to KSHV and HIV-1. Among the 282 individuals, 43 were female prostitutes working in the streets (group 1), 123 were female prostitutes working in luxury bars (group 2), 41 were non-prostitute females (group 3), and 75 were non-prostitute males (group 4). KSHV seroprevalence was 26, 20, 17, and 36% in groups 1, 2, 3, and 4, respectively. The seroprevalence of KSHV is not different between street or bar prostitutes and non-prostitute females (OR = 1.67; P = 0.34 and OR = 1.18; P = 0.73). These results suggest that in this endemic country commercial sex work does not seem to be a risk factor for KSHV infection and provides evidence against heterosexual transmission of KSHV in the female population studied.

  12. Supraglottic Kaposi's Sarcoma in HIV-Negative Patients: Case Report and Literature Review

    PubMed Central

    Server, Ela A.; Durna, Yusuf M.; Yigit, Ozgur; Bozkurt, Erol R.

    2016-01-01

    This paper presents a case report of an HIV-negative, supraglottic Kaposi's sarcoma patient. The 80-year-old male patient was admitted with complaints of hoarseness, difficulty in swallowing, and a stinging sensation in his throat for approximately six months. The endoscopic larynx examination revealed a lesion which had completely infiltrated the epiglottis, reached right aryepiglottic fold, was vegetating, pink and purple in color, multilobular, fragile, and shaped like a bunch of grapes, and partially blocked the bleeding airway passage. The case was discussed by the hospital's head-neck cancer committee and a surgery decision was made. A tracheotomy was performed under local anesthesia before the operation due to respiratory distress and endotracheal intubation difficulty. Direct laryngoscopy showed that the mass was limited in the supraglottic area, had invaded the entire left aryepiglottic fold and one-third of the front right aryepiglottic fold, and completely covered epiglottis. It should be remembered that although rare, Kaposi's sarcoma may be encountered in larynx malignancy cases. Disease-free survival may be achieved through local excision and postoperative radiotherapy. PMID:27375914

  13. Risk of classic Kaposi sarcoma with residential exposure to volcanic and related soils in Sicily

    PubMed Central

    Pelser, Colleen; Dazzi, Carmelo; Graubard, Barry I.; Lauria, Carmela; Vitale, Francesco; Goedert, James J.

    2009-01-01

    Purpose Before AIDS, endemic (African) Kaposi sarcoma (KS) was noted to occur in volcanic areas and was postulated to result from dirt chronically embedded in the skin of the lower extremities. The primary cause of all KS types is KS-associated herpesvirus (KSHV) infection, but co-factors contribute to the neoplasia. We investigated whether residential exposure volcanic or related soils was associated with the risk of classic Kaposi sarcoma (cKS) in Sicily. Methods Risk of incident cKS (n=141) compared to population-based KSHV seropositive controls (n=123) was estimated for residential exposure to four types of soil, categorized with maps from the European Soil Database and direct surveying. Questionnaire data provided covariates. Results Residents in communities high in luvisols were approximately 2.7-times more likely to have cKS than those in communities with no luvisols. Risk was not specific for cKS on the limbs, but it was elevated approximately 4–5-fold with frequent bathing or tap water drinking in high luvisols communities. Risk was unrelated to communities high in andosols, tephra, or clay soils. Conclusions Iron and alumino-silicate clay, major components of luvisols, may increase cKS risk, but formal investigation and consideration of other soil types and exposures are needed. PMID:19576540

  14. Kaposi's sarcoma-associated herpesvirus ORF6 gene is essential in viral lytic replication.

    PubMed

    Peng, Can; Chen, Jungang; Tang, Wei; Liu, Chunlan; Chen, Xulin

    2014-01-01

    Kaposi's sarcoma associated herpesvirus (KSHV) is associated with Kaposis's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. KSHV encodes at least 8 open reading frames (ORFs) that play important roles in its lytic DNA replication. Among which, ORF6 of KSHV encodes an ssDNA binding protein that has been proved to participate in origin-dependent DNA replication in transient assays. To define further the function of ORF6 in the virus life cycle, we constructed a recombinant virus genome with a large deletion within the ORF6 locus by using a bacterial artificial chromosome (BAC) system. Stable 293T cells carrying the BAC36 (wild type) and BACΔ6 genomes were generated. When monolayers of 293T-BAC36 and 293T-BACΔ6 cells were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, infectious virus was detected from the 293T-BAC36 cell supernatants only and not from the 293T- BACΔ6 cell supernatants. DNA synthesis was defective in 293T-BACΔ6 cells. Expression of ORF6 in trans in BACΔ6-containing cells was able to rescue both defects. Our results provide genetic evidence that ORF6 is essential for KSHV lytic replication. The stable 293T cells carrying the BAC36 and BACΔ6 genomes could be used as tools to investigate the detailed functions of ORF6 in the lytic replication of KSHV. PMID:24911362

  15. MicroRNAs encoded by Kaposi's sarcoma-associated herpesvirus regulate viral life cycle.

    PubMed

    Lu, Chih-Chung; Li, Zhonghan; Chu, Chia-Ying; Feng, Jiaying; Feng, Jun; Sun, Ren; Rana, Tariq M

    2010-10-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with Kaposi's sarcoma and lymphomas. The pathogenesis of KSHV depends on the balance between two phases of the viral cycle: latency and lytic replication. In this study, we report that KSHV-encoded microRNAs (miRNAs) function as regulators by maintaining viral latency and inhibiting viral lytic replication. MiRNAs are short, noncoding, small RNAs that post-transcriptionally regulate the expression of messenger RNAs. Of the 12 viral miRNAs expressed in latent KSHV-infected cells, we observed that expression of miR-K3 can suppress both viral lytic replication and gene expression. Further experiments indicate that miR-K3 can regulate viral latency by targeting nuclear factor I/B. Nuclear factor I/B can activate the promoter of the viral immediate-early transactivator replication and transcription activator (RTA), and depletion of nuclear factor I/B by short hairpin RNAs had similar effects on the viral life cycle to those of miR-K3. Our results suggest a role for KSHV miRNAs in regulating the viral life cycle. PMID:20847741

  16. Multiplexed colorimetric detection of Kaposi's sarcoma associated herpesvirus and Bartonella DNA using gold and silver nanoparticles

    NASA Astrophysics Data System (ADS)

    Mancuso, Matthew; Jiang, Li; Cesarman, Ethel; Erickson, David

    2013-01-01

    Kaposi's sarcoma (KS) is an infectious cancer occurring most commonly in human immunodeficiency virus (HIV) positive patients and in endemic regions, such as Sub-Saharan Africa, where KS is among the top four most prevalent cancers. The cause of KS is the Kaposi's sarcoma-associated herpesvirus (KSHV, also called HHV-8), an oncogenic herpesvirus that while routinely diagnosed in developed nations, provides challenges to developing world medical providers and point-of-care detection. A major challenge in the diagnosis of KS is the existence of a number of other diseases with similar clinical presentation and histopathological features, requiring the detection of KSHV in a biopsy sample. In this work we develop an answer to this challenge by creating a multiplexed one-pot detection system for KSHV DNA and DNA from a frequently confounding disease, bacillary angiomatosis. Gold and silver nanoparticle aggregation reactions are tuned for each target and a multi-color change system is developed capable of detecting both targets down to levels between 1 nM and 2 nM. The system developed here could later be integrated with microfluidic sample processing to create a final device capable of solving the two major challenges in point-of-care KS detection.

  17. Detection of Kaposi's Sarcoma Associated Herpesvirus Nucleic Acids Using a Smartphone Accessory

    PubMed Central

    Mancuso, Matthew; Cesarman, Ethel; Erickson, David

    2014-01-01

    Kaposi's sarcoma (KS) is an infectious cancer occurring in immune-compromised patients, caused by Kaposi's sarcoma associated herpesvirus (KSHV). Our vision is to simplify the process of KS diagnosis through the creation of a smartphone based point-of-care system capable of yielding an actionable diagnostic readout starting from a raw biopsy sample. In this work we develop the sensing mechanism for the overall system, a smartphone accessory capable of detecting KSHV nucleic acids. The accessory reads out microfluidic chips filled with a colorimetric nanoparticle assay targeted at KSHV. We calculate that our final device can read out gold nanoparticle solutions with an accuracy of .05 OD, and we demonstrate that it can detect DNA sequences from KSHV down to 1 nM. We believe that through integration with our previously developed components, a smartphone based system like the one studied here can provide accurate detection information, as well as a simple platform for field based clinical diagnosis and research. PMID:25117534

  18. Association between malaria exposure and Kaposi's sarcoma-associated herpes virus seropositivity in Uganda

    PubMed Central

    Nalwoga, Angela; Cose, Stephen; Wakeham, Katie; Miley, Wendell; Ndibazza, Juliet; Drakeley, Christopher; Elliott, Alison; Whitby, Denise; Newton, Robert

    2015-01-01

    Objective Unlike other herpes viruses, Kaposi's sarcoma-associated herpes virus (KSHV) is not ubiquitous worldwide and is most prevalent in sub-Saharan Africa. The reasons for this are unclear. As part of a wider investigation of factors that facilitate transmission in Uganda, a high prevalence country, we examined the association between antimalaria antibodies and seropositivity against KSHV. Methods Antibodies against P. falciparum merozoite surface protein (PfMSP)-1, P. falciparum apical membrane antigen (PfAMA)-1 and KSHV antigens (ORF73 and K8.1) were measured in samples from 1164 mothers and 1227 children. Results Kaposi's sarcoma-associated herpes virus seroprevalence was 69% among mothers and 15% children. Among mothers, KSHV seroprevalence increased with malaria antibody titres: from 60% to 82% and from 54% to 77%, comparing those with the lowest and highest titres for PfMSP-1 and PfAMA-1, respectively (P < 0.0001). Among children, only antibodies to PfAMA-1 were significantly associated with KSHV seropositivity, (P < 0.0001). In both mothers and children, anti-ORF73 antibodies were more strongly associated with malaria antibodies than anti-K8.1 antibodies. Conclusion The association between malaria exposure and KSHV seropositivity suggests that malaria is a cofactor for KSHV infection or reactivation. PMID:25611008

  19. Monocytes in Kaposi's sarcoma lesions are productively infected by human herpesvirus 8.

    PubMed Central

    Blasig, C; Zietz, C; Haar, B; Neipel, F; Esser, S; Brockmeyer, N H; Tschachler, E; Colombini, S; Ensoli, B; Stürzl, M

    1997-01-01

    PCR analysis and serological studies demonstrated a close association between Kaposi's sarcoma (KS)-associated herpesvirus, or human herpesvirus 8 (HHV-8), and the development of Kaposi's sarcoma (KS). The majority of the KS cells were shown to be latently infected by the virus. In this study we investigated which type of cell is productively infected in KS lesions. In situ hybridization was performed with strand-specific RNA probes complementary to the sequences coding for the minor capsid protein (VP23) of HHV-8. The VP23 gene is specifically expressed during the lytic or replicative period of the virus life cycle, and therefore it is a useful marker to detect productively infected cells. By in situ hybridization of KS lesions, a strong hybridization signal was detected only in a small subset of the KS cells of the lesions. Simultaneous application of immunohistochemical staining and in situ hybridization identified the virus-replicating cells to be of monocytic origin. Productively infected monocytes may be an important reservoir for transmission of the virus and for the increase and maintenance of the high load of HHV-8 generally observed in nodular KS lesions during late stages of infection. PMID:9311888

  20. Supraglottic Kaposi's Sarcoma in HIV-Negative Patients: Case Report and Literature Review.

    PubMed

    Server, Ela A; Durna, Yusuf M; Yigit, Ozgur; Bozkurt, Erol R

    2016-01-01

    This paper presents a case report of an HIV-negative, supraglottic Kaposi's sarcoma patient. The 80-year-old male patient was admitted with complaints of hoarseness, difficulty in swallowing, and a stinging sensation in his throat for approximately six months. The endoscopic larynx examination revealed a lesion which had completely infiltrated the epiglottis, reached right aryepiglottic fold, was vegetating, pink and purple in color, multilobular, fragile, and shaped like a bunch of grapes, and partially blocked the bleeding airway passage. The case was discussed by the hospital's head-neck cancer committee and a surgery decision was made. A tracheotomy was performed under local anesthesia before the operation due to respiratory distress and endotracheal intubation difficulty. Direct laryngoscopy showed that the mass was limited in the supraglottic area, had invaded the entire left aryepiglottic fold and one-third of the front right aryepiglottic fold, and completely covered epiglottis. It should be remembered that although rare, Kaposi's sarcoma may be encountered in larynx malignancy cases. Disease-free survival may be achieved through local excision and postoperative radiotherapy. PMID:27375914

  1. Kaposi Sarcoma of the eyelid as an initial manifestation of AIDS.

    PubMed

    Teixeira, Ana Isabel; Neno, Miguel; Badura, Robert; Borges-Costa, João; Filipe, Paulo Leal

    2016-01-01

    Kaposi sarcoma (KS) is a multifocal systemic disease that originates in the vascular endothelium related to Human Herpes Virus 8 (HHV-8). In the early 1980s the first series of cases of disseminated Kaposi Sarcoma in HIV infected patients were reported. However, with the advent of highly active antiretroviral therapy (HAART) since 1997, these cases are less frequently observed by clinicians. We report the case of a 40-year-old woman, presenting with two asymptomatic purpuric nodules localized in the superior and inferior left eyelids, occluding the palpebral fissure, which were present for 4 months prior to presentation. The eyelid nodules were determined to represent KS, but there were no additional cutaneous lesions. Pulmonary and gastric KS involvement was documented. Antiretroviral therapy was initiated along with pegylated liposomal doxorubicin. The nodules gradually disappeared and her immune status eventually improved. Ocular and periorbital involvement of KS associated with HIV-1 infection as the initial clinical manifestations is a rare advent. This case is important as it illustrates that disseminated KS was not to be predicted by the number or the extension of cutaneous lesions. PMID:27617725

  2. The three-dimensional microvascular architecture of the human Kaposi sarcoma implanted in nude mice: a SEM corrosion casting study.

    PubMed

    Sangiorgi, S; Congiu, T; Manelli, A; Dell'Eva, R; Noonan, D M

    2006-11-01

    The human Kaposi sarcoma represents one of the most common skin lesions associated with AIDS. Its clinical presentation and anatomopathological structure seem to demonstrate a particularly rich vascularity. The latest therapies aim to limit its intrinsic angiogenic activity in an attempt to reduce vascular density and the formation of new vessels. For these reasons, we decided to study the microvascular architecture of Kaposi sarcoma in three dimensions. We used a corrosion casting technique applied to nude mice previously transplanted subcutaneously with human modified neoplastic Kaposi sarcoma cells. The cooption of host vessels made by the tumor was demonstrated by three-dimensional scanning electron microscopy (SEM) images. At high magnification several angiogenic patterns were observed in the form of potato-shaped vessels, sprouts, intussusceptions and mouse tailed end tipped capillaries along with some ultrastructural features such as intercellular extravasations and endothelial cell modifications. Our investigation allowed us to build a detailed map of tumor vasculature in human Kaposi sarcoma. Furthermore, this study want to shed light on the sharp morphological three-dimensional conformation of angiogenic sprouts so to be able to better understand their modifications occurred during time and after antiangiogenic experimental therapies, by now observed only by immunohistochemical or immunofluorescent assays. PMID:16920158

  3. Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium.

    PubMed

    Maor, Yehoshua; Yu, Jinlong; Kuzontkoski, Paula M; Dezube, Bruce J; Zhang, Xuefeng; Groopman, Jerome E

    2012-07-01

    Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised individuals such as organ transplant recipients and AIDS patients. Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host's immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer. In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with which KSHV infected ECs, it reduced proliferation and induced apoptosis in those infected by the virus. CBD inhibited the expression of KSHV viral G protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma. PMID:23264851

  4. Differences in Kaposi sarcoma-associated herpesvirus-specific and herpesvirus-non-specific immune responses in classic Kaposi sarcoma cases and matched controls in Sicily.

    PubMed

    Amodio, Emanuele; Goedert, James J; Barozzi, Patrizia; Riva, Giovanni; Firenze, Alberto; Bonura, Filippa; Viviano, Enza; Romano, Nino; Luppi, Mario

    2011-10-01

    Kaposi sarcoma (KS) might develop because of incompetent immune responses, both non-specifically and specifically against the KS-associated herpesvirus (KSHV). Peripheral blood mononuclear cells from 15 classic (non-AIDS) KS cases, 13 KSHV seropositives (without KS) and 15 KSHV-seronegative controls were tested for interferon-γ T-cell (enzyme-linked immunospot [Elispot]) responses to KSHV-latency-associated nuclear antigen (LANA), KSHV-K8.1 and CMV/Epstein-Barr virus (EBV) peptide pools. The forearm and thigh of each participant was also tested for delayed-type hypersensitivity (DTH) against common recall antigens. Groups were compared with Fisher exact test and multinomial logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). A KSHV Elispot response was detected in 10 (67%) classic KS cases, 11 (85%) KSHV seropositives (without KS) and two (13%) seronegative controls. All four cases with KSHV-LANA responses had current KS lesions, whereas five of six cases with KSHV-K8.1 responses had no lesions (P = 0.048). No case responded to both LANA and K8.1. Compared with the seronegative controls, the risk for classic KS was inversely related to DTH in the thigh (OR 0.71, 95% CI 0.55-0.94, P = 0.01), directly associated with DTH in the forearm (OR 1.35, 95% CI 1.02-1.80, P = 0.04) and tended to be increased fivefold per KSHV Elispot response (OR 5.13, 95% CI 0.86-30.77, P = 0.07). Compared with KSHV seropositives (without KS), the risk for classic KS was reduced fivefold (OR 0.20, CI 0.03-0.77, P = 0.04) per KSHV response. The CMV/EBV Elispot responses were irrelevant. Deficiency of both KSHV-specific and KSHV-non-specific immunity is associated with classic KS. This might clarify why Kaposi sarcoma responds to immune reconstitution.

  5. A negative element involved in Kaposi's sarcoma-associated herpesvirus-encoded ORF11 gene expression

    SciTech Connect

    Chen, Lei

    2009-01-01

    The ORF11 of the Kaposi's sarcoma-associated herpesvirus (KSHV) is a lytic viral gene with delayed-early expression kinetics. How the ORF11 gene expression is regulated in the KSHV lytic cascade is largely unknown. Here we report that the deletion of the KSHV viral IL-6 gene from the viral genome leads to deregulated ORF11 gene expression. The KSHV-encoded viral IL-6 protein was found not to be essentially involved in the regulation of ORF11, suggesting a potential transcriptional cis-regulation. A negative element was identified downstream of the ORF11 gene, which suppresses the ORF11 basal promoter activity in a position-independent manner.

  6. Relationship between oral Kaposi 's sarcoma and HAART: contribution of two case reports.

    PubMed

    Campo-Trapero, Julián; Del Romero-Guerrero, Jorge; Cano-Sánchez, Jorge; Rodríguez-Martín, Carmen; Martínez-González, José Ma; Bascones-Martínez, Antonio

    2008-11-01

    Two HIV infected patients not receiving Highly Active Antiretroviral Treatment (HAART) presented with epidemic Kaposi's sarcoma of the oral cavity. One patient initially refused HAART, but when the lesion became large enough to be noticeable he agreed to HAART associated with excision of the intraoral lesion by CO2 laser. The other patient developed KS and progressed to AIDS at two years after ceasing HAART due to adverse effects; he was referred to hospital for renewed administration of HAART. In both cases, the lesions observed in the oral cavity were the first clinical manifestation of AIDS. These reports underline the close relationship between the use of HAART and the control of KS lesions, highlighting the important role of the dentist in the identification and early diagnosis of these oral lesions.

  7. Osteolytic lesions and bacillary angiomatosis in HIV infection: radiologic differentiation from AIDS-related Kaposi sarcoma.

    PubMed

    Baron, A L; Steinbach, L S; LeBoit, P E; Mills, C M; Gee, J H; Berger, T G

    1990-10-01

    Bacillary angiomatosis is a newly recognized multisystem bacterial infectious disease seen in the setting of human immunodeficiency virus (HIV) infection. The disease is marked by cutaneous vascular lesions that contain a bacterium similar to the cat scratch disease bacillus. Antibiotic therapy leads to the resolution of both cutaneous and systemic manifestations. Of 17 HIV-infected patients with cutaneous lesions of bacillary angiomatosis, six (35%) had symptomatic osteolytic bone lesions that improved following antibiotic therapy. The authors describe the appearance of the bone lesions on radiographs, computed tomographic (CT) scans, magnetic resonance (MR) images, and radionuclide studies. Osteolytic lesions are a relatively common feature of bacillary angiomatosis in patients with HIV infection. The presence of bone lesions aids in differentiation of bacillary angiomatosis from acquired immunodeficiency syndrome-related Kaposi sarcoma, which has similar cutaneous abnormalities but no associated bone lesions.

  8. Disseminated Kaposi's Sarcoma in an HIV-Positive Patient: A Rare Entity in an Indian Patient

    PubMed Central

    Behera, Biswanath; Chandrashekar, Laxmisha; Thappa, Devinder Mohan; Toi, Pampa Ch; Vinod, Kolar Vishwanath

    2016-01-01

    AIDS-associated disseminated Kaposi sarcoma (KS) is a rare entity, especially in India due to the low prevalence of human herpes virus-8 infections in Indian population. Due to its rapid and progressive nature, early diagnosis and institution of highly active antiretroviral therapy is crucial in AIDS-associated KS, with a view to achieving favorable prognosis. We report a case of disseminated KS in an HIV-1 positive patient, who presented with two months history of multiple violaceous patches and plaques over the trunk, bilateral upper limbs, lower limbs, and hard palate. The patient died of recurrent massive pleural effusion before starting antiretroviral therapy. This case is being reported due to the paucity of KS in the Indian literature, especially the disseminated type and to highlight its rapidly progressive course which can be fatal. PMID:27293276

  9. Modulation of Immune System by Kaposi's Sarcoma-Associated Herpesvirus: Lessons from Viral Evasion Strategies.

    PubMed

    Lee, Hye-Ra; Brulois, Kevin; Wong, Laiyee; Jung, Jae U

    2012-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV), a member of the herpesvirus family, has evolved to establish a long-term, latent infection of cells such that while they carry the viral genome gene expression is highly restricted. Latency is a state of cryptic viral infection associated with genomic persistence in their host and this hallmark of KSHV infection leads to several clinical-epidemiological diseases such as KS, a plasmablastic variant of multicentric Castleman's disease, and primary effusion lymphoma upon immune suppression of infected hosts. In order to sustain efficient life-long persistency as well as their life cycle, KSHV dedicates a large portion of its genome to encode immunomodulatory proteins that antagonize its host's immune system. In this review, we will describe our current knowledge of the immune evasion strategies employed by KSHV at distinct stages of its viral life cycle to control the host's immune system.

  10. Incidentally Detected Kaposi Sarcoma of Adrenal Gland with Anaplastic Features in an HIV Negative Patient

    PubMed Central

    Celik, Murat; Sen, Erdem; Cebeci, Hakan; Ata, Ozlem; Yavas, Cagdas

    2016-01-01

    Kaposi sarcoma (KS), a vascular tumor caused by infection with human herpesvirus 8 (HHV8), is a systemic disease that can present with cutaneous lesions with or without visceral involvement. Very few cases of KS, most of which were associated with AIDS, have been reported in the adrenal gland. Anaplastic transformation of KS is a rare clinical presentation known as an aggressive disease with local recurrence and metastatic potential. We report here a 47-year-old HIV negative male presented with extra-adrenal symptoms and had an incidentally detected anaplastic adrenal KS exhibited aggressive clinical course. To the best of our knowledge, this is the first case of anaplastic primary adrenal KS without mucocutaneous involvement but subsequently developed other side adrenal metastases in an HIV negative patient. PMID:27747121

  11. A Challenging Case of Rapid Progressive Kaposi Sarcoma After Renal Transplantation

    PubMed Central

    Reuter, Stefan; Vrachimis, Alexis; Huss, Sebastian; Wardelmann, Eva; Weckesser, Mathias; Pavenstädt, Hermann

    2014-01-01

    Abstract De-novo malignancy is a serious posttransplant complication. While the incidence of Kaposi sarcoma (KS) is low, the time for its diagnosis is early after renal transplantation. Typically, it can be identified because of the classical skin lesion. We herein report an unusual case of rapid progressive KS without skin lesions in a 52-year-old patient leading to death within 8 months after kidney transplantation. This striking case illustrates the usefulness of [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography for demonstrating the cause of unexplained deterioration of patient’s condition. Early identification of KS is critical because early (modification of) therapy can substantially improve patient’s prognosis. PMID:25192485

  12. Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs

    PubMed Central

    Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming

    2009-01-01

    Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators. PMID:19851479

  13. Efficient lytic induction of Kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines.

    PubMed

    Kang, Hyunju; Song, Jaehyung; Choi, Kwangman; Kim, Hyeongki; Choi, Miri; Lee, So-Young; Kim, Chonsaeng; Lee, Sang Jun; Song, Moon Jung; Kang, Hyojeung; Back, Sung Hoon; Han, Sang-Bae; Cho, Sungchan

    2014-09-30

    Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection.

  14. Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus

    PubMed Central

    Nguyen, David; Struckhoff, Amanda P.; Doyle, Lisa; Bonstaff, Karlie; Del Valle, Luis; Parsons, Chris; Toole, Bryan P.; Renne, Rolf; Qin, Zhiqiang

    2016-01-01

    Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly elevated in both CD147-overexpressing and KSHV-infected HUVEC cells when compared to control cells. In the current study, we further identify the regulation of HO-1 expression and mediated cellular functions by both CD147 and KSHV-encoded LANA proteins. Targeting HO-1 by either RNAi or the chemical inhibitor, SnPP, effectively induces cell death of KSHV-infected endothelial cells (the major cellular components of KS) through DNA damage and necrosis process. By using a KS-like nude mouse model, we found that SnPP treatment significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, our data demonstrate the important role of HO-1 in the pathogenesis and tumorigenesis of KSHV-infected endothelial cells, the underlying regulatory mechanisms for HO-1 expression and targeting HO-1 may represent a promising therapeutic strategy against KSHV-related malignancies. PMID:26859574

  15. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Raggo, Camilo; Ruhl, Rebecca; McAllister, Shane; Koon, Henry; Dezube, Bruce J; Früh, Klaus; Moses, Ashlee V

    2005-06-15

    Kaposi's sarcoma-associated herpesvirus (KSHV) is involved in the development of lymphoproliferative diseases and Kaposi's sarcoma. The oncogenicity of this virus is reflected in vitro by its ability to transform B cells and endothelial cells. Infection of dermal microvascular endothelial cells (DMVEC) transforms the cells from a cobblestone-like monolayer to foci-forming spindle cells. This transformation is accompanied by dramatic changes in the cellular transcriptome. Known oncogenes, such as c-Kit, are among the KSHV-induced host genes. We previously showed that c-Kit is an essential cellular component of the KSHV-mediated transformation of DMVEC. Here, we test the hypothesis that the transformation process can be used to discover novel oncogenes. When expression of a panel of KSHV-induced cellular transcripts was inhibited with antisense oligomers, we observed inhibition of DMVEC proliferation and foci formation using antisense molecules to RDC1 and Neuritin. We further showed that transformation of KSHV-infected DMVEC was inhibited by small interfering RNA directed at RDC1 or Neuritin. Ectopic expression of Neuritin in NIH 3T3 cells resulted in changes in cell morphology and anchorage-independent growth, whereas RDC1 ectopic expression significantly increased cell proliferation. In addition, both RDC1- and Neuritin-expressing cells formed tumors in nude mice. RDC1 is an orphan G protein-coupled receptor, whereas Neuritin is a growth-promoting protein known to mediate neurite outgrowth. Neither gene has been previously implicated in tumorigenesis. Our data suggest that KSHV-mediated transformation involves exploitation of the hitherto unrealized oncogenic properties of RDC1 and Neuritin. PMID:15958552

  16. Modulation of Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Function by Hypoxia-Upregulated Protein 1

    PubMed Central

    Giffin, Louise; Yan, Feng; Major, M. Ben

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV expresses several proteins that modulate host cell signaling pathways. One of these proteins is viral interleukin-6 (vIL-6), which is a homolog of human IL-6 (hIL-6). vIL-6 is able to prevent apoptosis and promote proinflammatory signaling, angiogenesis, and cell proliferation. Although it can be secreted, vIL-6 is mainly an intracellular protein that is retained in the endoplasmic reticulum (ER). We performed affinity purification and mass spectrometry to identify novel vIL-6 binding partners and found that a cellular ER chaperone, hypoxia-upregulated protein 1 (HYOU1), interacts with vIL-6. Immunohistochemical staining reveals that both PEL and KS tumor tissues express significant amounts of HYOU1. We also show that HYOU1 increases endogenous vIL-6 protein levels and that HYOU1 facilitates vIL-6-induced JAK/STAT signaling, migration, and survival in endothelial cells. Furthermore, our data suggest that HYOU1 also modulates vIL-6's ability to induce CCL2, a chemokine involved in cell migration. Finally, we investigated the impact of HYOU1 on cellular hIL-6 signaling. Collectively, our data indicate that HYOU1 is important for vIL-6 function and may play a role in the pathogenesis of KSHV-associated cancers. IMPORTANCE KSHV vIL-6 is detectable in all KSHV-associated malignancies and promotes tumorigenesis and inflammation. We identified a cellular protein, called hypoxia-upregulated protein 1 (HYOU1), that interacts with KSHV vIL-6 and is present in KSHV-infected tumors. Our data suggest that HYOU1 facilitates the vIL-6-induced signaling, migration, and survival of endothelial cells. PMID:24920810

  17. An Alternative Kaposi's Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis

    PubMed Central

    Prasad, Alka; Lu, Michael; Lukac, David M.

    2012-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several neoplastic diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV replicates actively, via a controlled gene expression program, but can also remain latent. It had been thought that the transition from latent to lytic replication was controlled exclusively by the replication and transcription activator protein RTA (open reading frame 50 [ORF50] gene product). A dominant-negative (DN) ORF50 mutant, ORF50ΔSTAD, blocks gene expression and replication. We produced a PEL cell line derivative containing both latent KSHV genomes and an inducible ORF50ΔSTAD. We unexpectedly found that induction of apoptosis triggered high-level viral replication, even when DN ORF50ΔSTAD was present, suggesting that apoptosis triggers KSHV replication through a distinct RTA-independent pathway. We verified that apoptosis triggers KSHV replication independent of RTA using ORF50 small interfering RNA (siRNA) and also showed that caspase activity is required to trigger KSHV replication. We showed that when apoptosis triggers KSHV replication, the kinetics of late gene expression is accelerated by 12 to 24 h and that virus produced following apoptosis has reduced infectivity. KSHV therefore appears to replicate via two distinct pathways, a conventional pathway requiring RTA, with slower replication kinetics, producing virus with higher infectivity, and an alternative apoptosis-triggered pathway that does not require RTA, has faster replication kinetics, and produces virus with lower infectivity. The existence of a distinct apoptosis-triggered, accelerated replication pathway may have evolutionary advantages for the virus and clinical significance for the treatment of KSHV-associated neoplasms. It also provides further evidence that KSHV can sense and react to its environment. PMID:22345480

  18. Kaposi's Sarcoma

    MedlinePlus

    ... are nodular and infiltrating. While it can have aggressive skin involvement the internal involvement is usually mild. ... the age of 10 years. It has an aggressive nature and its victims usually die within 2 ...

  19. CD147 and downstream ADAMTSs promote the tumorigenicity of Kaposi's sarcoma-associated herpesvirus infected endothelial cells

    PubMed Central

    Dai, Lu; Trillo-Tinoco, Jimena; Chen, Yihan; Bonstaff, Karlie; Del Valle, Luis; Parsons, Chris; Ochoa, Augusto C.; Zabaleta, Jovanny; Toole, Bryan P.; Qin, Zhiqiang

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS), which preferentially arise in immunocompromised patients and lack effective therapeutic options. We have previously shown that KSHV or viral protein LANA up-regulates the glycoprotein CD147, thereby inducing primary endothelial cell invasiveness. In the current study, we identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among downstream genes, two specific metalloproteases, ADAMTS1 and 9, are strongly expressed in AIDS-KS tissues and contribute to KSHV-infected endothelial cell invasiveness through up-regulation of IL-6 and VEGF. By using a KS-like nude mouse model, we found that targeting CD147 and downstream ADAMTSs significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, targeting CD147 and associated proteins may represent a promising therapeutic strategy against these KSHV-related malignancies. PMID:26675551

  20. Characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear RNA encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8).

    PubMed Central

    Zhong, W; Ganem, D

    1997-01-01

    Infection with Kaposi's sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus 8) is strongly linked to all forms of Kaposi's sarcoma. We have previously identified two polyadenylated KSHV transcripts that are actively transcribed in Kaposi's sarcoma (KS) tumors and in KSHV-infected B-lymphoma cells. One of these RNAs (termed T1.1 or nut-1 RNA) is a 1.1-kb transcript present in a subpopulation of KS tumor cells. This RNA is localized to the nucleus of infected cells and has no open reading frames longer than 62 codons, suggesting that it may not function as an mRNA in vivo. Here we demonstrate that nut-1 RNA is a lytic-cycle gene product that is found in high-molecular-weight ribonucleoprotein complexes in infected cell nuclei. The transcript lacks the trimethylguanosine (TMG) cap found in many U-like small nuclear RNAs, but a subpopulation of nut-1 RNAs can associate with Sm protein-containing small nuclear ribonucleoproteins, as judged by immunoprecipitation analyses using monoclonal anti-Sm and anti-TMG antibodies. This interaction does not require other viral gene products, and deletion of the sole candidate Sm binding site on nut-1 RNA does not ablate this association. This finding suggests an indirect interaction with Sm-containing structures, and models for such associations are presented. PMID:8995643

  1. Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.

    PubMed

    Shamay, Meir; Krithivas, Anita; Zhang, Jun; Hayward, S Diane

    2006-09-26

    The Kaposi's sarcoma-associated herpesvirus LANA protein is expressed in all Kaposi's sarcoma-associated herpesvirus-infected cells, including the tumor cells of endemic and AIDS-associated Kaposi sarcoma, primary effusion lymphoma, and Castleman disease. LANA modulates cell gene expression, but the mechanisms of LANA-mediated transcriptional reprogramming are poorly understood. LANA-repressed cell genes were identified by using retroviral-transduced telomerase-immortalized microvascular endothelial cells. Transciptional repression of targeted genes was relieved by treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine, suggesting a role for DNA methylation in repression. We found that LANA coprecipitated with DNA methyltransferases (Dnmts) and recruited endogenous DNA methyltransferase activity from the cell extract. LANA preferentially relocalized Dnmt3a from the nuclear matrix into the chromatin fraction. Further, LANA associated with repressed cellular promoters, recruited Dnmt3a to DNA, and facilitated de novo promoter methylation of a down-regulated gene, cadherin 13 (H-cadherin). The data provide an example of promoter-specific epigenetic DNA modification through viral protein recruitment of de novo Dnmt activity. PMID:16983096

  2. Productively Infected Murine Kaposi's Sarcoma-Like Tumors Define New Animal Models for Studying and Targeting KSHV Oncogenesis and Replication

    PubMed Central

    Ashlock, Brittany M.; Ma, Qi; Issac, Biju; Mesri, Enrique A.

    2014-01-01

    Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). KS tumors are composed of KSHV-infected spindle cells of vascular origin with aberrant neovascularization and erythrocyte extravasation. KSHV genes expressed during both latent and lytic replicative cycles play important roles in viral oncogenesis. Animal models able to recapitulate both viral and host biological characteristics of KS are needed to elucidate oncogenic mechanisms, for developing targeted therapies, and to trace cellular components of KS ontogeny. Herein, we describe two new murine models of Kaposi's sarcoma. We found that murine bone marrow-derived cells, whether established in culture or isolated from fresh murine bone marrow, were infectable with rKSHV.219, formed KS-like tumors in immunocompromised mice and produced mature herpesvirus-like virions in vivo. Further, we show in vivo that the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) enhanced viral lytic reactivation. We propose that these novel models are ideal for studying both viral and host contributions to KSHV-induced oncogenesis as well as for testing virally-targeted antitumor strategies for the treatment of Kaposi's sarcoma. Furthermore, our isolation of bone marrow-derived cell populations containing a cell type that, when infected with KSHV, renders a tumorigenic KS-like spindle cell, should facilitate systematic identification of KS progenitor cells. PMID:24489895

  3. Steroids are a risk factor for Kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection

    PubMed Central

    Fernández-Sánchez, Mónica; Iglesias, María C.; Ablanedo-Terrazas, Yuria; Ormsby, Christopher E.; Alvarado-de la Barrera, Claudia; Reyes-Terán, Gustavo

    2016-01-01

    Objectives: To investigate the association between Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) and mortality, with the use of glucocorticoids in HIV-infected individuals. Design: Case–control study. Methods: We reviewed the medical records of 145 individuals with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. The association of different variables with KS-IRIS and Kaposi's sarcoma-related mortality was explored by univariate and multivariate analyses. The main exposure of interest was the use of glucocorticoids. We also compared the time to KS-IRIS and the time to death of individuals treated with glucocorticoids vs. those nontreated with glucocorticoids, and the time to death of individuals with KS-IRIS vs. those without KS-IRIS by hazards regression. Results: Sixty of 145 individuals received glucocorticoids (41.4%) for the management or suspicion of Pneumocystis jirovecii pneumonia. Fifty individuals had KS-IRIS (37%). The use of glucocorticoids was more frequent in individuals with KS-IRIS than in those without KS-IRIS (54.9 vs. 36.47%, P = 0.047). Kaposi's sarcoma-related mortality occurred in 17 cases (11.7%), and glucocorticoid use was more frequent in this group (76.47 vs. 36.7%, P = 0.003). Glucocorticoid use was a risk factor for mortality (adjusted odds ratio = 4.719, 95% confidence interval = 1.383–16.103, P = 0.0132), and was associated with shorter periods to KS-IRIS (P = 0.03) and death (P = 0.0073). KS-IRIS was a risk factor for mortality (P = 0.049). Conclusion: In HIV-infected individuals, the use of glucocorticoids is a risk factor for KS-IRIS and Kaposi's sarcoma-associated mortality. In addition, KS-IRIS is a risk factor for mortality. Therefore, glucocorticoid administration in this population requires careful consideration based on individualized risk–benefit analysis. PMID:26636923

  4. MicroRNA-Mediated Transformation by the Kaposi's Sarcoma-Associated Herpesvirus Kaposin Locus

    PubMed Central

    Forte, Eleonora; Raja, Archana N.; Shamulailatpam, Priscilla; Manzano, Mark; Schipma, Matthew J.; Casey, John L.

    2014-01-01

    ABSTRACT The human oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a set of ∼20 viral microRNAs (miRNAs). miR-K10a stands out among these miRNAs because its entire stem-loop precursor overlaps the coding sequence for the Kaposin (Kap) A/C proteins. The ectopic expression of KapA has been reported to lead to transformation of rodent fibroblasts. However, these experiments inadvertently also introduced miR-K10a, which raises the question whether the transforming activity of the locus could in fact be due to miR-K10a expression. To answer this question, we have uncoupled miR-K10a and KapA expression. Our experiments revealed that miR-K10a alone transformed cells with an efficiency similar to that when it was coexpressed with KapA. Maintenance of the transformed phenotype was conditional upon continued miR-K10a but not KapA protein expression, consistent with its dependence on miRNA-mediated changes in gene expression. Importantly, miR-K10a taps into an evolutionarily conserved network of miR-142-3p targets, several of which are expressed in 3T3 cells and are also known inhibitors of cellular transformation. In summary, our studies of miR-K10a serve as an example of an unsuspected function of an mRNA whose precursor is embedded within a coding transcript. In addition, our identification of conserved miR-K10a targets that limit transformation will point the way to a better understanding of the role of this miRNA in KSHV-associated tumors. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus. The viral Kaposin locus has known oncogenic potential, which has previously been attributed to the encoded KapA protein. Here we show that the virally encoded miR-K10a miRNA, whose precursor overlaps the KapA-coding region, may account for the oncogenic properties of this locus. Our data suggest that miR-K10a mimics the cellular miRNA miR-142-3p and thereby represses several known inhibitors of oncogenic transformation. Our work

  5. Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma.

    PubMed

    Little, Richard F; Pluda, James M; Wyvill, Kathleen M; Rodriguez-Chavez, Isaac R; Tosato, Giovanna; Catanzaro, Andrew T; Steinberg, Seth M; Yarchoan, Robert

    2006-06-15

    Interleukin-12 (IL-12) enhances Th1-type T-cell responses and exerts antiangiogenic effects. We initiated a phase 1 pilot study of IL-12 in 32 patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS) whose KS was progressing while on antiretroviral therapy. Fifteen patients had poor prognosis T(1)S(1) disease. IL-12 was administered subcutaneously twice weekly at doses from 100 to 625 ng/kg. The maximum tolerated dose was 500 ng/kg, and the principal toxicities were flulike symptoms, transaminase or bilirubin elevations, neutropenia, hemolytic anemia, and depression. No tumor responses were seen at the lowest dose (100 ng/kg), but 17 of 24 evaluable patients at the higher doses had partial or complete responses (response rate, 71%; 95% confidence interval, 48%-89%). Only 3 of 17 patients had a change in antiretroviral therapy before responding, and there were no significant differences between responders and nonresponders with regard to changes in CD4 counts or viral loads. Patients had increases in their serum IL-12, interferon-gamma, and inducible protein-10 (IP-10) after the first dose, and increases above baseline persisted after week 4. These results provide preliminary evidence that IL-12 has substantial activity against AIDS-related KS with acceptable toxicity and warrants further investigation for this indication.

  6. African Kaposi's sarcoma in the light of global AIDS: antiblackness and viral visibility.

    PubMed

    Singh, Pawan; Cartwright, Lisa; Visperas, Cristina

    2014-12-01

    Drawing on the theoretical frameworks of antiblackness and intersectionality and the concept of viral visibility, this essay attends to the considerable archive of research about endemic Kaposi's sarcoma (KS) in sub-Saharan Africa accrued during the mid-20th century. This body of data was inexplicably overlooked in Western research into KS during the first decade of the AIDS epidemic, during which period European and Mediterranean KS cases were most often cited as precedents despite the volume of African data available. This paper returns to the research on KS conducted in Africa during the colonial and postcolonial period to consider visibility, racial erasure, and discourses of global epidemiology, suggesting that the dynamics of medical research on HIV/AIDS have proceeded according to a tacit paradigm of antiblackness manifest in multiple exclusions of Africa from global health agendas--most recently the exclusion of the region from antiretroviral (ARV) drug therapy during the first decades of the treatment's availability. During that decade KS all but disappeared among people with access to ARV therapy while KS became even more prevalent in sub-Saharan Africa, escalating along with HIV.

  7. Kaposi's sarcoma with HHV8 infection and ANCA-associated vasculitis in a hemodialysis patient.

    PubMed

    Fatma, Lilia Ben; Rais, Lamia; Mebazza, Amel; Azzouz, Haifa; Beji, Somaya; Krid, Madiha; Smaoui, Wided; Maiz, Hedi Ben; Zouaghi, Karim; Zitouna, Moncef; Osmane, Amel Ben; Moussa, Fatma Ben

    2013-11-01

    The association between Kaposi's sarcoma (KS) and human herpes virus eight (HHV-8) infection is rarely reported in hemodialysis (HD) patients. We report here the rare association of KS, HHV-8 and hepatitis C virus (HCV) infection as well as syphilis in a HD patient. We report the case of a 72-year-old woman who presented with microscopic polyangiitis with alveolar hemorrhage and pauci-immune necrosing and crescentic glomerulonephritis as well as renal failure requiring HD. Biological tests showed positive HCV and syphilis tests. The patient was treated by HD and intravenous pulse, followed by oral corticosteroids and six cyclophosphamide monthly pulses with remission of the alveolar hemorrhage, but without renal functional recovery as the patient remained HD dependent. Five months after the first treatment administration, she developed extensive purpuric lesions on her lower limbs, abdomen face and neck. A skin biopsy showed KS. The HHV-8 test was positive, with positive polymerase chain reaction-HHV8 in the serum and skin. After immunosuppression withdrawal, the KS skin lesions regressed rapidly without relapse after 12 months of follow-up, but alveolar hemorrhage relapsed after 16 months of follow-up. Our case showed that the immunosuppressed state related to multiple factors such as aging, vasculitis, HHV-8, HCV, syphilis, immunosuppressive therapy and HD may all have contributed to the development of KS in our patient. PMID:24231484

  8. HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS

    PubMed Central

    Lamers, Susanna L.; Nolan, David J.; Barbier, Andrew E.; Salemi, Marco

    2016-01-01

    Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression. PMID:27651732

  9. Efficient lytic induction of Kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines.

    PubMed

    Kang, Hyunju; Song, Jaehyung; Choi, Kwangman; Kim, Hyeongki; Choi, Miri; Lee, So-Young; Kim, Chonsaeng; Lee, Sang Jun; Song, Moon Jung; Kang, Hyojeung; Back, Sung Hoon; Han, Sang-Bae; Cho, Sungchan

    2014-09-30

    Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection. PMID:25237786

  10. Characteristics of HIV-1-associated Kaposi's sarcoma among women and men in South Africa.

    PubMed

    Mosam, A; Hurkchand, H P; Cassol, E; Page, T; Cassol, S; Bodasing, U; Aboobaker, J; Dawood, H; Friedland, G H; Coovadia, H M

    2008-06-01

    Despite the increase of HIV-1-associated Kaposi's sarcoma (KS), little is known about HIV-associated KS in the African setting, particularly among women. A descriptive study of the demographic, clinical, immunological and virological features of AIDS-associated KS from KwaZulu-Natal, South Africa was undertaken. Consecutively, recruited patients were clinically staged; CD4/CD8 cell counts, HIV-1 viral loads and clinical parameters were evaluated. Of the 152 patients (77 male and 75 female) 99% were black. Females were significantly younger (P = 0.02) and had poorer disease prognosis (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.4-5.4, P = 0.003) and were more likely to have extensive cutaneous KS when compared with males (OR = 3.1, 95% CI = 1.4-6.7, P = 0.003). One-third of patients had coexisting HIV-related disease, most commonly tuberculosis, and these were more frequent in females (56.7 vs. 43.3%). In conclusion, HIV-associated KS in South Africans has an equal female-to-male ratio. Females are younger and have more severe disease than males. PMID:18595878

  11. An immunohistochemical study of p53 protein expression in classical Kaposi's sarcoma.

    PubMed

    Bergman, R; Ramon, M; Kilim, S; Lichtig, C; Friedman-Birnbaum, R

    1996-08-01

    The present study was performed to determine the frequency of p53 protein immunoreactivity in classical Kaposi's sarcoma (KS) as a whole and in relation to the histological subtypes which are considered to correspond to the developmental stages of the tumor. The accumulation of p53 protein was studied immunohistochemically using monoclonal antibody BP53-12 on formalin-fixed paraffin-embedded sections of 36 KS lesions, of which 14 were classified histologically as early type and 22 as spindle-cell or mixed type. No positive immunoreactivity was detected in any of the 14 early-type lesions. Among the 22 spindle-cell and mixed variants, positive staining was detected in 5-10% of the tumor cells in one lesion, 1-5% of the cells in six lesions, and in < 1% of the cells in two lesions. These very small percentages of positively stained cells in less than half of the cases of the spindle-cell and mixed variants do not support a significant role for p53 in tumor progression and evolution in KS.

  12. Tertiary syphilis and Kaposi sarcoma mistaken for systemic sarcoidosis in an HIV-negative patient.

    PubMed

    Anyasodor, M C; Bewley, A

    2015-12-01

    We describe a case of an HIV-negative man who was mistakenly diagnosed as having systemic sarcoidosis, which led to a delay in diagnosing tertiary syphilis and Kaposi sarcoma (KS). The patient presented initially with scrotal swelling and leg oedema. Initial blood tests were unremarkable and HIV testing was negative. The patient then developed unilateral limb weakness. Computed tomography showed lung lesions and hilar lymphadenopathy, while magnetic resonance imaging showed an increased signal in the cervical cord. Serum angiotensin-converting enzyme was raised, and a diagnosis of sarcoidosis was made and the patient started on steroids. Subsequently, his clinical symptoms and radiological abnormalities improved. However, he then developed progressive neurological deficits over several weeks, together with uveitis and cutaneous lesions. A uveitis screen showed a raised venereal disease research laboratory test titre and the cause of his multisystemic symptoms was revisited. He was diagnosed with tertiary syphilis and treated with antibiotics. Dermatologists reviewed the skin lesions and diagnosed KS, which was confirmed with biopsies. The patient's neurological deficit remains. Syphilis should be considered in the differential diagnosis of any patient presenting with neurological problems, skin lesions or symptoms affecting multiple systems. Co-existing KS presented an extra therapeutic challenge in this case.

  13. HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS

    PubMed Central

    Lamers, Susanna L.; Nolan, David J.; Barbier, Andrew E.; Salemi, Marco

    2016-01-01

    Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression.

  14. Trends in Kaposi's Sarcoma in Miami Beach from 1987 to 2007

    PubMed Central

    Zeichner, Simon B.; Ruiz, Ana L.; Suciu, Gabriel P.; Zeichner, Rachel Lerner; Rodriguez, Estelamari

    2012-01-01

    Purpose. Kaposi's sarcoma (KS) is a rare low-grade vascular tumor associated with the human herpes virus 8. By analyzing the epidemiology, staging, and treatment of KS, we hoped to improve the quality of care at our institution. Methods. Review of the Mount Sinai Medical Center tumor registry database in Miami Beach, FL, USA, identified 143 cases of KS between January 1, 1987 and December 31, 2007. Results. The majority of patients were non-Hispanic whites, non smoking males diagnosed between 1987 and 1996. Most of the patients were HIV positive, with an equal percentage diagnosed with local or distant disease. Most patients received no chemotherapy or radiation. There were no significant differences in patient survival based on sex, HIV status, or radiation received. There was a trend toward improved survival among older patients who smoked, received no chemotherapy, and had localized stage at diagnosis. Multivariate analysis revealed that non-Hispanic whites had a significant worse survival than Hispanic whites (HR = 0.55, 95% CI (0.33, 0.90), P = 0.02). Patients diagnosed between 1987 and 1996 had a worse survival than those between 1997 and 2007 (HR = 0.33 (95% CI 0.19, 0.55), P < 0.0001). Conclusion. This large retrospective study provides further insight into KS. Ethnicity and date of diagnosis are important predictors of long-term survival. PMID:23320191

  15. HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS.

    PubMed

    Lamers, Susanna L; Rose, Rebecca; Nolan, David J; Fogel, Gary B; Barbier, Andrew E; Salemi, Marco; McGrath, Michael S

    2016-01-01

    Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression. PMID:27651732

  16. Kaposi's sarcoma with HHV8 infection and ANCA-associated vasculitis in a hemodialysis patient.

    PubMed

    Fatma, Lilia Ben; Rais, Lamia; Mebazza, Amel; Azzouz, Haifa; Beji, Somaya; Krid, Madiha; Smaoui, Wided; Maiz, Hedi Ben; Zouaghi, Karim; Zitouna, Moncef; Osmane, Amel Ben; Moussa, Fatma Ben

    2013-11-01

    The association between Kaposi's sarcoma (KS) and human herpes virus eight (HHV-8) infection is rarely reported in hemodialysis (HD) patients. We report here the rare association of KS, HHV-8 and hepatitis C virus (HCV) infection as well as syphilis in a HD patient. We report the case of a 72-year-old woman who presented with microscopic polyangiitis with alveolar hemorrhage and pauci-immune necrosing and crescentic glomerulonephritis as well as renal failure requiring HD. Biological tests showed positive HCV and syphilis tests. The patient was treated by HD and intravenous pulse, followed by oral corticosteroids and six cyclophosphamide monthly pulses with remission of the alveolar hemorrhage, but without renal functional recovery as the patient remained HD dependent. Five months after the first treatment administration, she developed extensive purpuric lesions on her lower limbs, abdomen face and neck. A skin biopsy showed KS. The HHV-8 test was positive, with positive polymerase chain reaction-HHV8 in the serum and skin. After immunosuppression withdrawal, the KS skin lesions regressed rapidly without relapse after 12 months of follow-up, but alveolar hemorrhage relapsed after 16 months of follow-up. Our case showed that the immunosuppressed state related to multiple factors such as aging, vasculitis, HHV-8, HCV, syphilis, immunosuppressive therapy and HD may all have contributed to the development of KS in our patient.

  17. African Kaposi's sarcoma in the light of global AIDS: antiblackness and viral visibility.

    PubMed

    Singh, Pawan; Cartwright, Lisa; Visperas, Cristina

    2014-12-01

    Drawing on the theoretical frameworks of antiblackness and intersectionality and the concept of viral visibility, this essay attends to the considerable archive of research about endemic Kaposi's sarcoma (KS) in sub-Saharan Africa accrued during the mid-20th century. This body of data was inexplicably overlooked in Western research into KS during the first decade of the AIDS epidemic, during which period European and Mediterranean KS cases were most often cited as precedents despite the volume of African data available. This paper returns to the research on KS conducted in Africa during the colonial and postcolonial period to consider visibility, racial erasure, and discourses of global epidemiology, suggesting that the dynamics of medical research on HIV/AIDS have proceeded according to a tacit paradigm of antiblackness manifest in multiple exclusions of Africa from global health agendas--most recently the exclusion of the region from antiretroviral (ARV) drug therapy during the first decades of the treatment's availability. During that decade KS all but disappeared among people with access to ARV therapy while KS became even more prevalent in sub-Saharan Africa, escalating along with HIV. PMID:25304011

  18. AIDS-related Kaposi's sarcoma: evidence for direct stimulatory effect of glucocorticoid on cell proliferation.

    PubMed Central

    Guo, W. X.; Antakly, T.

    1995-01-01

    Glucocorticoid therapy has been linked to increased risk of development of Kaposi's sarcoma (KS), which has become epidemic among HIV-infected individuals. However, no experimental evidence is available to explain the role of glucocorticoid in KS biopathology. We investigated the direct effect of dexamethasone (Dex) on the growth of cultured KS cells derived from acquired immune deficiency syndrome (AIDS) patients (AIDS-KS). Dex significantly stimulated the proliferation of AIDS-KS cells. Moreover, simultaneous exposure to Dex and oncostatin M, a KS major cytokine, produced a dramatic synergistic effect on proliferation of AIDS-KS cell. This suggests an interaction between glucocorticoid and growth factor intracellular pathways in KS cells. The expression of glucocorticoid receptor protein and mRNA in AIDS-KS cell cultures was examined by radioimmunoassay and in situ hybridization, respectively. Compared with other well studied cell lines, AIDS-KS cells contain an unusually high level of glucocorticoid receptor protein, which is further upregulated by glucocorticoid treatment. RU-486, a glucocorticoid receptor antagonist, completely abolished the stimulatory effect of Dex and reduced the synergistic effect of Dex and oncostatin M on proliferation of AIDS-KS. These findings demonstrate that glucocorticoid stimulates directly the proliferation of AIDS-KS cells via the modulation of glucocorticoid receptor expression. Images Figure 3 PMID:7887453

  19. Gastrointestinal Bleeding and Diffuse Skin Thickening as Kaposi Sarcoma Clinical Presentation.

    PubMed

    Querido, Sara; Sousa, Henrique Silva; Pereira, Tiago Assis; Birne, Rita; Matias, Patrícia; Jorge, Cristina; Weigert, André; Adragão, Teresa; Bruges, Margarida; Machado, Domingos

    2015-01-01

    A 56-year-old African patient received a kidney from a deceased donor with 4 HLA mismatches in April 2013. He received immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil, and prednisone. Immediate diuresis and a good allograft function were soon observed. Six months later, the serum creatinine level increased to 2.6 mg/dL. A renal allograft biopsy revealed interstitial fibrosis and tubular atrophy grade II. Toxicity of calcineurin inhibitor was assumed and, after a switch for everolimus, renal function improved. However, since March 2014, renal function progressively deteriorated. A second allograft biopsy showed no new lesions. Two months later, the patient was admitted due to anuria, haematochezia with anaemia, requiring 5 units of packed red blood cells, and diffuse skin thickening. Colonoscopy showed haemorrhagic patches in the colon and the rectum; histology diagnosis was Kaposi sarcoma (KS). A skin biopsy revealed cutaneous involvement of KS. Rapid clinical deterioration culminated in death in June 2014. This case is unusual as less than 20 cases of KS with gross gastrointestinal bleeding have been reported and only 6 cases had the referred bleeding originating in the lower gastrointestinal tract. So, KS should be considered in differential diagnosis of gastrointestinal bleeding in some kidney transplant patients. PMID:26783491

  20. Identification and characterization of Kaposi's sarcoma-associated herpesvirus open reading frame 11 promotor activation

    SciTech Connect

    Chen, Lei

    2008-01-01

    Open reading frame 11 (ORF11) of Kaposi's sarcoma-associated herpesvirus belongs to a herpesviral homologous protein family shared by some members of the gamma- herpesvirus subfamily. Little is known about this ORF11 homologous protein family. We have characterized an unknown open reading frame, ORF11, located adjacent and in the opposite orientation to a well-characterized viral IL-6 gene. Northern blot analysis reveals that ORF11 is expressed during the KSHV lytic cycle with delayed-early transcription kinetics. We have determined the 5{prime} and 3{prime} untranslated region of the unspliced ORF11 transcript and identified both the transcription start site and the transcription termination site. Core promoter region, representing ORF11 promoter activity, was mapped to a 159nt fragment 5{prime} most proximal to the transcription start site. A functional TATA box was identified in the core promoter region. Interestingly, we found that ORF11 transcriptional activation is not responsive to Rta, the KSHV lytic switch protein. We also discovered that part of the ORF11 promoter region, the 209nt fragment upstream of the transcription start site, was repressed by phorbol esters. Our data help to understand transcription regulation of ORF11 and to elucidate roles of ORF11 in KSHV pathogenesis and life cycle.

  1. The role of vascular endothelial growth factor (VEGF) in AIDS-related Kaposi's sarcoma.

    PubMed

    Arastéh, K; Hannah, A

    2000-01-01

    Kaposi's sarcoma (KS) is the most common neoplasm associated with human immunodeficiency virus-1 (HIV-1) infection. KS involves the skin and mucous membranes as well as other organs and can lead to tumor-associated edema and ulcerations. Despite therapy with highly active antiviral agents, most patients with HIV-1-related KS eventually develop disseminated disease. In the treatment of KS, a strong rationale exists for the use of agents that inhibit vascular endothelial growth factor (VEGF). Angiogenesis appears to be an important feature of this disease, and recent experimental studies have demonstrated the role of VEGF and its receptors in the pathogenesis of KS. Thus, therapeutic agents that target the VEGF pathway may be an effective strategy in reducing the tumor growth and edema associated with KS. Phase I study results with SU5416, a synthetic low molecular-weight inhibitor of the VEGF-Flk-1/KDR receptor tyrosine kinase, demonstrate that this agent is well tolerated. Preliminary results show that in a majority of patients with autoimmune deficiency syndrome (AIDS)-related disease, SU5416 clearly has biological activity (it flattens, shrinks, or dissolves lesions and reduces or resolves edema) or stabilizes the disease. Angiogenesis inhibition with SU5416 is a promising therapeutic approach in treating patients with KS, and further clinical evaluation is currently under way.

  2. Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

    PubMed Central

    Hanson, Ryan S.; Manion, Rory D.

    2015-01-01

    Kaposi's sarcoma (KS) is common in Africa, but economic constraints hinder successful treatment in most patients. Propranolol, a generic β-adrenergic antagonist, decreased proliferation of KS-associated herpesvirus (KSHV)-infected cells. Downregulation of cyclin A2 and cyclin-dependent kinase 1 (CDK1) recapitulated this phenotype. Additionally, propranolol induced lytic gene expression in association with downregulation of CDK6. Thus, propranolol has diverse effects on KSHV-infected cells, and this generic drug has potential as a therapeutic agent for KS. PMID:26269192

  3. Disintegrin-like domain of glycoprotein B regulates Kaposi's sarcoma-associated herpesvirus infection of cells.

    PubMed

    Walker, Lia R; Hussein, Hosni A M; Akula, Shaw M

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) glycoprotein B (gB) is a lytic structural protein expressed on the envelope of mature virions and on the membrane of cells supporting lytic infection. In addition to this viral glycoprotein's interaction with integrins via its RGD (Arg-Gly-Asp) motif, KSHV gB possesses a disintegrin-like domain (DLD), which binds integrins as well. Prior to this study, there has been minimal research involving the less common integrin-binding motif, DLD, of gB as it pertains to herpesvirus infection. By using phage display peptide library screening and molecular biology techniques, the DLD of KSHV gB was shown to interact specifically with non-RGD binding α9β1 integrins. Similarly, monitoring wild-type infection confirmed α9β1:DLD interactions to be critical to successful KSHV infection of human foreskin fibroblast (HFF) cells and human dermal microvascular endothelial cells (HMVEC-d) compared with 293 cells. To further demonstrate the importance of the DLD of gB in KSHV infection, two recombinant virus constructs were generated using a bacterial artificial chromosome (BAC) system harbouring the KSHV genome (BAC36): BAC36ΔD-KSHV (lacking a functionally intact DLD of gB and containing an introduced tetracycline cassette) and BAC36.T-KSHV (containing an intact DLD sequence and an introduced tetracycline cassette). Accordingly, BAC36ΔD-KSHV presented significantly lower infection rates in HFF and HMVEC-d cells compared with the comparable infection rates achieved by wild-type BAC36-KSHV and BAC36.T-KSHV. Thus, the present report has delineated a critical role for the DLD of gB in KSHV infection, which may lead to a broader knowledge regarding the sophisticated mechanisms utilized by virus-encoded structural proteins in KSHV entry and infection.

  4. Desferrioxamine enhances AIDS-associated Kaposi's sarcoma tumor development in a xenograft model.

    PubMed

    Simonart, Thierry; Boelaert, Johan R; Andrei, Graciela; van den Oord, Joost J; Degraef, Chantale; Hermans, Philippe; Noel, Jean-Christophe; Van Vooren, Jean-Paul; Heenen, Michel; De Clercq, Erik; Snoeck, Robert

    2002-07-10

    Iron is suspected to be involved in the induction and/or progression of various human tumors. More particularly, we have previously shown that iron may be involved in the pathogenesis of Kaposi's sarcoma (KS). We have also shown that the iron chelator desferrioxamine (DFO) has a potent anti-KS activity in vitro, suggesting that it may represent a potential therapeutic approach for the treatment of KS. The present study was designed to investigate the effect of DFO on the growth of human KS xenografts in immunodeficient mice. Unexpectedly, we found that mice treated with DFO (400 mg/kg, 3 times weekly) (n = 30) exhibited a marked enhancement of tumor growth compared with control mice (n = 33) (230 +/- 134 mm(2) versus 143 +/- 70 mm p < 0.01). No enhancement of tumor growth was seen in mice treated with iron-saturated DFO. At least 2 findings suggest that this paradoxic pro-KS activity occurred independently of mice iron stores. First, treatment with DFO had only a marginal effect on ferritin and hematocrit levels. Second, induction of effective iron depletion by an iron-poor diet (6.7 mg iron/kg diet) (n = 23) did not have a deleterious effect on the growth of the KS xenografts. The lesions obtained from the DFO-treated animals exhibited a significantly decreased apoptotic index (p < 0.05), indicating that some antiapoptotic mechanism induced by DFO may be operating in vivo to favour tumor growth. In conclusion, our data show that DFO has a stimulatory effect on KS growth in immunodeficient mice, suggesting that this drug is not indicated in patients with KS.

  5. Lipid- and adenoviral-mediated gene transfer into AIDS-Kaposi's sarcoma cell lines.

    PubMed

    Campain, J A; Matassa, A A; Felgner, P L; Barnhart, K M; Curiel, D T; Harrison, G S

    1998-01-01

    Kaposi's sarcoma (KS) is the most frequent malignancy occurring in HIV-positive individuals. AIDS-KS is a more aggressive disease than the classical form, frequently having a rapid clinical course with numerous serious complications. Current systemic treatments for KS, such as chemotherapy and the administration of biological modifiers, are complicated by both the drug resistance of the tumor and the dose-limiting toxicity of the reagents. The relative accessibility of many KS lesions makes the disease a particularly attractive candidate for in vivo gene therapy protocols. In this regard, we are interested in delivering conditionally toxic suicide and/or antiangiogenic vectors to accomplish targeted cell death selectively in AIDS-KS cells. To this end, we examined both cationic lipid- and adenoviral-mediated DNA transfection methods. Using the firefly luciferase reporter gene, we optimized numerous variables known to be important in lipid-mediated DNA transfection, including lipid formulation, the amount of lipid and DNA, lipid/DNA ratio, and cell concentration. Under optimal transfection conditions, approximately 5-25% of KS cells expressed the introduced DNA sequences. Adenoviral-mediated DNA delivery was more efficient than lipid delivery in 4 of 5 primary KS cell lines. Two of the lines (RW248 and RW376) were transduced by adenovirus at frequencies approaching 100%; two cell lines (CVU-1 and RW80) gave efficiencies of 20-35%. Two immortalized KS cell lines (KS Y-1 and KS SLK) were poorly infected, giving a transduction efficiency of <5%. These findings demonstrate that gene transfer into AIDS-KS cells is feasible, and suggest that vector strategies may be permissive for translating gene therapy approaches for the disease.

  6. Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)

    PubMed Central

    Alcendor, Donald; Knobel, Susan

    2010-01-01

    Currently KS is the most predominant HIV/AIDS related malignancy in Southern Africa and hence the world.1,2 It is characterized as an angioproliferative tumor of vascular endothelial cells and produces rare B cell lymphoproliferative diseases in the form of pleural effusion lymphomas (PEL) and some forms of multicentric Castleman's disease.3-5 Only 1-5% of cells in KS lesions actively support lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent associated with KS, and it is clear that cellular factors must interact with viral factors in the process of oncogenesis and tumor progression.6,7 Identifying novel host-factor determinants which contribute to KS pathology is essential for developing prognostic markers for tumor progression and metastasis as well as for developing novel therapeutics for the treatment of KS.8 The accompanying video details the methods we use to identify host cell gene expression programs altered in dermal microvascular endothelial cells (DMVEC) after KSHV infection and in KS tumor tissue.9 Once dysregulated genes are identified by microarray analysis, changes in protein expression are confirmed by immunoblot and dual labeled immunofluorescence. Changes in transcriptional expression of dysregulated genes are confirmed in vitro by quantitative real-time polymerase chain reaction (qRT-PCR). Validation of in vitro findings using archival KS tumor tissue is also performed by dual labeled immunochemistry and tissue microarrays.8,10 Our approach to identifying dysregulated genes in the KS tumor tissue microenvironment will allow the development of in vitro and subsequently in vivo model systems for discovery and evaluation of potential novel therapeutic for the treatment of KS. PMID:20864930

  7. Intracellular-activated Notch1 can reactivate Kaposi's sarcoma-associated herpesvirus from latency

    SciTech Connect

    Lan, Ke; Murakami, Masanao; Choudhuri, Tathagata; Kuppers, Daniel A.; Robertson, Erle S. . E-mail: erle@mail.med.upenn.edu

    2006-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a predominantly latent infection in the infected host. Importantly, during latency, only a small number of viral encoded genes are expressed. This viral gene expression pattern contributes to the establishment of long-term infection as well as the ability of the virus to evade the immune system. Previous studies have been shown that the replication and transcription activator (RTA) encoded by ORF50 activates it downstream genes and initiates viral lytic reactivation through functional interaction with RBP-J{kappa}, the major downstream effector of the Notch signaling pathway. This indicates that RTA can usurp the conserved Notch signaling pathway and mimic the activities of intracellular Notch1 to modulate gene expression. In this report, we show that the activated intracellular domain of Notch1 (ICN) is aberrantly accumulated in KSHV latently infected pleural effusion lymphoma (PEL) cells. ICN activated the RTA promoter in a dose-dependent manner, and forced expression of ICN in latently infected KSHV-positive cells initiated full blown lytic replication with the production of infectious viral progeny. However, latency-associated nuclear antigen (LANA) which is predominantly expressed during latency can specifically down-modulate ICN-mediated transactivation of RTA and so control KSHV for lytic reactivation. These results demonstrate that LANA can inhibit viral lytic replication by antagonizing ICN function and suggest that LANA is a critical component of the regulatory control mechanism for switching between viral latent and lytic replication by directly interacting with effectors of the conserved cellular Notch1 pathway.

  8. A novel mechanism inducing genome instability in Kaposi's sarcoma-associated herpesvirus infected cells.

    PubMed

    Jackson, Brian R; Noerenberg, Marko; Whitehouse, Adrian

    2014-05-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX) proteins have been identified in high-grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1) ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. PMID:24788796

  9. Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis.

    PubMed

    Chudasama, P; Konrad, A; Jochmann, R; Lausen, B; Holz, P; Naschberger, E; Neipel, F; Britzen-Laurent, N; Stürzl, M

    2015-01-29

    The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV-infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection. PMID:24469037

  10. HHV-8 infection in patients with AIDS-related Kaposi's sarcoma in Brazil.

    PubMed

    Keller, R; Zago, A; Viana, M C; Bourboulia, D; Desgranges, C; Casseb, J; Moura, W V; Dietze, R; Collandre, H

    2001-07-01

    The aims of the present study were to determine the prevalence of human herpesvirus type 8 (HHV-8) in HIV-positive Brazilian patients with (HIV+/KS+) and without Kaposi's sarcoma (HIV+/KS-) using PCR and immunofluorescence assays, to assess its association with KS disease, to evaluate the performance of these tests in detecting HHV-8 infection, and to investigate the association between anti-HHV-8 antibody titers, CD4 counts and staging of KS disease. Blood samples from 66 patients, 39 HIV+/KS+ and 27 HIV+/KS-, were analyzed for HHV-8 viremia in peripheral blood mononuclear cells by PCR and HHV-8 antigenemia for latent and lytic infection by immunofluorescence assay. Positive samples for latent nuclear HHV-8 antigen (LNA) antibodies were titrated out from 1/100 to (1/4)09,600 dilution. Clinical information was collected from medical records and risk behavior was assessed through an interview. HHV-8 DNA sequences were detected by PCR in 74.3% of KS+ patients and in 3.7% of KS- patients. Serological assays were similar in detecting anti-LNA antibodies and anti-lytic antigens in sera from KS+ patients (79.5%) and KS- patients (18.5%). HHV-8 was associated with KS whatever the method used, i.e., PCR (odds ratio (OR) = 7.4, 95% confidence interval (CI) = 2.16-25.61) or anti-LNA and anti-lytic antibodies (OR = 17.0, 95%CI = 4.91-59.14). Among KS+ patients, HHV-8 titration levels correlated positively with CD4 counts (rho 0.48, P = 0.02), but not with KS staging. HHV-8 is involved in the development of KS in different geographic areas worldwide, as it is in Brazil, where HHV-8 is more frequent among HIV+ patients. KS severity was associated with immunodeficiency, but no correlation was found between HHV-8 antibody titers and KS staging.

  11. The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

    PubMed Central

    Hellert, Jan; Weidner-Glunde, Magdalena; Krausze, Joern; Lünsdorf, Heinrich; Ritter, Christiane; Schulz, Thomas F.; Lührs, Thorsten

    2015-01-01

    Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains (“LANA speckles”), a hallmark of KSHV latency. PMID:25947153

  12. The protease and the assembly protein of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8).

    PubMed Central

    Unal, A; Pray, T R; Lagunoff, M; Pennington, M W; Ganem, D; Craik, C S

    1997-01-01

    A genomic clone encoding the protease (Pr) and the assembly protein (AP) of Kaposi's sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus 8) has been isolated and sequenced. As with other herpesviruses, the Pr and AP coding regions are present within a single long open reading frame. The mature KSHV Pr and AP polypeptides are predicted to contain 230 and 283 residues, respectively. The amino acid sequence of KSHV Pr has 56% identity with that of herpesvirus salmiri, the most similar virus by phylogenetic comparison. Pr is expressed in infected human cells as a late viral gene product, as suggested by RNA analysis of KSHV-infected BCBL-1 cells. Expression of the Pr domain in Escherichia coli yields an enzymatically active species, as determined by cleavage of synthetic peptide substrates, while an active-site mutant of this same domain yields minimal proteolytic activity. Sequence comparisons with human cytomegalovirus (HCMV) Pr permitted the identification of the catalytic residues, Ser114, His46, and His134, based on the known structure of the HCMV enzyme. The amino acid sequences of the release site of KSHV Pr (Tyr-Leu-Lys-Ala*Ser-Leu-Ile-Pro) and the maturation site (Arg-Leu-Glu-Ala*Ser-Ser-Arg-Ser) show that the extended substrate binding pocket differs from that of other members of the family. The conservation of amino acids known to be involved in the dimer interface region of HCMV Pr suggests that KSHV Pr assembles in a similar fashion. These features of the viral protease provide opportunities to develop specific inhibitors of its enzymatic activity. PMID:9261433

  13. Nationwide Registry-Based Analysis of Cancer Clustering Detects Strong Familial Occurrence of Kaposi Sarcoma

    PubMed Central

    Vahteristo, Pia; Patama, Toni; Li, Yilong; Saarinen, Silva; Kilpivaara, Outi; Pitkänen, Esa; Knekt, Paul; Laaksonen, Maarit; Artama, Miia; Lehtonen, Rainer; Aaltonen, Lauri A.; Pukkala, Eero

    2013-01-01

    Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this

  14. Accuracy of Clinical Suspicion and Pathologic Diagnosis of Kaposi Sarcoma in East Africa

    PubMed Central

    Woodruff, Carina Martin; Forrestel, Amy; Wenger, Megan; McCalmont, Timothy; LeBoit, Philip; Maurer, Toby; Laker-Oketta, Miriam; Muyindike, Winnie; Bwana, Mwebesa; Buziba, Nathan; Busakhala, Naftali; Wools-Kaloustian, Kara; Martin, Jeffrey

    2016-01-01

    Background: HIV-associated Kaposi sarcoma (KS) is one of the most common malignancies in sub-Saharan Africa. The diagnosis is often based on clinical suspicion, without histopathologic confirmation. When biopsies are performed, the accuracy of interpretation by local pathologists is poorly understood. We assessed the accuracy of clinical suspicion and pathologic diagnosis of KS in 2 East African countries. Methods: At 2 large HIV care sites in Uganda and Kenya, we evaluated consecutive biopsies performed from October 2008 to January 2013 on HIV-infected adults with clinically suspected KS. Biopsies were interpreted by both local African pathologists and a group of US-based dermatopathologists from a high volume medical center. For the purpose of this analysis, the US-based dermatopathologist interpretation was used as the gold standard. Positive predictive value was used to characterize accuracy of local African clinical suspicion of KS, and concordance, sensitivity, and specificity were used to characterize accuracy of local pathologic diagnosis. Results: Among 1106 biopsies, the positive predictive value of clinical suspicion of KS was 77% (95% confidence interval: 74% to 79%). When KS was not histopathologically diagnosed, clinically banal conditions were found in 35%, medically significant disorders which required different therapy in 59% and life-threatening diseases in 6%. Concordance between African pathologists and US-based dermatopathologists was 69% (95% confidence interval: 66% to 72%). Sensitivity and specificity of African pathologic diagnoses were 68% and 89%, respectively. Conclusions: Among East African HIV-infected patients, we found suboptimal positive predictive value of clinical suspicion of KS and specific, but not sensitive, histopathologic interpretation. The findings call for abandonment of isolated clinical diagnosis of KS in the region and augmentation of local dermatopathologic services. PMID:26452066

  15. Identification, expression, and immunogenicity of Kaposi's sarcoma-associated herpesvirus-encoded small viral capsid antigen.

    PubMed Central

    Lin, S F; Sun, R; Heston, L; Gradoville, L; Shedd, D; Haglund, K; Rigsby, M; Miller, G

    1997-01-01

    We describe a recombinant antigen for use in serologic tests for antibodies to Kaposi's sarcoma (KS)-associated herpesvirus (KSHV). The cDNA for a small viral capsid antigen (sVCA) was identified by immunoscreening of a library prepared from the BC-1 body cavity lymphoma cell line induced into KSHV lytic gene expression by sodium butyrate. The cDNA specified a 170-amino-acid peptide with homology to small viral capsid proteins encoded by the BFRF3 gene of Epstein-Barr virus and the ORF65 gene of herpesvirus saimiri. KSHV sVCA was expressed from a 0.85-kb mRNA present late in lytic KSHV replication in BC-1 cells. This transcript was sensitive to phosphonoacetic acid and phosphonoformic acid, inhibitors of herpesvirus DNA replication. KSHV sVCA expressed in mammalian cells or Escherichia coli or translated in vitro was recognized as an antigen by antisera from KS patients. Rabbit antisera raised to KSHV sVCA expressed in E. coli detected a 22-kDa protein in KSHV-infected human B cells. Overexpressed KSHV sVCA purified from E. coli and used as an antigen in immunoblot screening assay did not cross-react with EBV BFRF3. Antibodies to sVCA were present in 89% of 47 human immunodeficiency virus (HIV)-positive patients with KS, in 20% of 54 HIV-positive patients without KS, but in none of 122 other patients including children born to HIV-seropositive mothers and patients with hemophilia, autoimmune disease, or nasopharyngeal carcinoma. Low-titer antibody was detected in three sera from 28 healthy subjects. Antibodies to recombinant sVCA correlate with KS in high-risk populations. Recombinant sVCA can be used to examine the seroepidemiology of infection with KSHV in the general population. PMID:9060668

  16. Rapamycin with Antiretroviral Therapy in AIDS-Associated Kaposi Sarcoma: An AIDS Malignancy Consortium Study

    PubMed Central

    Krown, Susan E.; Roy, Debasmita; Lee, Jeannette Y.; Dezube, Bruce J.; Reid, Erin G.; Venkataramanan, Raman; Han, Kelong; Cesarman, Ethel; Dittmer, Dirk P.

    2011-01-01

    Purpose The mammalian target of rapamycin (mTOR) is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mTOR-dependent signaling. Methods Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phospho-Ribosomal S6 protein (pRPS6), and phospho-Akt expression. Interleukin-6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored. Results Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of four subjects whose biopsies were studied at ≥day 50 showed decreased pRPS6 staining. Conclusions Rapamycin appears safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit. PMID:22067664

  17. Vascular endothelial growth factor regulates angiogenesis and vascular permeability in Kaposi's sarcoma.

    PubMed Central

    Cornali, E.; Zietz, C.; Benelli, R.; Weninger, W.; Masiello, L.; Breier, G.; Tschachler, E.; Albini, A.; Stürzl, M.

    1996-01-01

    Abundant vasculature with increased permeability is a prominent histological feature of Kaposi's sarcoma (KS), a multifocal, cytokine-regulated tumor. Here we report on the role of vascular endothelial growth factor (VEGF) in AIDS-KS angiogenesis and vascular permeability. We demonstrate that different cytokines, which were previously shown to be active in KS development, modulate VEGF expression in KS spindle cells and cooperate with VEGF on the functional level. Northern blot analysis as well as studies on single cells using in situ hybridization revealed that VEGF expression in cultivated AIDS-KS spindle cells is up-regulated by platelet-derived growth factor-B and interleukin-1 beta. Western blot and enzyme-linked immunosorbent assay analysis of cell culture supernatants demonstrated that the VEGF protein is secreted by stimulated AIDS-KS spindle cells in sufficiently high amounts to activate proliferation of human dermal microvascular endothelial cells. Basic fibroblast growth factor did not increase VEGF expression but acted synergistically with VEGF in the induction of angiogenic KS-like lesions in a mouse model in vivo. Angiogenesis and cellularity of KS-like lesions were clearly increased when both factors were injected simultaneously into the flanks of mice, compared with separate injection of each factor. A comparable angiogenic reaction as obtained by simultaneous injection of basic fibroblast growth factor and VEGF was observed when cell culture supernatants of AIDS-KS spindle cells were used for these experiments. Finally, analysis of primary human AIDS-KS lesions revealed that high amounts of VEGF mRNA and protein were present in KS spindle cells in vivo. These data provide evidence that VEGF, in concert with platelet-derived growth factor-B, interleukin-1 beta, and basic fibroblast growth factor, is a key mediator of angiogenesis and vascular permeability in KS lesions in vivo. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8

  18. Platelet activating factor produced in vitro by Kaposi's sarcoma cells induces and sustains in vivo angiogenesis.

    PubMed Central

    Bussolino, F; Arese, M; Montrucchio, G; Barra, L; Primo, L; Benelli, R; Sanavio, F; Aglietta, M; Ghigo, D; Rola-Pleszczynski, M R

    1995-01-01

    Imbalance in the network of soluble mediators may play a pivotal role in the pathogenesis of Kaposi's sarcoma (KS). In this study, we demonstrated that KS cells grown in vitro produced and in part released platelet activating factor (PAF), a powerful lipid mediator of inflammation and cell-to-cell communication. IL-1, TNF, and thrombin enhanced the synthesis of PAF. PAF receptor mRNA and specific, high affinity binding site for PAF were present in KS cells. Nanomolar concentration of PAF stimulated the chemotaxis and chemokinesis of KS cells, endothelial cells, and vascular smooth muscle cells. The migration response to PAF was inhibited by WEB 2170, a hetrazepinoic PAF receptor antagonist. Because neoangiogenesis is essential for the growth and progression of KS and since PAF can activate vascular endothelial cells, we examined the potential role of PAF as an instrumental mediator of angiogenesis associated with KS. Conditioned medium (CM) from KS cells (KS-CM) or KS cells themselves induced angiogenesis and macrophage recruitment in a murine model in which Matrigel was injected subcutaneously. These effects were inhibited by treating mice with WEB 2170. Synthetic PAF or natural PAF extracted from plasma of patients with classical KS also induced angiogenesis, which in turn was inhibited by WEB 2170. The action of PAF was amplified by expression of other angiogenic factors and chemokines: these included basic and acidic fibroblast growth factor, placental growth factor, vascular endothelial growth factor and its specific receptor flk-1, hepatocyte growth factor, KC, and macrophage inflammatory protein-2. Treatment with WEB 2170 abolished the expression of the transcripts of these molecules within Matrigel containing KS-CM. These results indicate that PAF may cooperate with other angiogenic molecules and chemokines in inducing vascular development in KS. Images PMID:7543496

  19. Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of Cellular miR-23

    PubMed Central

    Manzano, Mark; Shamulailatpam, Priscilla; Raja, Archana N.

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) expresses ∼20 viral microRNAs (miRNAs) in latently infected cells. We have previously shown that two of these miRNAs function as mimics of the cellular miRNAs miR-155 and miR-142-3p. Two additional KSHV miRNAs, miR-K3+1 and miR-K3, share perfect and offset 5′ homology with cellular miR-23, respectively. Here, we report a single nucleotide polymorphism that causes miR-K3+1 expression in a subset of KSHV-infected primary effusion lymphoma cell lines as a consequence of altered processing of the primary transcript by the Microprocessor complex. We confirm that miR-K3+1 regulates miR-23 targets, which is expected because these miRNAs share the entire seed region (nucleotides 2 to 8). Surprisingly, we found that miR-K3 also regulates miR-23 targets, despite offset seed sequences. In addition, the offset homology of miR-K3 to miR-23 likely allows this viral miRNA to expand its target repertoire beyond the targets of miR-23. Because miR-23 is highly expressed in endothelial cells but expressed at only low levels in B cells, we hypothesize that miR-K3 may function to introduce miR-23-like activities into KSHV-infected B cells. Together, our data demonstrate that KSHV has evolved at least three distinct viral miRNAs to tap into evolutionarily conserved cellular miRNA-regulatory networks. Furthermore, our data allow fundamental insights into the generation and functional impact of miRNA 5′ end variation. PMID:23986579

  20. Phase II Trial of Imatinib in AIDS-Associated Kaposi's Sarcoma: AIDS Malignancy Consortium Protocol 042

    PubMed Central

    Koon, Henry B.; Krown, Susan E.; Lee, Jeannette Y.; Honda, Kord; Rapisuwon, Suthee; Wang, Zhenghe; Aboulafia, David; Reid, Erin G.; Rudek, Michelle A.; Dezube, Bruce J.; Noy, Ariela

    2014-01-01

    Purpose Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. Patients and Methods This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. Results Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. Conclusion Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS. PMID:24378417

  1. A prospective ascertainment of cancer incidence in sub-Saharan Africa: The case of Kaposi sarcoma.

    PubMed

    Semeere, Aggrey; Wenger, Megan; Busakhala, Naftali; Buziba, Nathan; Bwana, Mwebesa; Muyindike, Winnie; Amerson, Erin; Maurer, Toby; McCalmont, Timothy; LeBoit, Philip; Musick, Beverly; Yiannoutsos, Constantin; Lukande, Robert; Castelnuovo, Barbara; Laker-Oketta, Miriam; Kambugu, Andrew; Glidden, David; Wools-Kaloustian, Kara; Martin, Jeffrey

    2016-05-01

    In resource-limited areas, such as sub-Saharan Africa, problems in accurate cancer case ascertainment and enumeration of the at-risk population make it difficult to estimate cancer incidence. We took advantage of a large well-enumerated healthcare system to estimate the incidence of Kaposi sarcoma (KS), a cancer which has become prominent in the HIV era and whose incidence may be changing with the rollout of antiretroviral therapy (ART). To achieve this, we evaluated HIV-infected adults receiving care between 2007 and 2012 at any of three medical centers in Kenya and Uganda that participate in the East Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortium. Through IeDEA, clinicians received training in KS recognition and biopsy equipment. We found that the overall prevalence of KS among 102,945 HIV-infected adults upon clinic enrollment was 1.4%; it declined over time at the largest site. Among 140,552 patients followed for 319,632 person-years, the age-standardized incidence rate was 334/100,000 person-years (95% CI: 314-354/100,000 person-years). Incidence decreased over time and was lower in women, persons on ART, and those with higher CD4 counts. The incidence rate among patients on ART with a CD4 count >350 cells/mm(3) was 32/100,000 person-years (95% CI: 14-70/100,000 person-years). Despite reductions over time coincident with the expansion of ART, KS incidence among HIV-infected adults in East Africa equals or exceeds the most common cancers in resource-replete settings. In resource-limited settings, strategic efforts to improve cancer diagnosis in combination with already well-enumerated at-risk denominators can make healthcare systems attractive platforms for estimating cancer incidence.

  2. A Novel Mechanism Inducing Genome Instability in Kaposi's Sarcoma-Associated Herpesvirus Infected Cells

    PubMed Central

    Jackson, Brian R.; Noerenberg, Marko; Whitehouse, Adrian

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX) proteins have been identified in high-grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1) ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. PMID:24788796

  3. Kaposi΄s sarcoma-associated herpesvirus ORF36 protein induces chromosome condensation and phosphorylation of histone H3.

    PubMed

    Kim, Sunmi; Cha, Seho; Jang, Jun Hyeong; Kim, Yejin; Seo, Taegun

    2013-01-01

    Kaposi΄s sarcoma-associated herpesvirus (KSHV) has been known as an agent causing Kaposi΄s sarcoma, primary effusion lymphoma, and multicentric Castleman΄s disease. In the lytic phase of the virus cycle, various viral genes are expressed, which causes host cell dysregulation. Among the lytic genes, viral protein kinase (vPK) encoded by ORF36 is a member of serine/threonine protein kinase (CHPK) family, which is involved in viral gene expression, viral DNA replication and encapsidation, and nuclear egress of virions. Recent studies have shown that the BGLF4 protein of Epstein-Barr virus (EBV), a member of the CHPK family, alters the host cell chromatin structure through phosphorylation of its key regulators. The role of KSHV ORF36 in cellular mitotic events, however, is not yet understood. In the current study, we showed that KSHV ORF36 induced chromosome condensation and phosphorylation of histone H3 on Ser 10, which are known as cellular mitosis markers. These processes have occurred in a kinase activity-dependent manner. PMID:23530827

  4. Evasion and subversion of interferon-mediated antiviral immunity by Kaposi's sarcoma-associated herpesvirus: an overview.

    PubMed

    Sathish, Narayanan; Yuan, Yan

    2011-11-01

    Viral invasion of a host cell triggers immune responses with both innate and adaptive components. The innate immune response involving the induction of type I interferons (alpha and beta interferons [IFN-α and -β]) constitutes the first line of antiviral defenses. The type I IFNs signal the transcription of a group of antiviral effector proteins, the IFN-stimulated genes (ISGs), which target distinct viral components and distinct stages of the viral life cycle, aiming to eliminate invading viruses. In the case of Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma (KS), a sudden upsurge of type I IFN-mediated innate antiviral signals is seen immediately following both primary de novo infection and viral lytic reactivation from latency. Potent subversion of these responses thus becomes mandatory for the successful establishment of a primary infection following viral entry as well as for efficient viral assembly and egress. This review gives a concise overview of the induction of the type I IFN signaling pathways in response to viral infection and provides a comprehensive understanding of the antagonizing effects exerted by KSHV on type I IFN pathways wielded at various stages of the viral life cycle. Information garnered from this review should result in a better understanding of KSHV biology essential for the development of immunotherapeutic strategies targeted toward KSHV-associated malignancies. PMID:21775463

  5. Increasing incidence of Kaposi's sarcoma in black South Africans in KwaZulu-Natal, South Africa (1983-2006).

    PubMed

    Mosam, A; Carrara, H; Shaik, F; Uldrick, T; Berkman, A; Aboobaker, J; Coovadia, H M

    2009-08-01

    The aim of the study was to describe the temporal trends in the incidence of Kaposi's sarcoma (KS) in black South Africans in KwaZulu-Natal (KZN). The study was designed as a retrospective record review. The incidence of Kaposi's sarcoma was estimated using administrative records for patients receiving care for KS through public sector oncology clinics in KZN, 1983-2006. Annual age-standardized incidence rates were calculated using provincial census data for the denominator. Age-specific rates were calculated for the pre-AIDS (1983-1989) and for the generalized AIDS epidemic eras (2006). Age-standardized incidence of KS increased in KZN from <1:100,000 in 1990 to at least 15:100,000 in 2006; this increase was observed in both men and women. There was a shift in the peak age-specific incidence rates from the sixth decade of life in the pre-AIDS era to the fourth and fifth decades in the AIDS era. In conclusion, KS is a growing public health problem in KZN, South Africa. These data reinforce the need for comprehensive national access to and roll-out of antiretroviral drugs, given their success in prevention and treatment of KS in first-world settings. PMID:19625587

  6. Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus.

    PubMed Central

    Kedes, D H; Lagunoff, M; Renne, R; Ganem, D

    1997-01-01

    Over 85% of patients with Kaposi's sarcoma (KS) are seropositive for antibodies to the latency-associated nuclear antigen (LANA) expressed in B cell lines infected with Kaposi's sarcoma-associated herpesvirus (KSHV). The presence of antibodies to LANA strongly correlates with the risk of developing the disease. However, the identity of the protein(s) comprising LANA and the corresponding gene(s) has remained unclear. To identify potential latent gene candidates for LANA, we probed total RNA extracted from BCBL-1 cells (a B cell line latently infected with KSHV) using lambda clones that span the KSHV genome. One region encoding latent transcripts spanned KSHV open reading frames (orfs) 71 (K13), 72 (v-cyclin), and 73. Among these, however, only orf 73, when expressed in heterologous mammalian cell systems, reacted with KSHV antibody-positive human sera, resulting in a punctate nuclear staining pattern reminiscent of LANA in BCBL-1 cells. Furthermore, extracts from cells expressing the orf 73 protein product specifically blocked the binding of KS patient antibodies to LANA. Finally, seroreactivity with recombinant orf 73 protein exactly paralleled reactivity with classical LANA as expressed in BCBL-1 cells, both in KS patients and in other groups. Together, these data support the identification of KSHV orf 73 as the gene encoding the dominant immunogenic component of LANA. PMID:9366576

  7. Kaposi's Sarcoma-Associated Herpesvirus Inhibits Interleukin-4-Mediated STAT6 Phosphorylation To Regulate Apoptosis and Maintain Latency▿

    PubMed Central

    Cai, Qiliang; Verma, Subhash C.; Choi, Ji-Young; Ma, Michelle; Robertson, Erle S.

    2010-01-01

    Cytokine-mediated JAK/STAT signaling controls numerous important biologic responses like immune function, cellular growth, and differentiation. Inappropriate activation of this signaling pathway is associated with a range of malignancies. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious viral agent associated with Kaposi's sarcoma and may also contribute to B-cell disorders, which include primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, regulation of cytokine-mediated lymphocytic immune response by KSHV is not fully understood. In this report, we demonstrate that KSHV suppresses the interleukin-4 (IL-4)-stimulated immune response of B-lymphocyte activation and cell proliferation. Moreover, we show that the latency-associated nuclear antigen (LANA) encoded by KSHV is essential for viral blocking of IL-4-induced signaling. LANA reduces phosphorylation of the signal transducers and activators of transcription 6 (STAT6) on Y-641 and concomitantly its DNA binding ability. Importantly, knockdown of endogenous STAT6 dramatically increases the sensitivity of PEL cells to low-serum stress or chemical-mediated cellular apoptosis and reactivation of KSHV from latent replication. Thus, these findings suggest that the IL-4/STAT6 signaling network is precisely controlled by KSHV for survival, maintenance of latency, and suppression of the host cytokine immune response of the virus-infected cells. PMID:20719954

  8. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    SciTech Connect

    Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Kitai, Yuichi; Kon, Shigeyuki; Oritani, Kenji; Matsuda, Tadashi

    2015-07-31

    Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR.

  9. The Crystal Structure of PF-8, the DNA Polymerase Accessory Subunit from Kaposi's Sarcoma-Associated Herpesvirus

    SciTech Connect

    Baltz, Jennifer L.; Filman, David J.; Ciustea, Mihai; Silverman, Janice Elaine Y.; Lautenschlager, Catherine L.; Coen, Donald M.; Ricciardi, Robert P.; Hogle, James M.

    2009-12-01

    Kaposi's sarcoma-associated herpesvirus is an emerging pathogen whose mechanism of replication is poorly understood. PF-8, the presumed processivity factor of Kaposi's sarcoma-associated herpesvirus DNA polymerase, acts in combination with the catalytic subunit, Pol-8, to synthesize viral DNA. We have solved the crystal structure of residues 1 to 304 of PF-8 at a resolution of 2.8 {angstrom}. This structure reveals that each monomer of PF-8 shares a fold common to processivity factors. Like human cytomegalovirus UL44, PF-8 forms a head-to-head dimer in the form of a C clamp, with its concave face containing a number of basic residues that are predicted to be important for DNA binding. However, there are several differences with related proteins, especially in loops that extend from each monomer into the center of the C clamp and in the loops that connect the two subdomains of each protein, which may be important for determining PF-8's mode of binding to DNA and to Pol-8. Using the crystal structures of PF-8, the herpes simplex virus catalytic subunit, and RB69 bacteriophage DNA polymerase in complex with DNA and initial experiments testing the effects of inhibition of PF-8-stimulated DNA synthesis by peptides derived from Pol-8, we suggest a model for how PF-8 might form a ternary complex with Pol-8 and DNA. The structure and the model suggest interesting similarities and differences in how PF-8 functions relative to structurally similar proteins.

  10. Human herpes virus 8 (HHV-8) in Kaposi's sarcoma: lack of association with Bcl-2 and p53 protein expression.

    PubMed Central

    Kennedy, M M; O'Leary, J J; Oates, J L; Lucas, S B; Howells, D D; Picton, S; McGee, J O

    1998-01-01

    AIMS: Human herpes virus 8 (HHV-8) is the infectious agent implicated in the pathogenesis of Kaposi's sarcoma, although its mode of action is unclear. Recent work indicates that the HHV-8 genome encodes a viral Bcl-2 homologue (v-Bcl-2). The aim of this study was to explore Bcl-2 expression in Kaposi's sarcoma using a unique set of HHV-8 positive and negative cases, and to determine whether there is a relation with p53 expression. METHODS: Up to 18 specimens from 17 patients were selected. HHV-8 status was determined using nested polymerase chain reaction (PCR) to the open reading frame (ORF) 26, with further confirmation by TaqMan PCR. In addition, Bcl-2 and p53 immunohistochemistry were performed using standard protocols. RESULTS: The results suggest that Bcl-2 and p53 expression is independent of HHV-8 status. In addition, there does not appear to be a direct correlation with disease stage. CONCLUSIONS: HHV8 histopathogenesis is likely to be a multifactorial complex process, which may be mediated in part by viral genes and apoptosis regulating homologues. PMID:9850339

  11. Clinical and pathological features and treatment of AIDS-related cutaneous Kaposi's sarcoma in Chinese Han patients.

    PubMed

    Zheng, X-K; Lu, S-H; Liu, J-F; Lai, Y-R

    2015-01-01

    This retrospective study aimed to observe the clinicopathological features and immunological phenotypes, and explore effective treatment and prognosis for 12 Chinese Han patients with acquired immunodeficiency syndrome-related cutaneous Kaposi's sarcoma. All 12 patients were human immunodeficiency virus-positive, and underwent the standard highly active antiretroviral therapy (HAART). Skin lesions mainly presented as purple, or rufous papules, or plaques; skin biopsy showed diffuse or flaky infiltration of spindle cells, active proliferation of slit-like vasculature, erythrocyte exudation, hemosiderin deposition, and inflammatory cell infiltration. Immunohistochemical analysis showed the expression of Ubiquitin C-terminal hydrolase L1 (+), and CD31 (+) in T-cells; factor VIII (+) and HHF-35 (+) in the proliferating vascular endothelial cells; vimentin (+) and S-100 protein (-) in the vessel wall; and CD34 (+++) in the spindle cells of 6 cases, with 1 case of negative CD34 expression. Four patients with confined lesions underwent surgery and microwave therapy, and received a favorable prognosis. Two patients with limited lesions underwent microwave therapy, and the lesions subsided. Of six patients with widely distributed sarcomas, five underwent microwave therapy and one received combined chemotherapy; five attained significant efficacy, and one died. There were no significant differences in the clinicopathological features and immunological phenotypes between the Chinese Han patients and those from other populations. Along with basal HAART, patients in early stages, with sarcomas <2 cm in diameter should undergo surgery and microwave therapy, while patients with sarcomas >2 cm in diameter should undergo chemotherapy and microwave therapy.

  12. Coexistence of intestinal Kaposi sarcoma and plasmablastic lymphoma in an HIV/AIDS patient: case report and review of the literature

    PubMed Central

    Wang, Bing; Song, Bingbing; Oster, Cyrus; Cao, Jeffery; Raza, Anwar

    2016-01-01

    Human immunodeficiency virus (HIV) infection or acquired immunodeficiency disease (AIDS) is associated with increased risk for various malignancies including Kaposi sarcoma (KS) and lymphoma. We report a rare case of coexistence of KS and plasmablastic lymphoma (PBL) in the gastrointestinal (GI) tract in a HIV/AIDS patient. A brief review of literature is also presented. PMID:27034819

  13. ORF57 Overcomes the Detrimental Sequence Bias of Kaposi's Sarcoma-Associated Herpesvirus Lytic Genes

    PubMed Central

    Vogt, Carolin; Hackmann, Christian; Rabner, Alona; Koste, Lars; Santag, Susann; Kati, Semra; Mandel-Gutfreund, Yael; Schulz, Thomas F.

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intronless KSHV genes on multiple posttranscriptional levels. However, it remains elusive how ORF57 recognizes viral RNAs. Here, we demonstrate that ORF57 also increases the expression of the multiple intron-containing K15 gene. The nucleotide bias of the K15 cDNA revealed an unusual high AT content. Thus, we optimized the K15 cDNA by raising the frequency of GC nucleotides, yielding an ORF57-independent version. To further prove the importance of the sequence bias of ORF57-dependent RNAs, we grouped KSHV mRNAs according to their AT content and found a correlation between AT-richness and ORF57 dependency. More importantly, latent genes, which have to be expressed in the absence of ORF57, have a low AT content and are indeed ORF57 independent. The nucleotide composition of K15 resembles that of HIV gag, which cannot be expressed unless RNA export is facilitated by the HIV Rev protein. Interestingly, ORF57 can partially rescue HIV Gag expression. Thus, the KSHV target RNAs of ORF57 and HIV gag RNA may share certain motifs based on the nucleotide bias. A bioinformatic comparison between wild-type and sequence-optimized K15 revealed a higher density for hnRNP-binding motifs in the former. We speculate that binding of particular hnRNPs to KSHV lytic transcripts is the prerequisite for ORF57 to enhance their expression. IMPORTANCE The mostly intronless genes of KSHV are only expressed in the presence of the viral regulator protein ORF57, but how ORF57 recognizes viral RNAs remains elusive. We focused on the multiple intron-containing KSHV gene K15 and revealed that its expression is also increased by ORF57. Moreover, sequences in the K15 cDNA mediate this enhancement. The quest for a target sequence or a response element for ORF57 in the lytic genes was not successful. Instead, we found the nucleotide bias to be the critical determinant of ORF57 dependency. Based on

  14. Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells.

    PubMed

    Marginean, Alexandru; Sharma-Walia, Neelam

    2015-08-01

    Lipoxin A4 (LXA4) is an endogenously produced host molecule with anti-inflammatory resolution effects. Previous studies demonstrated it to be involved in anti-vascular endothelial growth factor (VEGF)-mediated angiogenesis and in a possible anticancer role via interaction with its receptor, lipoxin A 4 receptor (ALXR). Here, we examined the effects of LXA4 and its epimer 15-epi-LXA4 in inhibiting proinflammatory and angiogenic functions in a human Kaposi's sarcoma tumor-derived cell line (KS-IMM). KS-IMM cells expressed increased levels of inflammatory cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LO) pathway enzymes when compared with human microvascular dermal endothelial cells (HMVEC-d). KS-IMM cells secreted high levels of prostaglandin E2 (PGE2) and chemotactic leukotriene B4 (LTB4). Treatment with LXA4 or 15-epi-LXA4 effectively reduced the levels of COX-2, 5-LO proteins, and secretion of PGE2 and LTB4 in KS-IMM cells. LXA4 or 15-epi-LXA4 treatment also decreased secretion of proinflammatory interleukin 6 (IL-6) and IL-8 cytokines but induced the secretion of anti-inflammatory IL-10. LXA4 treatment reduced the phosphorylation of VEGF receptor (VEGFR) and ephrin family receptor tyrosine kinases. LXA4 treatment effectively induced dephosphorylation of multiple cellular kinases such as Focal Adhesion Kinase, Protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and Extracellular signal-regulated kinases (ERK)1/2, and reduced angiogenic factor VEGF-C secretion in KS cells. LX treatment drastically induced the Src-homology 2 domain-containing phosphatase tyrosine (Y542) phosphatase and reduced VEGFR-2 phosphorylation at sites Y1059, Y1175, and Y1212. Treatment of KS-IMM cells with LXA4 resulted in selective localization of VEGFR-2 in nonlipid raft (non-LR) and ALXR to LR fractions. These results demonstrated that LXA4 or 15-epi-LXA4 induce anti-inflammatory and antiangiogenic effects in KS cells and suggest that treatment with LXs is

  15. Definition of an optimal cytotoxic T lymphocyte epitope in the latently expressed Kaposi's sarcoma-associated herpesvirus kaposin protein.

    PubMed

    Brander, C; O'Connor, P; Suscovich, T; Jones, N G; Lee, Y; Kedes, D; Ganem, D; Martin, J; Osmond, D; Southwood, S; Sette, A; Walker, B D; Scadden, D T

    2001-07-15

    Cytotoxic T lymphocytes (CTL) recognize and kill virus-infected cells and contribute to immunologic control of viral replication. For many herpesviruses (e.g., Epstein-Barr and cytomegalovirus), virus-specific CTL responses can be readily detected in infected persons, but CTL responses against Kaposi's sarcoma-associated herpesvirus (KSHV) appear to be weak and remain poorly characterized. Using a human leukocyte antigen (HLA) binding motif-based epitope prediction algorithm, we identified 37 HLA-A*0201 binding peptides from 8 KSHV open-reading frames (ORFs). After in vitro stimulation of peripheral blood mononuclear cells from KSHV-infected persons, CTL responses against 1 peptide in the KSHV kaposin protein (ORF K12) were detected in 2 HLA-A*0201-positive subjects. The optimal CTL epitope was identified by HLA restriction analysis and peptide titration assays. These data describe a latent phase viral gene product targeted by CTL that may be relevant for KSHV immunopathogenesis.

  16. The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions.

    PubMed Central

    Renne, R; Lagunoff, M; Zhong, W; Ganem, D

    1996-01-01

    The genome of a novel human herpesvirus has been detected in specimens of Kaposi's sarcoma (KS) and in several AIDS-related lymphoproliferative disorders. Here we examine the size and genomic conformation of the DNA of this virus (known as KS-associated herpesvirus or human herpesvirus 8) in latently and lytically infected cells and in virions. Pulsed-field gel electrophoresis of viral DNA shows that the viral genome is similar in size to those of other gammaherpesviruses (160 to 170 kb). As with Epstein-Barr virus, KS-associated herpesvirus DNA is stably maintained in latently infected B cells as episomal monomer circles and induction from latency is associated with the selective accumulation of linear genomic forms. PMID:8892944

  17. Broad target cell selectivity of Kaposi's sarcoma-associated herpesvirus glycoprotein-mediated cell fusion and virion entry

    SciTech Connect

    Kaleeba, Johnan A.R.; Berger, Edward A. . E-mail: edward_berger@nih.gov

    2006-10-10

    The molecular mechanism of Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) entry is poorly understood. We tested a broad variety of cell types of diverse species and tissue origin for their ability to function as targets in a quantitative reporter gene assay for KSHV-glycoprotein-mediated cell fusion. Several human, non-human primate, and rabbit cell lines were efficient targets, whereas rodent and all human lymphoblastoid cell lines were weak targets. Parallel findings were obtained with a virion entry assay using a recombinant KSHV encoding a reporter gene. No correlation was observed between target cell activity and surface expression of {alpha}3{beta}1 integrin, a proposed KSHV receptor. We hypothesize that target cell permissiveness in both the cell fusion and virion entry assays reflects the presence of a putative KSHV fusion-entry receptor.

  18. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group.

    PubMed Central

    Goebel, F. D.; Goldstein, D.; Goos, M.; Jablonowski, H.; Stewart, J. S.

    1996-01-01

    The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients. PMID:8611437

  19. Celecoxib Inhibits the Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus through Down-Regulation of RTA Expression by Inhibiting the Activation of p38 MAPK.

    PubMed

    Chen, Jungang; Jiang, Liangyu; Lan, Ke; Chen, Xulin

    2015-05-01

    Kaposi's sarcoma associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV's lytic replication cycle is critical for the pathogenesis of KSHV-associated diseases. Despite recent progress in the development of treatments for KSHV associated malignancies, these therapies are not completely efficacious and cause side effects. Therefore, more effective therapies with antiviral agents against KSHV are urgently needed. In this study, we identified celecoxib as an antiviral agent against KSHV. Our data suggest that celecoxib inhibits the lytic activation of KSHV through the down-regulation of the expression of the lytic switch protein, replication and transcription activator (RTA), by inhibiting the activation of p38 MAPK. Therefore, celecoxib may provide a candidate inhibitor for the therapeutic research of KSHV-related malignancies.

  20. Mycosis Fungoides Associated with Kaposi's Sarcoma, T-cell Rich B-cell Lymphoma, and T-cell Lymphoma with Angioimmunoblastic Features.

    PubMed

    Samuelov, Liat; Gat, Andrea; Bergman, Reuven; Sprecher, Eli; Goldberg, Ilan

    2016-08-01

    A patient with mycosis fungoides (MF), Kaposi's sarcoma, T-cell rich B-cell lymphoma, and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell rich B-cell lymphoma which he underwent. PMID:27663924

  1. The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Contains an Immunoreceptor Tyrosine-Based Inhibitory Motif That Activates Shp2 ▿

    PubMed Central

    Philpott, Nicola; Bakken, Thomas; Pennell, Christopher; Chen, Liwei; Wu, Jie; Cannon, Mark

    2011-01-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) G protein-coupled receptor (vGPCR) is a constitutively active, highly angiogenic homologue of the interleukin-8 (IL-8) receptors that signals in part via the cytoplasmic protein tyrosine phosphatase Shp2. We show that vGPCR contains a bona fide immunoreceptor tyrosine-based inhibitory motif (ITIM) that binds and constitutively activates Shp2. PMID:21047965

  2. [Moritz Kaposi: further currency].

    PubMed

    Rácz, I

    1987-03-01

    In connection with the frequent appearance of Kaposi's sarcoma in AIDS, the biography of Moritz Kohn/Kaposi, a dermatologist of Hungarian origin in Vienna, is presented. The merits and failures of his morphologically oriented concept are discussed. Today his activity is high estimed by dermatologists all over the world.

  3. [Hyperkeratotic Kaposi sarcoma with leg lymphoedema after prolonged corticosteroid therapy for SLE. Case report and review of the literature].

    PubMed

    Fagone, S; Cavaleri, A; Camuto, M; Iannello, S; Belfiore, F

    2001-06-01

    Kaposi sarcoma (KS) is a malignant vascular neoplasia with a viral etiology, characterized by development of multiple hyperpigmentate lesions, primarily at cutaneous level with associated edema and ulcerations, but frequently involving also the mucous membranes and/or visceral organs. In this study, we describe (in the light of the relevant literature) the clinical case of an elderly (78 yrs-old) woman, who developed red-blues multiple hyperkeratotic nodules in the right leg and foot with marked lymphoedema, blushing and pain, after a long period of a low-dose corticosteroid therapy for LES (at least 10 years of continuous treatment). The diagnosis of KS was made on the basis of histologic findings. The patient HLA-typing showed the haplotypes HLA-A2-10, -B21-35, -Bw4-6, -Cw4 and HLA-DR11-13 (some of which are known to predispose to LES, but not to KS). The KS, first described by Moritz Kaposi in 1872, has been a very rare pathology until the 80s, afterwards its frequency has steadly increased, favored by immunosuppressive therapy for autoimmune diseases or tranplants and by immunodepression of AIDS. Concerning the pathogenesis, it is crucial the role of HHV-8 of the herpesvirus family (found in the lesions and in the circulating cells of all KS patients), for which a prevailing sexual transmission is postulated. General physicians and specialists of internal medicine and angiology should know this disease, which can be undiagnosed because of the low incidence in the general population and the consequent poor knowledge of this vascular neoplastic disease, which is now reported with increasing frequency. PMID:11404728

  4. Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi's sarcoma-associated herpesvirus infection promotes cell proliferation.

    PubMed

    Valiya Veettil, Mohanan; Dutta, Dipanjan; Bottero, Virginie; Bandyopadhyay, Chirosree; Gjyshi, Olsi; Sharma-Walia, Neelam; Dutta, Sujoy; Chandran, Bala

    2014-10-01

    Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with endothelial Kaposi's sarcoma (KS) and B-cell proliferative primary effusion lymphoma (PEL), common malignancies seen in immunocompromised HIV-1 infected patients. The progression of these cancers occurs by the proliferation of cells latently infected with KSHV, which is highly dependent on autocrine and paracrine factors secreted from the infected cells. Glutamate and glutamate receptors have emerged as key regulators of intracellular signaling pathways and cell proliferation. However, whether they play any role in the pathological changes associated with virus induced oncogenesis is not known. Here, we report the first systematic study of the role of glutamate and its metabotropic glutamate receptor 1 (mGluR1) in KSHV infected cell proliferation. Our studies show increased glutamate secretion and glutaminase expression during de novo KSHV infection of endothelial cells as well as in KSHV latently infected endothelial and B-cells. Increased mGluR1 expression was detected in KSHV infected KS and PEL tissue sections. Increased c-Myc and glutaminase expression in the infected cells was mediated by KSHV latency associated nuclear antigen 1 (LANA-1). In addition, mGluR1 expression regulating host RE-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF) was retained in the cytoplasm of infected cells. KSHV latent protein Kaposin A was also involved in the over expression of mGluR1 by interacting with REST in the cytoplasm of infected cells and by regulating the phosphorylation of REST and interaction with β-TRCP for ubiquitination. Colocalization of Kaposin A with REST was also observed in KS and PEL tissue samples. KSHV infected cell proliferation was significantly inhibited by glutamate release inhibitor and mGluR1 antagonists. These studies demonstrated that elevated glutamate secretion and mGluR1 expression play a role in KSHV induced cell proliferation and

  5. The exonuclease and host shutoff functions of the SOX protein of Kaposi's sarcoma-associated herpesvirus are genetically separable.

    PubMed

    Glaunsinger, Britt; Chavez, Leonard; Ganem, Don

    2005-06-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) SOX protein, encoded by ORF37, promotes shutoff of host cell gene expression during lytic viral replication by dramatically impairing mRNA accumulation. SOX is the KSHV homolog of the alkaline exonuclease of other herpesviruses, which has been shown to function as a DNase involved in processing and packaging the viral genome. Although the exonuclease activity of these proteins is widely conserved across all herpesviruses, the host shutoff activity observed for KSHV SOX is not. We show here that SOX expression sharply reduces the half-life of target mRNAs. Extensive mutational analysis reveals that the DNase and host shutoff activities of SOX are genetically separable. Lesions affecting the DNase activity cluster in conserved regions of the protein, but residues critical for mRNA degradation are not conserved across the viral family. Additionally, we present evidence suggesting that the two different functions of SOX occur within distinct cellular compartments-DNase activity in the nucleus and host shutoff activity in the cytoplasm.

  6. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma.

    PubMed

    Little, Richard F; Aleman, Karen; Kumar, Pallavi; Wyvill, Kathleen M; Pluda, James M; Read-Connole, Elizabeth; Wang, Victoria; Pittaluga, Stefania; Catanzaro, Andrew T; Steinberg, Seth M; Yarchoan, Robert

    2007-12-15

    Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m(2)) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T(1)S(1)). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at (http://www.clinicaltrials.gov) as no. NCT00020449.

  7. A case of Kaposi sarcoma in an immunocompetent, heterosexual Irish man: a discussion of etiology and viral transmission.

    PubMed

    Florek, Aleksandra G; Eilers, David; Armstrong, April W

    2015-10-01

    Four types of Kaposi sarcoma (KS) have been described, all of which are caused by human herpesvirus-8 (HHV-8).  The incidence of KS in the United States is highest among HIV-positive homosexual men and elderly men of Eastern European, Jewish, or Mediterranean descent. However, few reports describe KS in HIV-negative, immunocompetent heterosexual men in the United States. HHV-8 is transmitted largely via saliva and close sexual contact, whereas there are only a handful of reports of transmission via blood and blood products. We report a case of an HIV-negative, immunocompetent heterosexual man who acquired KS via blood transfusion. A 77-year-old immunocompetent, monogamously heterosexual, HIV-negative Irish man presented with a biopsy-proven KS lesion on the right thigh. Past surgical history included a coronary artery bypass graft, during which he received a blood transfusion from an unknown donor source.  His ecchymotic KS lesions progressed while on doxycycline, intralesional vinblastine, and topical anti-angiogenic medications.  The patient eventually achieved stabilization of KS lesions with acitretin. Our case report emphasizes the need to characterize the phenotype and transmission route of HHV-8 in heterosexual, immunocompetent patients in geographic regions with low HHV-8 seroprevalence. PMID:26632797

  8. A virally encoded small peptide regulates RTA stability and facilitates Kaposi's sarcoma-associated herpesvirus lytic replication.

    PubMed

    Jaber, Tareq; Yuan, Yan

    2013-03-01

    In both mammalian and viral genomes, a large proportion of sequences are transcribed and annotated as noncoding RNAs. A polyadenylated RNA of 3.0 kb (T3.0) is transcribed from the opposite strand of the open reading frame 50 (ORF50) DNA template in the genome of Kaposi's sarcoma-associated herpesvirus (KSHV) and has been annotated previously as a noncoding RNA. ORF50 encodes the replication and transcription activator (RTA), which controls the switch of the virus between the latent and lytic phases of the life cycle. Here we show that T3.0 encodes a small peptide of 48 amino acids (designated viral small peptide 1 [vSP-1]). vSP-1 interacts with RTA at the protein abundance regulatory signal (PARS) motifs, and the association prevents RTA from being subjected to degradation through the ubiquitin-proteasome pathway. As a consequence, vSP-1 facilitates KSHV gene expression and lytic replication. This finding reveals a novel mechanism of gene regulation in the viral life cycle. PMID:23302891

  9. Enhancement of autophagy during lytic replication by the Kaposi's sarcoma-associated herpesvirus replication and transcription activator.

    PubMed

    Wen, Hui-Ju; Yang, Zhilong; Zhou, You; Wood, Charles

    2010-08-01

    Autophagy is one of two major degradation systems in eukaryotic cells. The degradation mechanism of autophagy is required to maintain the balance between the biosynthetic and catabolic processes and also contributes to defense against invading pathogens. Recent studies suggest that a number of viruses can evade or subvert the host cell autophagic pathway to enhance their own replication. Here, we investigated the effect of autophagy on the KSHV (Kaposi's sarcoma-associated herpesvirus) life cycle. We found that the inhibition of autophagy reduces KSHV lytic reactivation from latency, and an enhancement of autophagy can be detected during KSHV lytic replication. In addition, RTA (replication and transcription activator), an essential viral protein for KSHV lytic reactivation, is able to enhance the autophagic process, leading to an increase in the number of autophagic vacuoles, an increase in the level of the lipidated LC3 protein, and the formation of autolysosomes. Moreover, the inhibition of autophagy affects RTA-mediated lytic gene expression and viral DNA replication. These results suggest that RTA increases autophagy activation to facilitate KSHV lytic replication. This is the first report demonstrating that autophagy is involved in the lytic reactivation of KSHV. PMID:20484505

  10. Evaluation of Non-Invasive Multispectral Imaging as a Tool for Measuring the Effect of Systemic Therapy in Kaposi Sarcoma

    PubMed Central

    Kainerstorfer, Jana M.; Polizzotto, Mark N.; Uldrick, Thomas S.; Rahman, Rafa; Hassan, Moinuddin; Najafizadeh, Laleh; Ardeshirpour, Yasaman; Wyvill, Kathleen M.; Aleman, Karen; Smith, Paul D.; Yarchoan, Robert; Gandjbakhche, Amir H.

    2013-01-01

    Diffuse multi-spectral imaging has been evaluated as a potential non-invasive marker of tumor response. Multi-spectral images of Kaposi sarcoma skin lesions were taken over the course of treatment, and blood volume and oxygenation concentration maps were obtained through principal component analysis (PCA) of the data. These images were compared with clinical and pathological responses determined by conventional means. We demonstrate that cutaneous lesions have increased blood volume concentration and that changes in this parameter are a reliable indicator of treatment efficacy, differentiating responders and non-responders. Blood volume decreased by at least 20% in all lesions that responded by clinical criteria and increased in the two lesions that did not respond clinically. Responses as assessed by multi-spectral imaging also generally correlated with overall patient clinical response assessment, were often detectable earlier in the course of therapy, and are less subject to observer variability than conventional clinical assessment. Tissue oxygenation was more variable, with lesions often showing decreased oxygenation in the center surrounded by a zone of increased oxygenation. This technique could potentially be a clinically useful supplement to existing response assessment in KS, providing an early, quantitative, and non-invasive marker of treatment effect. PMID:24386302

  11. The Kaposi's sarcoma-associated herpesvirus K5 E3 ubiquitin ligase modulates targets by multiple molecular mechanisms.

    PubMed

    Means, Robert E; Lang, Sabine M; Jung, Jae U

    2007-06-01

    Kaposi's sarcoma-associated herpesvirus encodes two highly related membrane-associated, RING-CH-containing (MARCH) family E3 ubiquitin ligases, K3 and K5, that can down regulate a variety of cell surface proteins through enhancement of their endocytosis and degradation. In this report we present data that while K5 modulation of major histocompatibility complex class I (MHC-I) closely mirrors the mechanisms used by K3, alternative molecular pathways are utilized by this E3 ligase in the down regulation of intercellular adhesion molecule 1 (ICAM-1) and B7.2. Internalization assays demonstrate that down regulation of each target can occur through increased endocytosis from the cell surface. However, mutation of a conserved tyrosine-based endocytosis motif in K5 resulted in a protein lacking the ability to direct an increased rate of MHC-I or ICAM-1 internalization but still able to down regulate B7.2 in a ubiquitin-dependent but endocytosis-independent manner. Further, mutation of two acidic clusters abolished K5-mediated MHC-I degradation while only slightly decreasing ICAM-1 or B7.2 protein destruction. This same mutant abolished detectable ubiquitylation of all targets. These data indicate that while K5 can act as an E3 ubiquitin ligase to directly mediate cell surface molecule destruction, regulation of its targets occurs through multiple pathways, including ubiquitin-independent mechanisms.

  12. The Kaposi's Sarcoma-Associated Herpesvirus K5 E3 Ubiquitin Ligase Modulates Targets by Multiple Molecular Mechanisms▿

    PubMed Central

    Means, Robert E.; Lang, Sabine M.; Jung, Jae U.

    2007-01-01

    Kaposi's sarcoma-associated herpesvirus encodes two highly related membrane-associated, RING-CH-containing (MARCH) family E3 ubiquitin ligases, K3 and K5, that can down regulate a variety of cell surface proteins through enhancement of their endocytosis and degradation. In this report we present data that while K5 modulation of major histocompatibility complex class I (MHC-I) closely mirrors the mechanisms used by K3, alternative molecular pathways are utilized by this E3 ligase in the down regulation of intercellular adhesion molecule 1 (ICAM-1) and B7.2. Internalization assays demonstrate that down regulation of each target can occur through increased endocytosis from the cell surface. However, mutation of a conserved tyrosine-based endocytosis motif in K5 resulted in a protein lacking the ability to direct an increased rate of MHC-I or ICAM-1 internalization but still able to down regulate B7.2 in a ubiquitin-dependent but endocytosis-independent manner. Further, mutation of two acidic clusters abolished K5-mediated MHC-I degradation while only slightly decreasing ICAM-1 or B7.2 protein destruction. This same mutant abolished detectable ubiquitylation of all targets. These data indicate that while K5 can act as an E3 ubiquitin ligase to directly mediate cell surface molecule destruction, regulation of its targets occurs through multiple pathways, including ubiquitin-independent mechanisms. PMID:17409151

  13. New insights into the expression and functions of the Kaposi's sarcoma-associated herpesvirus long noncoding PAN RNA.

    PubMed

    Conrad, Nicholas K

    2016-01-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) is a clinically relevant pathogen associated with several human diseases that primarily affect immunocompromised individuals. KSHV encodes a noncoding polyadenylated nuclear (PAN) RNA that is essential for viral propagation and viral gene expression. PAN RNA is the most abundant viral transcript produced during lytic replication. The accumulation of PAN RNA depends on high levels of transcription driven by the Rta protein, a KSHV transcription factor necessary and sufficient for latent-to-lytic phase transition. In addition, KSHV uses several posttranscriptional mechanisms to stabilize PAN RNA. A cis-acting element, called the ENE, prevents PAN RNA decay by forming a triple helix with its poly(A) tail. The viral ORF57 and the cellular PABPC1 proteins further contribute to PAN RNA stability during lytic phase. PAN RNA functions are only beginning to be uncovered, but PAN RNA has been proposed to control gene expression by several different mechanisms. PAN RNA associates with the KSHV genome and may regulate gene expression by recruiting chromatin-modifying factors. Moreover, PAN RNA binds the viral latency-associated nuclear antigen (LANA) protein and decreases its repressive activity by sequestering it from the viral genome. Surprisingly, PAN RNA was found to associate with translating ribosomes, so this noncoding RNA may be additionally used to produce viral peptides. In this review, I highlight the mechanisms of PAN RNA accumulation and describe recent insights into potential functions of PAN RNA.

  14. Seroprevalence and Determinants of Kaposi Sarcoma-Associated Human Herpesvirus 8 in Indian HIV-Infected Males

    PubMed Central

    Munawwar, Arshi; Sharma, Surendra K.; Gupta, Somesh

    2014-01-01

    Abstract In India Kaposi's sarcoma is rarely seen in AIDS patients. Hence the current belief is that the incidence of human herpesvirus-8 (HHV-8) is very low in this subcontinent, most probably due to the heterosexual route of HIV transmission. However, there is a scarcity of data on the prevalence of HHV-8 in India. In India the primary mode of HIV transmission is the heterosexual route. Therefore we aimed to determine the prevalence of antibodies against HHV-8 in North Indian HIV-infected men naive of antiretroviral therapy (ART). In a prospective study, 165 Indian adult males were recruited from an ART clinic. Blood samples were collected before administering any antiretroviral drug. The sera were tested for antibodies against HHV-8 using a commercial enzyme-linked immunosorbent assay (ELISA) kit, which detects IgG antibodies to lytic antigens of HHV-8. All positive samples were confirmed for the presence of anti-HHV-8 antibodies using an indirect immunofluorescence assay (IFA). The IFA kit is intended to detect primary, latent, persistent, or reactivated infection of HHV-8. Of the 165 males, 43 (26.06%) were positive by ELISA while 26 (15.8%) were also positive by IFA. Seroprevalence decreased with increasing age (p<0.05). Factors independently associated with HHV-8 infection were younger age group and alcohol consumption. These findings suggest that even in a heterosexual population, HHV-8 can be transmitted frequently. PMID:25375960

  15. KS-Detect - Validation of Solar Thermal PCR for the Diagnosis of Kaposi's Sarcoma Using Pseudo-Biopsy Samples.

    PubMed

    Snodgrass, Ryan; Gardner, Andrea; Jiang, Li; Fu, Cheng; Cesarman, Ethel; Erickson, David

    2016-01-01

    Resource-limited settings present unique engineering challenges for medical diagnostics. Diagnosis is often needed for those unable to reach central healthcare systems, making portability and independence from traditional energy infrastructure essential device parameters. In 2014, our group presented a microfluidic device that performed a solar-powered variant of the polymerase chain reaction, which we called solar thermal PCR. In this work, we expand on our previous effort by presenting an integrated, portable, solar thermal PCR system targeted towards the diagnosis of Kaposi's sarcoma. We call this system KS-Detect, and we now report the system's performance as a diagnostic tool using pseudo-biopsy samples made from varying concentrations of human lymphoma cell lines positive for the KS herpesvirus (KSHV). KS-Detect achieved 83% sensitivity and 70% specificity at high (≥ 10%) KSHV+ cell concentrations when diagnosing pseudo-biopsy samples by smartphone image. Using histology, we confirm that our prepared pseudo-biopsies contain similar KSHV+ cell concentrations as human biopsies positive for KS. Through our testing of samples derived from human cell lines, we validate KS-Detect as a viable, portable KS diagnostic tool, and we identify critical engineering considerations for future solar-thermal PCR devices.

  16. Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene.

    PubMed

    Huang, S K; Martin, F J; Jay, G; Vogel, J; Papahadjopoulos, D; Friend, D S

    1993-07-01

    Transgenic mice bearing the HIV tat gene develop dermal lesions resembling a common malignant tumor in AIDS, Kaposi's sarcoma (KS). To evaluate the permeability characteristics of these lesions and the therapeutic potential of drug-carrying liposomes, we have studied the localization of sterically stabilized liposomes, which show long circulation time in blood and increased accumulation in tumors. Liposomes encapsulating colloidal gold were injected intravenously into transgenic mice bearing KS lesions, and tissues were processed 24 hours later for both electron microscopy and for light microscopy with silver enhancement. Liposomes and silver marker were detected predominantly in the dermis surrounding the early and mature KS lesions, which were characterized by a proliferation of fibroblast-like spindle cells and abnormal blood vessels close to the epidermis. The silver-enhanced gold marker often surrounded vascular channels and scattered erythrocytes. As determined by electron microscopy, some spindle cells and macrophages had ingested intact liposomes. Transendothelial transport of liposomes was observed both through open channels between endothelial cells and also through endothelial cells lining intact vessels. Both extravasation and transcytosis of liposomes through irregular endothelium were much higher in KS lesions than in the adjacent normal skin. The high accumulation of sterically stabilized liposomes in KS lesions and their intracellular uptake by some spindle cells enhances their potential as carriers of chemotherapeutic agents against this neoplasm. PMID:8317543

  17. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

    PubMed Central

    Zhang, Guigen; Chan, Baca; Samarina, Naira; Abere, Bizunesh; Weidner-Glunde, Magdalena; Buch, Anna; Pich, Andreas; Brinkmann, Melanie M.; Schulz, Thomas F.

    2016-01-01

    The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING–dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle. PMID:26811480

  18. PA-seq for Global Identification of RNA Polyadenylation Sites of Kaposi's Sarcoma-Associated Herpesvirus Transcripts.

    PubMed

    Ni, Ting; Majerciak, Vladimir; Zheng, Zhi-Ming; Zhu, Jun

    2016-05-06

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncovirus linked to the development of several malignancies in immunocompromised patients. Like other herpesviruses, KSHV has a large DNA genome encoding more than 100 distinct gene products. Despite being transcribed and processed by cellular machinery, the structure and organization of KSHV genes in the virus genome differ from what is observed in cellular genes from the human genome. A typical feature of KSHV expression is the production of polycistronic transcripts initiated from different promoters but sharing the same polyadenylation site (pA site). This represents a challenge in determination of the 3' end of individual viral transcripts. Such information is critical for generation of a virus transcriptional map for genetic studies. Here we present PA-seq, a high-throughput method for genome-wide analysis of pA sites of KSHV transcripts in B lymphocytes with latent or lytic KSHV infection. Besides identification of all viral pA sites, PA-seq also provides quantitative information about the levels of viral transcripts associated with each pA site, making it possible to determine the relative expression levels of viral genes at various stages of infection. Due to the indiscriminate nature of PA-seq, the pA sites of host transcripts are also concurrently mapped in the testing samples. Therefore, this technology can simultaneously estimate the expression changes of host genes and RNA polyadenylation upon KSHV infection. © 2016 by John Wiley & Sons, Inc.

  19. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS.

    PubMed

    Zhang, Guigen; Chan, Baca; Samarina, Naira; Abere, Bizunesh; Weidner-Glunde, Magdalena; Buch, Anna; Pich, Andreas; Brinkmann, Melanie M; Schulz, Thomas F

    2016-02-23

    The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle. PMID:26811480

  20. Kaposi Sarcoma among HIV Infected Patients in Lagos University Teaching Hospital, Nigeria: A 14-Year Retrospective Clinicopathological Study

    PubMed Central

    Akinde, Olakanmi; Adeyemo, Titilope; Omoseebi, Oladipo; Ikeri, Nzechukwu; Okonkwo, Ikechukwu; Afolayan, Olatunji

    2016-01-01

    Background. Despite the increased incidence of Kaposi sarcoma (KS) resulting from the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) pandemic, there is still significant underreporting of KS in this environment. Objectives. This study was aimed at determining the incidence and clinicopathologic patterns of KS among HIV infected patients in Lagos University Teaching Hospital (LUTH), Nigeria, over a 14-year period: January 2000 to December 2013. Methodology. The materials for this study included patients' hospital clinical files, duplicate copies of histopathologic reports, and tissue blocks and corresponding archival slides in the Anatomic and Molecular Pathology Department and the HIV/AIDS unit of the Department of Haematology. Results. Within the study period, 182 cases of KS were diagnosed, accounting for 1.2% of all patients managed for HIV/AIDS and 2.99% of solid malignant tumours. The male-to-female ratio and modal age group were 1 : 1.3 and 5th decade, respectively. Most cases (90%) had purely mucocutaneous involvement with the lower limb being the commonest site (65.8%). The majority of lesions were plaques (65.8%). Vascular formation was the predominant histologic type seen (43.5%). Conclusion. KS in Lagos followed the same epidemiologic trend as other centers in Nigeria, with an increasing incidence in this era of HIV/AIDS. PMID:27034839

  1. KS-Detect - Validation of Solar Thermal PCR for the Diagnosis of Kaposi's Sarcoma Using Pseudo-Biopsy Samples.

    PubMed

    Snodgrass, Ryan; Gardner, Andrea; Jiang, Li; Fu, Cheng; Cesarman, Ethel; Erickson, David

    2016-01-01

    Resource-limited settings present unique engineering challenges for medical diagnostics. Diagnosis is often needed for those unable to reach central healthcare systems, making portability and independence from traditional energy infrastructure essential device parameters. In 2014, our group presented a microfluidic device that performed a solar-powered variant of the polymerase chain reaction, which we called solar thermal PCR. In this work, we expand on our previous effort by presenting an integrated, portable, solar thermal PCR system targeted towards the diagnosis of Kaposi's sarcoma. We call this system KS-Detect, and we now report the system's performance as a diagnostic tool using pseudo-biopsy samples made from varying concentrations of human lymphoma cell lines positive for the KS herpesvirus (KSHV). KS-Detect achieved 83% sensitivity and 70% specificity at high (≥ 10%) KSHV+ cell concentrations when diagnosing pseudo-biopsy samples by smartphone image. Using histology, we confirm that our prepared pseudo-biopsies contain similar KSHV+ cell concentrations as human biopsies positive for KS. Through our testing of samples derived from human cell lines, we validate KS-Detect as a viable, portable KS diagnostic tool, and we identify critical engineering considerations for future solar-thermal PCR devices. PMID:26799834

  2. Agonist Met antibodies define the signalling threshold required for a full mitogenic and invasive program of Kaposi's Sarcoma cells

    SciTech Connect

    Bardelli, Claudio; Sala, Marilena; Cavallazzi, Umberto; Prat, Maria . E-mail: mprat@med.unipmn.it

    2005-09-09

    We previously showed that the Kaposi Sarcoma line KS-IMM express a functional Met tyrosine kinase receptor, which, upon HGF stimulation, activates motogenic, proliferative, and invasive responses. In this study, we investigated the signalling pathways activated by HGF, as well as by Met monoclonal antibodies (Mabs), acting as full or partial agonists. The full agonist Mab mimics HGF in all biological and biochemical aspects. It elicits the whole spectrum of responses, while the partial agonist Mab induces only wound healing. These differences correlated with a more prolonged and sustained tyrosine phosphorylation of the receptor and MAPK evoked by HGF and by the full agonist Mab, relative to the partial agonist Mab. Since Gab1, JNK and PI 3-kinase are activated with same intensity and kinetics by HGF and by the two agonist antibodies, it is concluded that level and duration of MAPK activation by Met receptor are crucial for the induction of a full HGF-dependent mitogenic and invasive program in KS cells.

  3. The Kaposi's sarcoma-associated herpesvirus ORF34 protein binds to HIF-1α and causes its degradation via the proteasome pathway.

    PubMed

    Haque, Muzammel; Kousoulas, Konstantin G

    2013-02-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi's sarcoma (KS) and two other lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Kaposi's sarcoma is a highly vascular tumor, and recently both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α were detected in KS samples, indicating a role of HIFs in the KSHV life cycle. Previously, we showed that ORF34, a lytic gene of unassigned function, was activated by hypoxia and that ORF34 transcription was upregulated by both HIFs (M. Haque, D. A. Davis, V. Wang, I. Widmer, and R. Yarchoan, J Virol. 77:6761-6768, 2003). In the present study, we show that coexpression of ORF34 with HIF-1αm (degradation-resistant HIF-1α) caused substantial reduction in HIF-1α-dependent transcription, as evidenced by reporter assays. Two-way immunoprecipitation experiments revealed that ORF34 physically interacted with HIF-1αm in transient expression experiments. Deletion analysis revealed that three different ORF34 domains interacted with the amino-terminal domain of HIF-1α. Also, purified HIF-1α and ORF34 proteins interacted with each other. The observed transcriptional inhibition of HIF-1α-dependent promoters was attributed to degradation of HIF-1α after binding with ORF34, since the overall amount of wild-type HIF-1α but not the degradation-resistant one (HIF-1αm) was reduced in the presence of ORF34. Moreover, ORF34 caused degradation of HIF-1α in a dose-dependent manner. Inhibition of the ubiquitin-dependent pathway by the chemical proteasome inhibitor MG132 prevented HIF-1α degradation in the presence of ORF34. These results show that ORF34 binds to HIF-1α, leading to its degradation via the proteasome-dependent pathway. PMID:23221556

  4. Acroangiodermatitis (pseudo-Kaposi's sarcoma) in an HIV sero-positive patient with syphilis and hepatitis C virus coinfection: clinical and dermatopathological features.

    PubMed

    Bernardes Filho, Fred; Martins, Gustavo; Nery, José Augusto da Costa; Andrade, Cecília Vianna de; Kac, Bernard Kawa

    2014-01-01

    Acroangiodermatitis is an angioproliferative disease usually related to chronic venous insufficiency, and it is considered a clinical and histological simulator of Kaposi's sarcoma (KS). Immunohistochemistry is the suitable method to differentiate between these two entities. It reveals the following immunostaining profile: immunopositivity with anti-CD34 antibody is restricted to the vascular endothelium in acroangiodermatitis, and diffuse in the KS (endothelial cells and perivascular spindle cells); immunopositivity with anti-HHV-8 only in KS cases. We report the case of an HIV seropositive patient without apparent vascular disease, who presented violaceous and brownish erythematous lesions on the feet, and whose histopathology and immunohistochemistry indicated the diagnosis of acroangiodermatitis. PMID:25184919

  5. Classic Kaposi's sarcoma presenting first with gastrointestinal tract involvement in a HIV-negative Inuit male--a case report and review of the literature.

    PubMed

    Balachandra, Brinda; Tunitsky, Ellen; Dawood, Shaheenah; Hings, Ingrid; Marcus, Victoria A

    2006-01-01

    Kaposi's sarcoma (KS) is a multicentric low-grade vascular malignancy. In North America, it is usually seen in AIDS and solid organ transplant populations. Classic KS is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean, Eastern European, and Jewish descent. Patients with classic KS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon in classic KS, but may occur in the late stages of the disease. We report the first case of classic KS presenting in the gastrointestinal tract of an elderly HIV-negative Inuit male from Northern Quebec, Canada.

  6. Evaluation of the relationship between c-Kit expression and mean platelet volume in classic Kaposi's sarcoma*

    PubMed Central

    Sehitoglu, Ibrahim; Bedir, Recep; Cure, Erkan; Cure, Medine Cumhur; Yuce, Suleyman; Dilek, Nursel

    2016-01-01

    Background c-Kit is a proto-oncogene that encodes tyrosine kinase receptor (CD117). Mean platelet volume (MPV) is a useful marker, providing information on platelet function and diameter. Objective To investigate c-Kit expression and intensity in patients with Kaposi's sarcoma (KS) and to investigate the relation between Ki-67 proliferation and MPV. Methods A total of 32 patients, diagnosed with classic cutaneous KS, were included in this study. We reevaluated the histopathological reports with the preparations, confirmed the diagnosis and then determined the patients' histopathological stages. c-Kit expression and Ki-67 proliferation were investigated immunohistochemically in KS cases, while MPV in all cases was checked. Results Although c-Kit expression was detected in 22 cases (68.8%), it was not expressed in 10 cases (31.2%). We detected 8 cases with + (25%), 6 with ++ (18.8%) and 8 with +++ (25%). Ki-67 expression was 5.0% (min-max 1.0-20.0). Relapse was observed in 5 cases (15.6%) out of 32. There was positive correlation between c-Kit expression and MPV (rs=0.598, p<0.001), and between c-Kit intensity and MPV (rs=0.588, p<0.001). Conclusion c-Kit is highly positive in KS. c-Kit positivity indicates a high risk of tumor growth, invasion and relapse. Furthermore, c-Kit expression stimulates megakaryocytes to release young and large thrombocytes into the periphery. Thus, high MPV, c-Kit expression and immunostaining intensity indicate high invasion and relapse in KS subjects. PMID:27579736

  7. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induction by hypoxia and hypoxia-inducible factors.

    PubMed

    Veeranna, Ravindra P; Haque, Muzammel; Davis, David A; Yang, Min; Yarchoan, Robert

    2012-01-01

    Hypoxia and hypoxia-inducible factors (HIFs) play an important role in the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. In particular, hypoxia can activate lytic replication of KSHV and specific lytic genes, including the replication and transcription activator (RTA), while KSHV infection in turn can increase the levels and activity of HIFs. In the present study, we show that hypoxia increases the levels of mRNAs encoding KSHV latency-associated nuclear antigen (LANA) in primary effusion lymphoma (PEL) cell lines and also increases the levels of LANA protein. Luciferase reporter assays in Hep3B cells revealed a moderate activation of the LANA promoter region by hypoxia as well as by cotransfection with degradation-resistant HIF-1α or HIF-2α expression plasmids. Computer analysis of a 1.2-kb sequence upstream of the LANA translational start site identified six potential hypoxia-responsive elements (HRE). Sequential deletion studies revealed that much of this activity was mediated by one of these HREs (HRE 4R) oriented in the 3' to 5' direction and located between the constitutive (LTc) and RTA-inducible (LTi) mRNA start sites. Site-directed mutation of this HRE substantially reduced the response to both HIF-1α and HIF-2α in a luciferase reporter assay. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated binding of both HIF-1α and HIF-2α to this region. Also, HIF-1α was found to associate with RTA, and HIFs enhanced the activation of LTi by RTA. These results provide evidence that hypoxia and HIFs upregulate both latent and lytic KSHV replication and play a central role in the life cycle of this virus. PMID:22090111

  8. Functional characterization of Kaposi's sarcoma-associated herpesvirus open reading frame K8 by bacterial artificial chromosome-based mutagenesis.

    PubMed

    Wang, Yan; Sathish, Narayanan; Hollow, Charles; Yuan, Yan

    2011-03-01

    The open reading frame K8 of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a basic leucine zipper (bZip) protein that binds to the origin of viral DNA replication and is an integral component of viral lytic DNA replication complex. Moreover, K8 physically interacts with replication and transcription activator (RTA) and represses its transactivation activity on several viral promoters. To investigate the role of this protein in viral life cycle, we constructed two K8-null recombinant mutant viruses (BAC-ΔK8 and BAC-stopK8) by using a bacterial artificial chromosome (BAC) system. Latent viral infection can be reconstituted in 293T and BJAB cells with wild-type and the K8-null recombinant viruses by introducing the cloned viral genomes into the cells. When the cells carrying these viruses were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, no significant difference was seen in overall viral gene expression between wild-type and K8-null viruses, with lytic DNA replication still active in the latter. However, 293T cells harboring K8-null mutant viruses, either BAC-ΔK8 or BAC-stopK8, displayed lower copy numbers of latent KSHV genome in comparison with wild-type viruses. Furthermore, although K8 deficiency appeared to not affect infectivity when K8-null viruses were used to infect 293T, primary human microvascular dermal endothelial and human foreskin fibroblast cells, they exhibited much lower viral genome copy numbers in all types of cell compared to wild-type viruses. Taken together, these data suggest a possible role of K8 in abortive lytic DNA replication occurring in early stages of de novo infection or in the maintenance of latent viral genomes. PMID:21159864

  9. A hydrophobic domain within the small capsid protein of Kaposi's sarcoma-associated herpesvirus is required for assembly.

    PubMed

    Capuano, Christopher M; Grzesik, Peter; Kreitler, Dale; Pryce, Erin N; Desai, Keshal V; Coombs, Gavin; McCaffery, J Michael; Desai, Prashant J

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) capsids can be produced in insect cells using recombinant baculoviruses for protein expression. All six capsid proteins are required for this process to occur and, unlike for alphaherpesviruses, the small capsid protein (SCP) ORF65 is essential for this process. This protein decorates the capsid shell by virtue of its interaction with the capsomeres. In this study, we have explored the SCP interaction with the major capsid protein (MCP) using GFP fusions. The assembly site within the nucleus of infected cells was visualized by light microscopy using fluorescence produced by the SCP-GFP polypeptide, and the relocalization of the SCP to these sites was evident only when the MCP and the scaffold protein were also present - indicative of an interaction between these proteins that ensures delivery of the SCP to assembly sites. Biochemical assays demonstrated a physical interaction between the SCP and MCP, and also between this complex and the scaffold protein. Self-assembly of capsids with the SCP-GFP polypeptide was evident. Potentially, this result can be used to engineer fluorescent KSHV particles. A similar SCP-His6 polypeptide was used to purify capsids from infected cell lysates using immobilized affinity chromatography and to directly label this protein in capsids using chemically derivatized gold particles. Additional studies with SCP-GFP polypeptide truncation mutants identified a domain residing between aa 50 and 60 of ORF65 that was required for the relocalization of SCP-GFP to nuclear assembly sites. Substitution of residues in this region and specifically at residue 54 with a polar amino acid (lysine) disrupted or abolished this localization as well as capsid assembly, whereas substitution with non-polar residues did not affect the interaction. Thus, this study identified a small conserved hydrophobic domain that is important for the SCP-MCP interaction.

  10. CryoEM and mutagenesis reveal that the smallest capsid protein cements and stabilizes Kaposi's sarcoma-associated herpesvirus capsid.

    PubMed

    Dai, Xinghong; Gong, Danyang; Xiao, Yuchen; Wu, Ting-Ting; Sun, Ren; Zhou, Z Hong

    2015-02-17

    With just one eighth the size of the major capsid protein (MCP), the smallest capsid protein (SCP) of human tumor herpesviruses--Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV)--is vital to capsid assembly, yet its mechanism of action is unknown. Here, by cryoEM of KSHV at 6-Å resolution, we show that SCP forms a crown on each hexon and uses a kinked helix to cross-link neighboring MCP subunits. SCP-null mutation decreased viral titer by 1,000 times and impaired but did not fully abolish capsid assembly, indicating an important but nonessential role of SCP. By truncating the C-terminal half of SCP and performing cryoEM reconstruction, we demonstrate that SCP's N-terminal half is responsible for the observed structure and function whereas the C-terminal half is flexible and dispensable. Serial truncations further highlight the critical importance of the N-terminal 10 aa, and cryoEM reconstruction of the one with six residues truncated localizes the N terminus of SCP in the cryoEM density map and enables us to construct a pseudoatomic model of SCP. Fitting of this SCP model and a homology model for the MCP upper domain into the cryoEM map reveals that SCP binds MCP largely via hydrophobic interactions and the kinked helix of SCP bridges over neighboring MCPs to form noncovalent cross-links. These data support a mechanistic model that tumor herpesvirus SCP reinforces the capsid for genome packaging, thus acting as a cementing protein similar to those found in many bacteriophages.

  11. Efficient Infection of a Human B Cell Line with Cell-Free Kaposi's Sarcoma-Associated Herpesvirus

    PubMed Central

    Dollery, Stephen J.; Santiago-Crespo, Rey J.; Kardava, Lela; Moir, Susan

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is causatively linked to two B cell lymphoproliferative disorders, multicentric Castleman's disease and primary effusion lymphoma. Latently infected B cells are a major KSHV reservoir, and virus activation from tonsillar B cells can result in salivary shedding and virus transmission. Paradoxically, human B cells (primary and continuous) are notoriously refractory to infection, thus posing a major obstacle to the study of KSHV in this cell type. By performing a strategic search of human B cell lymphoma lines, we found that MC116 cells were efficiently infected by cell-free KSHV. Upon exposure to recombinant KSHV.219, enhanced green fluorescent protein reporter expression was detected in 17 to 20% of MC116 cells. Latent-phase transcription and protein synthesis were detected by reverse transcription-PCR and detection of latency-associated nuclear antigen expression, respectively, in cell lysates and individual cells. Selection based on the puromycin resistance gene in KSHV.219 yielded cultures with all cells infected. After repeated passaging of the selected KSHV-infected cells without puromycin, latent KSHV was maintained in a small fraction of cells. Infected MC116 cells could be induced into lytic phase with histone deacetylase inhibitors, as is known for latently infected non-B cell lines, and also selectively by the B cell-specific pathway involving B cell receptor cross-linking. Lytic-phase transition was documented by red fluorescent protein reporter expression, late structural glycoprotein (K8.1A, gH) detection, and infectious KSHV production. MC116 cells were CD27−/CD10+, characteristic of transitional B cells. These findings represent an important step in the establishment of an efficient continuous B cell line model to study the biologically relevant steps of KSHV infection. IMPORTANCE PMID:24257608

  12. Kaposi's sarcoma-associated herpesvirus LANA protein downregulates nuclear glycogen synthase kinase 3 activity and consequently blocks differentiation.

    PubMed

    Liu, Jianyong; Martin, Heather; Shamay, Meir; Woodard, Crystal; Tang, Qi-Qun; Hayward, S Diane

    2007-05-01

    The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen (LANA) protein interacts with glycogen synthase kinase 3 (GSK-3) and relocalizes GSK-3 in a manner that leads to stabilization of beta-catenin and upregulation of beta-catenin-responsive cell genes. The LANA-GSK-3 interaction was further examined to determine whether there were additional downstream consequences. In the present study, the nuclear GSK-3 bound to LANA in transfected cells and in BCBL1 primary effusion lymphoma cells was found to be enriched for the inactive serine 9-phosphorylated form of GSK-3. The mechanism of inactivation of nuclear GSK-3 involved LANA recruitment of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the ribosomal S6 kinase 1 (RSK1). ERK1/2 and RSK1 coprecipitated with LANA, and LANA was a substrate for ERK1 in vitro. A model is proposed for the overall inactivation of nuclear GSK-3 that incorporates the previously described GSK-3 phosphorylation of LANA itself. Functional inactivation of nuclear GSK-3 was demonstrated by the ability of LANA to limit phosphorylation of the known GSK-3 substrates C/EBPbeta and C/EBPalpha. The effect of LANA-mediated ablation of C/EBP phosphorylation on differentiation was modeled in the well-characterized 3T3L1 adipogenesis system. LANA-expressing 3T3L1 cells were impaired in their ability to undergo differentiation and adipogenesis. C/EBPbeta induction followed the same time course as that seen in vector-transduced cells, but there was delayed and reduced induction of C/EBPbeta transcriptional targets in LANA-expressing cells. We conclude that LANA inactivates nuclear GSK-3 and modifies the function of proteins that are GSK-3 substrates. In the case of C/EBPs, this translates into LANA-mediated inhibition of differentiation. PMID:17314169

  13. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia.

    PubMed

    Haque, Muzammel; Davis, David A; Wang, Victoria; Widmer, Isabelle; Yarchoan, Robert

    2003-06-01

    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as human herpesvirus 8, is an etiologic agent of KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease. We recently demonstrated that hypoxia can induce lytic replication of KSHV in PEL cell lines. Hypoxia induces the accumulation of hypoxia-inducible factors (HIF), and we hypothesized that the KSHV genome may respond to hypoxia through functional hypoxia response elements (HREs). Here, we demonstrate the presence of at least two promoters within the KSHV genome that are activated by hypoxia or hypoxia mimics. One is in the promoter region of the gene for Rta, the main lytic switch gene, and the other is within the promoter region of ORF34, a lytic gene of unknown function. The ORF34 promoter contains three putative consensus HREs oriented in the direction of the gene. Dissection and site-directed mutagenesis studies confirmed that one of the HREs of the ORF34 promoter is functional. Under conditions of hypoxia, the ORF34 promoter was strongly upregulated by HIF-1 alpha and HIF-2 alpha. By contrast, the promoter of the gene for Rta appeared to be preferentially upregulated by HIF-2 alpha. Reverse transcription-PCR analysis revealed that specific messages for ORF34 and ORF50 are upregulated in BCBL-1 cells exposed to hypoxia. An HIF-1 binding and competition assay demonstrated that the HRE sequence from the ORF34 promoter can compete for HIF-1 alpha binding to an erythropoietin HRE oligonucleotide while a mutant sequence cannot. Thus, we demonstrated that a viral gene can be activated by hypoxia through activation of a functional viral HRE. To our knowledge, this is the first example of a functional HRE in a viral promoter. PMID:12767996

  14. A hydrophobic domain within the small capsid protein of Kaposi's sarcoma-associated herpesvirus is required for assembly.

    PubMed

    Capuano, Christopher M; Grzesik, Peter; Kreitler, Dale; Pryce, Erin N; Desai, Keshal V; Coombs, Gavin; McCaffery, J Michael; Desai, Prashant J

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) capsids can be produced in insect cells using recombinant baculoviruses for protein expression. All six capsid proteins are required for this process to occur and, unlike for alphaherpesviruses, the small capsid protein (SCP) ORF65 is essential for this process. This protein decorates the capsid shell by virtue of its interaction with the capsomeres. In this study, we have explored the SCP interaction with the major capsid protein (MCP) using GFP fusions. The assembly site within the nucleus of infected cells was visualized by light microscopy using fluorescence produced by the SCP-GFP polypeptide, and the relocalization of the SCP to these sites was evident only when the MCP and the scaffold protein were also present - indicative of an interaction between these proteins that ensures delivery of the SCP to assembly sites. Biochemical assays demonstrated a physical interaction between the SCP and MCP, and also between this complex and the scaffold protein. Self-assembly of capsids with the SCP-GFP polypeptide was evident. Potentially, this result can be used to engineer fluorescent KSHV particles. A similar SCP-His6 polypeptide was used to purify capsids from infected cell lysates using immobilized affinity chromatography and to directly label this protein in capsids using chemically derivatized gold particles. Additional studies with SCP-GFP polypeptide truncation mutants identified a domain residing between aa 50 and 60 of ORF65 that was required for the relocalization of SCP-GFP to nuclear assembly sites. Substitution of residues in this region and specifically at residue 54 with a polar amino acid (lysine) disrupted or abolished this localization as well as capsid assembly, whereas substitution with non-polar residues did not affect the interaction. Thus, this study identified a small conserved hydrophobic domain that is important for the SCP-MCP interaction. PMID:24824860

  15. In vivo growth-restricted and reversible malignancy induced by Human Herpesvirus-8/ KSHV: a cell and animal model of virally induced Kaposi's sarcoma

    PubMed Central

    Mutlu, Agata D'Agostino; Cavallin, Lucas E.; Vincent, Loïc; Chiozzini, Chiara; Eroles, Pilar; Duran, Elda M.; Asgari, Zahra; Hooper, Andrea T.; La Perle, Krista M. D.; Hilsher, Chelsey; Gao, Shou-Jiang; Dittmer, Dirk P.; Rafii, Shahin; Mesri, Enrique A.

    2007-01-01

    Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to non-tumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene up-regulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth-restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS. PMID:17349582

  16. Acetylation changes at lysine 5 of histone H4 associated with lytic gene promoters during reactivation of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Hwang, L R; Cha, S; Jong, J E; Jang, J H; Seo, T

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a pathogenic agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease in humans. Similarly to other gammaherpesviruses such as Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), KSHV displays two alternative life cycles, latent and lytic one. The transactivation from latency to the lytic phase is the result of transcriptional changes in the KSHV genome caused by the replication and transcriptional activator (RTA). During KSHV reactivation, epigenetic modifications of histone protein on the viral genome occur, which regulate the transcriptional activation of a number of lytic genes. The reactivation of EBV from latency to lytic cycle, induced by an immediate-early Zta protein, was shown to be accompanied by acetylation of specific lysines in histone H4. Accordingly, we hypothesized that the RTA-induced transactivation of KSHV could also be accompanied by histone acetylation. To validate this hypothesis, we assayed alterations of acetyl-histone H4-lysine 5 (acH4K5) during the RTA-mediated KSHV reactivation. While the modified histone protein in a total cell lysate was not distinguished between control and RTA-expressed cells, upregulated acH4K5 was detected on several lytic gene promoter regions during KSHV reactivation. Our results clearly indicate that this epigenetic change is related to transcription of genes expressed in the lytic cycle of KSHV. PMID:25283865

  17. Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein.

    PubMed

    Chatterjee, Deboeeta; Chandran, Bala; Berger, Edward A

    2012-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication. PMID:22377676

  18. The single RBP-Jkappa site within the LANA promoter is crucial for establishing Kaposi's sarcoma-associated herpesvirus latency during primary infection.

    PubMed

    Lu, Jie; Verma, Subhash C; Cai, Qiliang; Robertson, Erle S

    2011-07-01

    Kaposi's sarcoma-associated herpesvirus (KSHV; or human herpesvirus 8 [HHV8]) is implicated in the pathogenesis of many human malignancies including Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). KSHV infection displays two alternative life cycles, referred to as the latent and lytic or productive cycle. Previously, we have reported that the replication and transcription activator (RTA), a major lytic cycle transactivator, contributes to the development of KSHV latency by inducing latency-associated nuclear antigen (LANA) expression during early stages of infection by targeting RBP-Jκ, the master regulator of the Notch signaling pathway. Here, we generated a bacterial artificial chromosome (BAC) KSHV recombinant virus with a deletion of the RBP-Jκ site within the LANA promoter to evaluate the function of the RBP-Jκ cognate site in establishing primary latent infection. The results showed that genetic disruption of the RBP-Jκ binding site within the KSHV LANA promoter led to enhanced expression of the KSHV-encoded immediate early RTA, resulting in an increase in lytic replication during primary infection of human peripheral blood mononuclear cells (PBMCs). This system provides a powerful tool for use in indentifying additional cellular and viral molecules involved in LANA-mediated latency maintenance during the early stages of KSHV infection. PMID:21507979

  19. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients

    PubMed Central

    1996-01-01

    Short DNA sequences have been identified, originally in association with Kaposi's sarcoma (KS) biopsies, that are highly homologous to oncogenic, lymphotropic herpesviruses. Recently a virus, Kaposi sarcoma associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), bearing these sequences has been identified in a cell line derived from a body cavity-based lymphoma. In this report, we show that the same sequences are present in KS biopsies as DNA molecules of a form and size characteristic of latent herpesviruses-large, covalently closed, circular episomes. The genomes migrate with an apparent size larger than the herpesvirus Epstein-Barr virus (172 kb). This form of the viral genome was found in four of four biopsies and three of five peripheral blood samples from KS patients. Linear forms of the viral genome, characteristic of viral replication, were not detected in the biopsies, but were present in the peripheral blood of three out of five patients. The sequences for KSHV/HHV-8 were also detected in the blood of four of five allograft patients and three of five healthy donors without KS suggesting that the virus is widespread throughout the human population. PMID:8691144

  20. Identification of two homologs of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in retroperitoneal fibromatosis of different macaque species.

    PubMed Central

    Rose, T M; Strand, K B; Schultz, E R; Schaefer, G; Rankin, G W; Thouless, M E; Tsai, C C; Bosch, M L

    1997-01-01

    Simian retroperitoneal fibromatosis (RF) is a vascular fibroproliferative neoplasm which has many morphological and histological similarities to human Kaposi's sarcoma (KS). Like epidemic KS in AIDS patients, RF is highly associated with an immunodeficiency syndrome (simian acquired immunodeficiency syndrome [SAIDS]) caused by a retrovirus infection. Recently, a new gammaherpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been identified in KS tumors, suggesting that KS has a viral etiology. Our previous experimental transmission studies and epidemiological data suggest that RF also has an infectious etiology. In order to determine whether a similar virus is also associated with RF, we have assayed for the presence of an unknown herpesvirus using degenerate PCR primers targeting the highly conserved DNA polymerase genes of the herpesvirus family. Here we provide DNA sequence evidence for two new herpesviruses closely related to KSHV from RF tissues of two macaque species, Macaca nemestrina and Macaca mulatta. Our data suggest that KSHV and the putative macaque herpesviruses define a new group within the subfamily Gammaherpesvirinae whose members are implicated in the pathogenesis of KS and KS-like neoplasms in different primate species. PMID:9094697

  1. Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR.

    PubMed

    Lang, Sabine M; Bynoe, Meisha O F; Karki, Roshan; Tartell, Michael A; Means, Robert E

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins. PMID:23460925

  2. The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1.

    PubMed Central

    Godden-Kent, D; Talbot, S J; Boshoff, C; Chang, Y; Moore, P; Weiss, R A; Mittnacht, S

    1997-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) is a novel gammaherpesvirus implicated in the cause of Kaposi's sarcoma and certain malignancies of lymphatic origin. One of the candidate genes possibly involved in promoting tumor development is an open reading frame (ORF) with sequence similarity to human type D cyclin genes. This cyclin-like gene, when expressed in tissue culture cells, promotes phosphorylation and inactivation of the retinoblastoma tumor suppressor protein and thereby may result in deregulation of cell division control. We report here the biochemical characterization of this cyclin (KSHV-cyc) and the kinase activity that it elicits upon expression in tissue culture cells. We demonstrate that the kinase activity associated with KSHV-cyc is sensitive to the cdk inhibitor p27 (KIP) and due to activation of cdk6. However, in contrast to cdk6 activated by cellular type D cyclins, the cdk6 activated by KSHV-cyc is capable of phosphorylating not only the retinoblastoma protein but also histone H1. This finding implies that activation by KSHV-cyc alters the substrate preference of this cdk. This may have important physiological consequences in that the kinase activity triggered by this viral cyclin may abrogate cell cycle checkpoints in addition to those targeted by cellular cyclin D-cdk6 kinase. PMID:9151805

  3. Array-Based Transcript Profiling and Limiting-Dilution Reverse Transcription-PCR Analysis Identify Additional Latent Genes in Kaposi's Sarcoma-Associated Herpesvirus▿ †

    PubMed Central

    Chandriani, Sanjay; Ganem, Don

    2010-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a B-lymphotropic herpesvirus strongly linked to both lymphoproliferative diseases and Kaposi's sarcoma. The viral latency program of KSHV is central to persistent infection and plays important roles in the pathogenesis of KSHV-related tumors. Up to six polypeptides and 18 microRNAs are known to be expressed in latency, but it is unclear if all major latency genes have been identified. Here, we have employed array-based transcript profiling and limiting-dilution reverse transcription-PCR (RT-PCR) methodologies to explore this issue in several KSHV-infected cell lines. Our results show that RNAs encoding the K1 protein are found at low levels in most latently infected cell lines. The gene encoding v-IL-6 is also expressed as a latent transcript in some contexts. Both genes encode powerful signaling molecules with particular relevance to B cell biology: K1 mimics signaling through the B cell receptor, and v-IL-6 promotes B cell survival. These data resolve earlier controversies about K1 and v-IL-6 expression and indicate that, in addition to core latency genes, some transcripts can be expressed in KSHV latency in a context-dependent manner. PMID:20219929

  4. Acetylation changes at lysine 5 of histone H4 associated with lytic gene promoters during reactivation of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Hwang, L R; Cha, S; Jong, J E; Jang, J H; Seo, T

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a pathogenic agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease in humans. Similarly to other gammaherpesviruses such as Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), KSHV displays two alternative life cycles, latent and lytic one. The transactivation from latency to the lytic phase is the result of transcriptional changes in the KSHV genome caused by the replication and transcriptional activator (RTA). During KSHV reactivation, epigenetic modifications of histone protein on the viral genome occur, which regulate the transcriptional activation of a number of lytic genes. The reactivation of EBV from latency to lytic cycle, induced by an immediate-early Zta protein, was shown to be accompanied by acetylation of specific lysines in histone H4. Accordingly, we hypothesized that the RTA-induced transactivation of KSHV could also be accompanied by histone acetylation. To validate this hypothesis, we assayed alterations of acetyl-histone H4-lysine 5 (acH4K5) during the RTA-mediated KSHV reactivation. While the modified histone protein in a total cell lysate was not distinguished between control and RTA-expressed cells, upregulated acH4K5 was detected on several lytic gene promoter regions during KSHV reactivation. Our results clearly indicate that this epigenetic change is related to transcription of genes expressed in the lytic cycle of KSHV.

  5. NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

    PubMed

    Hughes, David J; Wood, Jennifer J; Jackson, Brian R; Baquero-Pérez, Belinda; Whitehouse, Adrian

    2015-03-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies.

  6. ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells

    PubMed Central

    Kumar, Binod; Ansari, Mairaj Ahmed; Dutta, Dipanjan; Iqbal, Jawed; Gjyshi, Olsi; Bottero, Virginie; Chandran, Bala

    2016-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) enters human dermal microvascular endothelial cells (HMVEC-d), its natural in vivo target cells, by lipid raft-dependent macropinocytosis. The internalized viral envelope fuses with the macropinocytic membrane, and released capsid is transported to the nuclear vicinity, resulting in the nuclear entry of viral DNA. The endosomal sorting complexes required for transport (ESCRT) proteins, which include ESCRT-0, -I, -II, and -III, play a central role in endosomal trafficking and sorting of internalized and ubiquitinated receptors. Here, we examined the role of ESCRT-0 component Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) in KSHV entry into HMVEC-d by macropinocytosis. Knockdown of Hrs by short hairpin RNA (shRNA) transduction resulted in significant decreases in KSHV entry and viral gene expression. Immunofluorescence analysis (IFA) and plasma membrane isolation and proximity ligation assay (PLA) demonstrated the translocation of Hrs from the cytosol to the plasma membrane of infected cells and association with α-actinin-4. In addition, infection induced the plasma membrane translocation and activation of the serine/threonine kinase ROCK1, a downstream target of the RhoA GTPase. Hrs knockdown reduced these associations, suggesting that the recruitment of ROCK1 is an Hrs-mediated event. Interaction between Hrs and ROCK1 is essential for the ROCK1-induced phosphorylation of NHE1 (Na+/H+ exchanger 1), which is involved in the regulation of intracellular pH. Thus, our studies demonstrate the plasma membrane association of ESCRT protein Hrs during macropinocytosis and suggest that KSHV entry requires both Hrs- and ROCK1-dependent mechanisms and that ROCK1-mediated phosphorylation of NHE1 and pH change is an essential event required for the macropinocytosis of KSHV. IMPORTANCE Macropinocytosis is the major entry pathway of KSHV in human dermal microvascular endothelial cells, the natural target

  7. Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

    PubMed Central

    Johnston, Christine; Orem, Jackson; Okuku, Fred; Kalinaki, Mary; Saracino, Misty; Katongole-Mbidde, Edward; Ronald, Allan; McAdam, Keith; Huang, Meei-Li; Drolette, Linda; Selke, Stacy; Wald, Anna; Corey, Lawrence; Casper, Corey

    2009-01-01

    Introduction Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS. Methods Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR). Results 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs). Conclusions HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The

  8. Identification of the Essential Role of Viral Bcl-2 for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

    PubMed Central

    Liang, Qiming; Chang, Brian; Lee, Patrick; Brulois, Kevin F.; Ge, Jianning; Shi, Mude; Rodgers, Mary A.; Feng, Pinghui; Oh, Byung-Ha; Liang, Chengyu

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) evades host defenses through tight suppression of autophagy by targeting each step of its signal transduction: by viral Bcl-2 (vBcl-2) in vesicle nucleation, by viral FLIP (vFLIP) in vesicle elongation, and by K7 in vesicle maturation. By exploring the roles of KSHV autophagy-modulating genes, we found, surprisingly, that vBcl-2 is essential for KSHV lytic replication, whereas vFLIP and K7 are dispensable. Knocking out vBcl-2 from the KSHV genome resulted in decreased lytic gene expression at the mRNA and protein levels, a lower viral DNA copy number, and, consequently, a dramatic reduction in the amount of progeny infectious viruses, as also described in the accompanying article (A. Gelgor, I. Kalt, S. Bergson, K. F. Brulois, J. U. Jung, and R. Sarid, J Virol 89:5298–5307, 2015). More importantly, the antiapoptotic and antiautophagic functions of vBcl-2 were not required for KSHV lytic replication. Using a comprehensive mutagenesis analysis, we identified that glutamic acid 14 (E14) of vBcl-2 is critical for KSHV lytic replication. Mutating E14 to alanine totally blocked KSHV lytic replication but showed little or no effect on the antiapoptotic and antiautophagic functions of vBcl-2. Our study indicates that vBcl-2 harbors at least three important and genetically separable functions to modulate both cellular signaling and the virus life cycle. IMPORTANCE The present study shows for the first time that vBcl-2 is essential for KSHV lytic replication. Removal of the vBcl-2 gene results in a lower level of KSHV lytic gene expression, impaired viral DNA replication, and consequently, a dramatic reduction in the level of progeny production. More importantly, the role of vBcl-2 in KSHV lytic replication is genetically separated from its antiapoptotic and antiautophagic functions, suggesting that the KSHV Bcl-2 carries a novel function in viral lytic replication. PMID:25740994

  9. A microRNA encoded by Kaposi sarcoma-associated herpesvirus promotes B-cell expansion in vivo.

    PubMed

    Dahlke, Christine; Maul, Katrin; Christalla, Thomas; Walz, Nicole; Schult, Philipp; Stocking, Carol; Grundhoff, Adam

    2012-01-01

    The human gammaherpesvirus Kaposi sarcoma-associated herpesvirus is strongly linked to neoplasms of endothelial and B-cell origin. The majority of tumor cells in these malignancies are latently infected, and latency genes are consequently thought to play a critical role in virus-induced tumorigenesis. One such factor is kshv-miR-K12-11, a viral microRNA that is constitutively expressed in cell lines derived from KSHV-associated tumors, and that shares perfect homology of its seed sequence with the cellular miR-155. Since miR-155 is overexpressed in a number of human tumors, it is conceivable that mimicry of miR-155 by miR-K12-11 may contribute to cellular transformation in KSHV-associated disease. Here, we have performed a side-by-side study of phenotypic alterations associated with constitutive expression of either human miR-155 or viral miR-K12-11 in bone marrow-derived hematopoietic stem cells. We demonstrate that retroviral-mediated gene transfer and hematopoietic progenitor cell transplantation into C57BL/6 mice leads to increased B-cell fractions in lymphoid organs, as well as to enhanced germinal center formation in both microRNA-expressing mouse cohorts. We furthermore identify Jarid2, a component of Polycomb repressive complex 2, as a novel validated target of miR-K12-11, and confirm its downregulation in miR-K12-11 as well as miR-155 expressing bone marrow cells. Our findings confirm and extend previous observations made in other mouse models, and underscore the notion that miR-K12-11 may have arisen to mimic miR-155 functions in KSHV-infected B-cells. The expression of miR-K12-11 may represent one mechanism by which KSHV presumably aims to reprogram naïve B-cells towards supporting long-term latency, which at the same time is likely to pre-dispose infected lymphocytes to malignant transformation.

  10. Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

    PubMed Central

    Cheng, Fan; Sawant, Tanvee Vinod; Lan, Ke; Lu, Chun; Jung, Jae U.

    2015-01-01

    ABSTRACT Viruses often hijack cellular pathways to facilitate infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus etiologically associated with Kaposi's sarcoma, a vascular tumor of endothelial cells. Despite intensive studies, cellular pathways mediating KSHV infection and replication are still not well defined. Using an antibody array approach, we examined cellular proteins phosphorylated during primary KSHV infection of primary human umbilical vein endothelial cells. Enrichment analysis identified integrin/mitogen-activated protein kinase (integrin/MAPK), insulin/epidermal growth factor receptor (insulin/EGFR), and JAK/STAT as the activated networks during primary KSHV infection. The transcriptional factor CREB1 (cyclic AMP [cAMP]-responsive element-binding protein 1) had the strongest increase in phosphorylation. While knockdown of CREB1 had no effect on KSHV entry and trafficking, it drastically reduced the expression of lytic transcripts and proteins and the production of infectious virions. Chemical activation of CREB1 significantly enhanced viral lytic replication. In contrast, CREB1 neither influenced the expression of the latent gene LANA nor affected KSHV infectivity. Mechanistically, CREB1 was not activated through the classic cAMP/protein kinase A (cAMP/PKA) pathway or via the AKT, MK2, and RSK pathways. Rather, CREB1 was activated by the mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2). Consequently, chemical inhibition or knockdown of MSKs significantly inhibited the KSHV lytic replication program; however, it had a minimal effect on LANA expression and KSHV infectivity. Together, these results identify the MSK1/2-CREB1 proteins as novel essential effectors of KSHV lytic replication during primary infection. The differential effect of the MSK1/2-CREB1 pathway on the expression of viral latent and lytic genes might control the robustness of viral lytic replication, and therefore the

  11. Kaposi's sarcoma-associated herpesvirus infection of endothelial cells inhibits neutrophil recruitment through an interleukin-6-dependent mechanism: a new paradigm for viral immune evasion.

    PubMed

    Butler, L M; Jeffery, H C; Wheat, R L; Rae, P C; Townsend, K; Alkharsah, K R; Schulz, T F; Nash, G B; Blackbourn, D J

    2011-07-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an endothelial cell (EC) neoplasm characterized by dysregulated angiogenesis and inflammation. KSHV infection of EC causes production of proinflammatory mediators, regarded as possible initiators of the substantial mononuclear leukocyte recruitment seen in KS. Conversely, KSHV immune evasion strategies exist, such as degradation of EC leukocyte adhesion receptors by viral proteins. Here, we report the effects of KSHV infection of primary EC on recruitment of flowing leukocytes. Infection did not initiate adhesion of any leukocyte subset per se. However, on cytokine-stimulated EC, KSHV specifically inhibited neutrophil, but not PBL or monocyte, transmigration, an observation consistent with the inflammatory cell profile found in KS lesions in vivo. This inhibition could be recapitulated on uninfected EC using supernatant from infected cultures. These supernatants contained elevated levels of human interleukin 6 (hIL-6), and both the KSHV- and the supernatant-induced inhibitions of neutrophil transmigration were abrogated in the presence of a hIL-6 neutralizing antibody. Furthermore, preconditioning of EC with hIL-6 mimicked the effect of KSHV. Using RNA interference (RNAi), we show that upregulation of suppressor of cytokine signaling 3 (SOCS3) was necessary for this effect of hIL-6. These studies reveal a novel paracrine mode of KSHV immune evasion, resulting in reduced recruitment of neutrophils, a cell type whose antiviral and antitumor roles are becoming increasingly appreciated. Moreover, the findings have implications for our understanding of the contribution of hIL-6 to the pathogenesis of other inflammatory disorders and tumors in which this cytokine is abundant.

  12. The Cellular Peptidyl-Prolyl cis/trans Isomerase Pin1 Regulates Reactivation of Kaposi's Sarcoma-Associated Herpesvirus from Latency

    PubMed Central

    Guito, Jonathan; Gavina, Aileen; Palmeri, Diana

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma and primary effusion lymphoma. KSHV-infected cells are predominantly latent, with a subset undergoing lytic reactivation. Rta is the essential lytic switch protein that reactivates virus by forming transactivation-competent complexes with the Notch effector protein RBP-Jk and promoter DNA. Strikingly, Rta homolog analysis reveals that prolines constitute 17% of conserved residues. Rta is also highly phosphorylated in vivo. We previously demonstrated that proline content determines Rta homotetramerization and function. We hypothesize that proline-directed modifications regulate Rta function by controlling binding to peptidyl-prolyl cis/trans isomerases (PPIases). Cellular PPIase Pin1 binds specifically to phosphoserine- or phosphothreonine-proline (pS/T-P) motifs in target proteins. Pin1 dysregulation is implicated in myriad human cancers and can be subverted by viruses. Our data show that KSHV Rta protein contains potential pS/T-P motifs and binds directly to Pin1. Rta transactivation is enhanced by Pin1 at two delayed early viral promoters in uninfected cells. Pin1's effect, however, suggests a rheostat-like influence on Rta function. We show that in infected cells, endogenous Pin1 is active during reactivation and enhances Rta-dependent early protein expression induced by multiple signals, as well as DNA replication. Surprisingly, ablation of Pin1 activity by the chemical juglone or dominant-negative Pin1 enhanced late gene expression and production of infectious virus, while ectopic Pin1 showed inhibitory effects. Our data thus suggest that Pin1 is a unique, dose-dependent molecular timer that enhances Rta protein function, but inhibits late gene synthesis and virion production, during KSHV lytic reactivation. PMID:24173213

  13. CTCF and Rad21 act as host cell restriction factors for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription.

    PubMed

    Li, Da-Jiang; Verma, Dinesh; Mosbruger, Tim; Swaminathan, Sankar

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a human herpesvirus that causes Kaposi's sarcoma and is associated with the development of lymphoproliferative diseases. KSHV reactivation from latency and virion production is dependent on efficient transcription of over eighty lytic cycle genes and viral DNA replication. CTCF and cohesin, cellular proteins that cooperatively regulate gene expression and mediate long-range DNA interactions, have been shown to bind at specific sites in herpesvirus genomes. CTCF and cohesin regulate KSHV gene expression during latency and may also control lytic reactivation, although their role in lytic gene expression remains incompletely characterized. Here, we analyze the dynamic changes in CTCF and cohesin binding that occur during the process of KSHV viral reactivation and virion production by high resolution chromatin immunoprecipitation and deep sequencing (ChIP-Seq) and show that both proteins dissociate from viral genomes in kinetically and spatially distinct patterns. By utilizing siRNAs to specifically deplete CTCF and Rad21, a cohesin component, we demonstrate that both proteins are potent restriction factors for KSHV replication, with cohesin knockdown leading to hundred-fold increases in viral yield. High-throughput RNA sequencing was used to characterize the transcriptional effects of CTCF and cohesin depletion, and demonstrated that both proteins have complex and global effects on KSHV lytic transcription. Specifically, both proteins act as positive factors for viral transcription initially but subsequently inhibit KSHV lytic transcription, such that their net effect is to limit KSHV RNA accumulation. Cohesin is a more potent inhibitor of KSHV transcription than CTCF but both proteins are also required for efficient transcription of a subset of KSHV genes. These data reveal novel effects of CTCF and cohesin on transcription from a relatively small genome that resemble their effects on the cellular genome by acting as

  14. Kaposi's Sarcoma (KS)

    MedlinePlus

    ... over 80% since the introduction of antiretroviral therapy (ART). However, rare cases of KS are reported in ... KS. HOW IS KS TREATED? Suppressing HIV with ART is the best treatment for active KS. In ...

  15. K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

    PubMed Central

    Steinbrück, Lisa; Gustems, Montse; Medele, Stephanie; Schulz, Thomas F.; Lutter, Dominik

    2015-01-01

    ABSTRACT The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodes LMP2A, one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genes K1 or K15 in lieu of LMP2A and infected primary BCR-negative (BCR−) human B cells with them. We confirmed that the survival of BCR– B cells and their proliferation depended on an active LMP2A signal. Like LMP2A, the expression of K1 and K15 led to the survival of BCR− B cells prone to apoptosis, supported their proliferation, and regulated a similar set of cellular target genes. K1 and K15 encoded proteins appear to have noncomplementing, redundant functions in this model, but our findings suggest that both KSHV proteins can replace LMP2A's key activities contributing to the survival, activation and proliferation of BCR– PEL cells in vivo. IMPORTANCE Several herpesviruses encode oncogenes that are receptor-like proteins. Often, they are constitutively active providing important functions to the latently infected cells. LMP2A of Epstein-Barr virus (EBV) is such a receptor that mimics an activated B cell receptor, BCR. K1 and K15, related receptors of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in virus-associated tumors, have less obvious functions. We found in infection experiments that both viral receptors of KSHV can replace LMP2A and deliver functions

  16. Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during De Novo Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection

    PubMed Central

    Gjyshi, Olsi; Bottero, Virginie; Veettil, Mohanan Valliya; Dutta, Sujoy; Singh, Vivek Vikram; Chikoti, Leela; Chandran, Bala

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma. KSHV induces reactive oxygen species (ROS) early during infection of human dermal microvascular endothelial (HMVEC-d) cells that are critical for virus entry. One of the downstream targets of ROS is nuclear factor E2-related factor 2 (Nrf2), a transcription factor with important anti-oxidative functions. Here, we show that KS skin lesions have high Nrf2 activity compared to healthy skin tissue. Within 30 minutes of de novo KSHV infection of HMVEC-d cells, we observed Nrf2 activation through ROS-mediated dissociation from its inhibitor Keap1, Ser-40 phosphorylation, and subsequent nuclear translocation. KSHV binding and consequent signaling through Src, PI3-K and PKC-ζ were also important for Nrf2 stability, phosphorylation and transcriptional activity. Although Nrf2 was dispensable for ROS homeostasis, it was essential for the induction of COX-2, VEGF-A, VEGF-D, Bcl-2, NQO1, GCS, HO1, TKT, TALDO and G6PD gene expression in KSHV-infected HMVEC-d cells. The COX-2 product PGE2 induced Nrf2 activity through paracrine and autocrine signaling, creating a feed-forward loop between COX-2 and Nrf2. vFLIP, a product of KSHV latent gene ORF71, induced Nrf2 and its target genes NQO1 and HO1. Activated Nrf2 colocalized with the KSHV genome as well as with the latency protein LANA-1. Nrf2 knockdown enhanced ORF73 expression while reducing ORF50 and other lytic gene expression without affecting KSHV entry or genome nuclear delivery. Collectively, these studies for the first time demonstrate that during de novo infection, KSHV induces Nrf2 through intricate mechanisms involving multiple signal molecules, which is important for its ability to manipulate host and viral genes, creating a microenvironment conducive to KSHV infection. Thus, Nrf2 is a potential attractive target to intervene in KSHV infection and the associated maladies. PMID:25340789

  17. Excellent clinical outcomes and retention in care for adults with HIV-associated Kaposi sarcoma treated with systemic chemotherapy and integrated antiretroviral therapy in rural Malawi

    PubMed Central

    Herce, Michael E; Kalanga, Noel; Wroe, Emily B; Keck, James W; Chingoli, Felix; Tengatenga, Listern; Gopal, Satish; Phiri, Atupere; Mailosi, Bright; Bazile, Junior; Beste, Jason A; Elmore, Shekinah N; Crocker, Jonathan T; Rigodon, Jonas

    2015-01-01

    Introduction HIV-associated Kaposi sarcoma (HIV-KS) is the most common cancer in Malawi. In 2008, the non-governmental organization, Partners In Health, and the Ministry of Health established the Neno Kaposi Sarcoma Clinic (NKSC) to treat HIV-KS in rural Neno district. We aimed to evaluate 12-month clinical outcomes and retention in care for HIV-KS patients in the NKSC, and to describe our implementation model, which featured protocol-guided chemotherapy, integrated antiretroviral therapy (ART) and psychosocial support delivered by community health workers. Methods We conducted a retrospective cohort study using routine clinical data from 114 adult HIV-KS patients who received ART and ≥1 chemotherapy cycle in the NKSC between March 2008 and February 2012. Results At enrolment 97% of patients (n/N=103/106) had advanced HIV-KS (stage T1). Most patients were male (n/N=85/114, 75%) with median age 36 years (interquartile range, IQR: 29–42). Patients started ART a median of 77 days prior to chemotherapy (IQR: 36–252), with 97% (n/N=105/108) receiving nevirapine/lamivudine/stavudine. Following standardized protocols, we treated 20 patients (18%) with first-line paclitaxel and 94 patients (82%) with bleomycin plus vincristine (BV). Of the 94 BV patients, 24 (26%) failed to respond to BV requiring change to second-line paclitaxel. A Division of AIDS grade 3/4 adverse event occurred in 29% of patients (n/N=30/102). Neutropenia was the most common grade 3/4 event (n/N=17/102, 17%). Twelve months after chemotherapy initiation, 83% of patients (95% CI: 74–89%) were alive, including 88 (77%) retained in care. Overall survival (OS) at 12 months did not differ by initial chemotherapy regimen (p=0.6). Among patients with T1 disease, low body mass index (BMI) (adjusted hazard ratio, aHR=4.10, 95% CI: 1.06–15.89) and 1 g/dL decrease in baseline haemoglobin (aHR=1.52, 95% CI: 1.03–2.25) were associated with increased death or loss to follow-up at 12 months. Conclusions

  18. Protein kinase CK2 phosphorylation regulates the interaction of Kaposi's sarcoma-associated herpesvirus regulatory protein ORF57 with its multifunctional partner hnRNP K

    PubMed Central

    Malik, Poonam; Clements, J. Barklie

    2004-01-01

    ORF57 protein of Kaposi's sarcoma-associated herpesvirus has a counterpart in all herpesvirus of mammals and birds and regulates gene expression at transcriptional and post-transcriptional levels. ORF57 was capable of self-interaction and bound a rapidly migrating form of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a multifunctional cellular protein involved in gene expression. In virus infected cell extracts, ORF57 was present in a complex with hnRNP K that had protein kinase CK2 activity, and was phosphorylated by CK2. Different regions of ORF57 bound both catalytic α/α′ and regulatory β subunits of CK2. CK2 modification enhanced the ORF57–hnRNP K interaction, and may regulate the presence and activities of components in the complex. We suggest that ORF57 and hnRNP K interaction may modulate ORF57-mediated regulation of viral gene expression. Herpesviral ORF57 (Rhadinovirus) and ICP27 (Simplexvirus) proteins both interact with hnRNP K and CK2 implying that adaptation of the ancestral hnRNP K and CK2 to associate with viral regulatory ancestor protein likely pre-dates divergence of these Herpesviridae genera that occurred 200 million years ago. PMID:15486205

  19. Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma-associated herpesvirus ORF57 protein is required for RNA splicing.

    PubMed

    Majerciak, Vladimir; Lu, Mathew; Li, Xiaofan; Zheng, Zhi-Ming

    2014-11-01

    Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a multifunctional post-transcriptional regulator essential for viral gene expression during KSHV lytic infection. ORF57 requires interactions with various cellular proteins for its function. Here, we identified serine/arginine-rich splicing factor 3 (SRSF3, formerly known as SRp20) as a cellular cofactor involved in ORF57-mediated splicing of KSHV K8β RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits K8β splicing. Knockdown of SRSF3 promotes K8β splicing, mimicking the effect of ORF57. The N-terminal half of ORF57 binds to the RNA recognition motif of SRSF3, which prevents SRSF3 from associating with the K8β intron RNA and therefore attenuates the suppressive effect of SRSF3 on K8β splicing. ORF57 also promotes splicing of heterologous non-KSHV transcripts that are negatively regulated by SRSF3, indicating that the effect of ORF57 on SRSF3 activity is independent of RNA target. SPEN proteins, previously identified as ORF57-interacting partners, suppress ORF57 splicing activity by displacing ORF57 from SRSF3-RNA complexes. In summary, we have identified modulation of SRSF3 activity as the molecular mechanism by which ORF57 promotes RNA splicing.

  20. Kaposi's sarcoma associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a

    PubMed Central

    Punj, Vasu; Matta, Hittu; Schamus, Sandra; Tamewitz, Aletheia; Anyang, Bean; Chaudhary, Preet M.

    2009-01-01

    Kaposi's sarcoma (KS) associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 is a potent activator of the NF-κB pathway. Here we demonstrate that infection with KHSV and ectopic expression of K13, but not its NF-κB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3′ untranslated region of CXCR4 mRNA. Reporter studies identified two NF-κB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-κB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-κB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by increased expression of miR-146a. Our results demonstrate that K13-induced NF-κB activity suppresses CXCR4 via upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation. PMID:20023696

  1. Binding of cellular export factor REF/Aly by Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is not required for efficient KSHV lytic replication.

    PubMed

    Li, Da-Jiang; Verma, Dinesh; Swaminathan, Sankar

    2012-09-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is expressed early during lytic KSHV replication, enhances expression of many KSHV genes, and is essential for virus production. ORF57 is a member of a family of proteins conserved among all human and many animal herpesviruses that are multifunctional regulators of gene expression and act posttranscriptionally to increase accumulation of their target mRNAs. The mechanism of ORF57 action is complex and may involve effects on mRNA transcription, stability, and export. ORF57 directly binds to REF/Aly, a cellular RNA-binding protein component of the TREX complex that mediates RNA transcription and export. We analyzed the effects of an ORF57 mutation known to abrogate REF/Aly binding and demonstrate that the REF-binding mutant is impaired in activation of viral mRNAs and noncoding RNAs confined to the nucleus. Although the inability to bind REF leads to decreased ORF57 activity in enhancing gene expression, there is no demonstrable effect on nuclear export of viral mRNA or the ability of ORF57 to support KSHV replication and virus production. These data indicate that REF/Aly-ORF57 interaction is not essential for KSHV lytic replication but may contribute to target RNA stability independent of effects on RNA export, suggesting a novel role for REF/Aly in viral RNA metabolism.

  2. Clinical and immunological follow-up of patients with AIDS-associated Kaposi's sarcoma treated with an anti-IL-6 monoclonal antibody.

    PubMed

    Racadot, E; Audhuy, B; Duvernoy, H; Thyss, A; Lang, J M; Wijdenes, J; Hervé, P

    1995-06-01

    Ten AIDS patients with Kaposi's sarcoma (four in stage II A, four in stage III A, one in stage III B and one in stage IV of the disease) were treated for 14 days with B-E8, an anti-IL-6 monoclonal antibody (IgG1), at a daily dose of 10 mg. No side-effects were observed, but no patients experienced a complete or partial response. No modification was noted in the analysis of lymphocyte subsets, except for a transient decline in the number of cells expressing CD56, accompanied by altered NK activity in four of the seven evaluable patients. Anti-IL-6 mAb prevented the binding of IL-6 to its cell membrane receptor, as documented by the decline in C reactive protein levels. However, anti-IL-6 mAb induced the circulation of significant amounts of IL-6, probably in the form of monomeric immune complexes. The sera, analysed on B9 cell line, demonstrated a stimulating activity, indicating that hypersensitive cells were able to cleave these complexes. This observation, together with the clinical inefficacy of the treatment, should prompt us to be careful with the use of unmanipulated single monoclonal antibodies, especially in cancer patients. PMID:9384670

  3. An evaluation of the early effects of a combination antiretroviral therapy programme on the management of AIDS-associated Kaposi's sarcoma in KwaZulu-Natal, South Africa.

    PubMed

    Mosam, A; Uldrick, T S; Shaik, F; Carrara, H; Aboobaker, J; Coovadia, H

    2011-11-01

    Roll-out of combination antiretroviral therapy (cART) in South Africa should impact on AIDS-associated Kaposi's sarcoma (KS). Government provision began in 2003, with 23% coverage for World Health Organization (WHO) stage IV AIDS in 2006. To assess the effect of cART availability on KS management, we evaluated records from 701 KS patients seen at a tertiary oncology centre in KwaZulu-Natal, South Africa, from 1995 to 2006. Associations between cART use and measures of KS care were evaluated. cART availability was 0% prior to 2001, 9.6% (2001-2003) and 44% (2004-2006). Documentation of HIV status increased incrementally from 65% to 92%. cART was associated with chemotherapy administration: 56% on cART versus 17% not on cART (P < 0.001); and less loss to follow-up, 13% on cART versus 38% not on cART (P < 0.001). cART availability improves the care of AIDS-associated KS. Further increases in cART availability for this population are needed in South Africa. PMID:22096054

  4. Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4{sup +} T cell proliferation

    SciTech Connect

    Liu, Wan; Qin, Yan; Bai, Lei; Lan, Ke; Wang, Jian-Hua

    2013-06-05

    Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4{sup +} T cells.

  5. Expression of platelet-derived growth factor and its receptor in AIDS-related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor maintenance.

    PubMed Central

    Stürzl, M; Roth, W K; Brockmeyer, N H; Zietz, C; Speiser, B; Hofschneider, P H

    1992-01-01

    As previously described, proliferation of Kaposi sarcoma (KS)-derived cells in vitro is dependent on the presence of platelet-derived growth factor (PDGF). To test the hypothesis that PDGF may also be a major growth factor for KS cells in vivo, we performed in situ hybridization and immunohistochemical staining for PDGF and PDGF receptors in tissue sections of AIDS-related KS. The data suggest that KS consists of two types of tumor cells. (i) The main population are spindle-shaped cells with elongated nuclei (KS-s cells). They reveal a strong expression of PDGF beta receptors but do not express the PDGF-A and PDGF-B isoforms. (ii) A minor population of KS cells express PDGF beta receptor as well as PDGF-A and PDGF-B (KS-p cells). These cells are often grouped in whorls and surrounding vascular slits. They reveal spherical nuclei with evenly distributed chromatin and inconspicuous nucleoli. PDGF alpha receptor is not expressed in either form of KS cells. The results suggest that the isoforms of PDGF and the PDGF beta receptor are differentially expressed in two different cell types in KS and that PDGF isoforms may contribute to the pathogenesis of KS. Images PMID:1323124

  6. Task Shifting and Skin Punch for the Histologic Diagnosis of Kaposi's Sarcoma in Sub-Saharan Africa: A Public Health Solution to a Public Health Problem.

    PubMed

    Laker-Oketta, Miriam O; Wenger, Megan; Semeere, Aggrey; Castelnuovo, Barbara; Kambugu, Andrew; Lukande, Robert; Asirwa, F Chite; Busakhala, Naftali; Buziba, Nathan; Diero, Lameck; Wools-Kaloustian, Kara; Strother, Robert Matthew; Bwana, Mwebesa; Muyindike, Winnie; Amerson, Erin; Mbidde, Edward; Maurer, Toby; Martin, Jeffrey

    2015-01-01

    Fueled by HIV, sub-Saharan Africa has the highest incidence of Kaposi's sarcoma (KS) in the world. Despite this, KS diagnosis in the region is based mostly on clinical grounds. Where biopsy is available, it has traditionally been excisional and performed by surgeons, resulting in multiple appointments, follow-up visits for suture removal, and substantial costs. We hypothesized that a simpler approach - skin punch biopsy - would make histologic diagnosis more accessible. To address this, we provided training and equipment for skin punch biopsy of suspected KS to three HIV clinics in East Africa. The procedure consisted of local anesthesia followed by a disposable cylindrical punch blade to obtain specimens. Hemostasis is facilitated by Gelfoam®. Patients removed the dressing after 4 days. From 2007 to 2013, 2,799 biopsies were performed. Although originally targeted to be used by physicians, biopsies were performed predominantly by nurses (62%), followed by physicians (15%), clinical officers (12%) and technicians (11%). There were no reports of recurrent bleeding or infection. After minimal training and provision of inexpensive equipment (USD 3.06 per biopsy), HIV clinics in East Africa can integrate same-day skin punch biopsy for suspected KS. Task shifting from physician to non-physician greatly increases access. Skin punch biopsy should be part of any HIV clinic's essential procedures. This example of task shifting may also be applicable to the diagnosis of other cancers (e.g., breast) in resource-limited settings. PMID:25765812

  7. KSHV 2.0: A Comprehensive Annotation of the Kaposi's Sarcoma-Associated Herpesvirus Genome Using Next-Generation Sequencing Reveals Novel Genomic and Functional Features

    PubMed Central

    Arias, Carolina; Weisburd, Ben; Stern-Ginossar, Noam; Mercier, Alexandre; Madrid, Alexis S.; Bellare, Priya; Holdorf, Meghan; Weissman, Jonathan S.; Ganem, Don

    2014-01-01

    Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into the genomic architecture and gene expression control in Kaposi's sarcoma-associated herpesvirus (KSHV), we performed a systematic genome-wide survey of viral transcriptional and translational activity throughout the lytic cycle. Using mRNA-sequencing and ribosome profiling, we found that transcripts encoding lytic genes are promptly bound by ribosomes upon lytic reactivation, suggesting their regulation is mainly transcriptional. Our approach also uncovered new genomic features such as ribosome occupancy of viral non-coding RNAs, numerous upstream and small open reading frames (ORFs), and unusual strategies to expand the virus coding repertoire that include alternative splicing, dynamic viral mRNA editing, and the use of alternative translation initiation codons. Furthermore, we provide a refined and expanded annotation of transcription start sites, polyadenylation sites, splice junctions, and initiation/termination codons of known and new viral features in the KSHV genomic space which we have termed KSHV 2.0. Our results represent a comprehensive genome-scale image of gene regulation during lytic KSHV infection that substantially expands our understanding of the genomic architecture and coding capacity of the virus. PMID:24453964

  8. Metachronous Diffuse Large B-Cell Lymphoma and Kaposi Sarcoma of the Right Eyelid and Lacrimal Gland in a Patient with Granulomatous Common Variable Immunodeficiency

    PubMed Central

    Stenton, Sophie; Fernando, Malee; Currie, Zanna; Mudhar, Hardeep Singh

    2016-01-01

    Purpose To describe the ophthalmic and histopathological features of a female with granulomatous common variable immunodeficiency (CVID) who presented with upper-lid swelling. Procedures The patient underwent a biopsy of the right upper lid/palpebral lacrimal gland with imaging showing a left-sided nasopharyngeal mass, multiple lymph nodes within the mediastinum, bilateral lung nodules and a peritoneal nodule in the right iliac fossa. The right upper-lid swelling progressed and was subject to a second biopsy. Results The first right upper-lid biopsy revealed a diffuse large B-cell lymphoma (DLBCL), confirmed with clonal IgH gene rearrangement with PCR. The nasopharyngeal mass and lymph nodes were suspected clinically to be DLBCL. However, a biopsy of the nasopharyngeal mass showed Kaposi sarcoma (KS). The second biopsy of the right upper lid/palpebral lacrimal gland revealed KS with no evidence of DLBCL. Conclusion This is the first documentation of periocular/orbital metachronous DLBCL and KS in a patient with granulomatous CVID. We discuss the role of fluctuating immunity in CVID to explain the spontaneous regression of the DLBCL and the varying clinical picture. PMID:27239466

  9. Mutation of a C-Terminal Motif Affects Kaposi's Sarcoma-Associated Herpesvirus ORF57 RNA Binding, Nuclear Trafficking, and Multimerization ▿

    PubMed Central

    Taylor, Adam; Jackson, Brian R.; Noerenberg, Marko; Hughes, David J.; Boyne, James R.; Verow, Mark; Harris, Mark; Whitehouse, Adrian

    2011-01-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is essential for virus lytic replication. ORF57 regulates virus gene expression at multiple levels, enhancing transcription, stability, nuclear export, and translation of viral transcripts. To enhance the nuclear export of viral intronless transcripts, ORF57 (i) binds viral intronless mRNAs, (ii) shuttles between the nucleus, nucleolus, and the cytoplasm, and (iii) interacts with multiple cellular nuclear export proteins to access the TAP-mediated nuclear export pathway. We investigated the implications on the subcellular trafficking, cellular nuclear export factor recruitment, and ultimately nuclear mRNA export of an ORF57 protein unable to bind RNA. We observed that mutation of a carboxy-terminal RGG motif, which prevents RNA binding, affects the subcellular localization and nuclear trafficking of the ORF57 protein, suggesting that it forms subnuclear aggregates. Further analysis of the mutant shows that although it still retains the ability to interact with cellular nuclear export proteins, it is unable to export viral intronless mRNAs from the nucleus. Moreover, computational molecular modeling and biochemical studies suggest that, unlike the wild-type protein, this mutant is unable to self-associate. Therefore, these results suggest the mutation of a carboxy-terminal RGG motif affects ORF57 RNA binding, nuclear trafficking, and multimerization. PMID:21593148

  10. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene.

    PubMed

    Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy; Gao, Shou-Jiang; Oh, Tae-Kwang; Kim, Myung Hee; Ha, Taekjip; Jung, Jae U

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication. PMID:26491150

  11. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene.

    PubMed

    Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy; Gao, Shou-Jiang; Oh, Tae-Kwang; Kim, Myung Hee; Ha, Taekjip; Jung, Jae U

    2015-10-21

    Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication.

  12. Weekly oral etoposide in patients with Kaposi's sarcoma associated with human immunodeficiency virus infection: a phase I multicenter trial of the AIDS Clinical Trials Group.

    PubMed

    Paredes, J; Kahn, J O; Tong, W P; Feldstein, M L; Lin, S; Bennett, J M; Metroka, C E; Ratner, L; Krown, S E

    1995-06-01

    We conducted a Phase I trial to evaluate the safety, maximally tolerated dose (MTD), antitumor activity, and pharmacology of once-weekly oral etoposide in patients with Kaposi's sarcoma (KS) and AIDS. From September 1990 to October 1991, 27 eligible patients with biopsy-confirmed KS were treated at six etoposide dose levels, ranging from 150 to 400 mg weekly. Patients were treated until their tumor progressed or until unacceptable toxicity developed. On the first day of therapy, etoposide plasma concentrations were measured by high-performance liquid chromatography. The MTD was defined as the etoposide dose that induced reversible grade 3 toxicity in three of six patients during the first 4 weeks. Although dose-limiting toxicity was uncommon during the first 4 weeks of treatment (three of 27 patients), and the MTD was not reached, with longer treatment > 50% of patients developed dose-limiting toxicities, most commonly neutropenia. Responses were observed at all dosage levels (except 350 mg weekly), with partial tumor regression documented in nine (36%) of 25 evaluable patients. There was marked variability in etoposide area under the plasma concentration versus time curve, elimination half-time (t1/2), and urinary excretion. These pharmacokinetic features were not, however, associated with the presence of gastrointestinal symptoms, the severity of side effects, or tumor response. We conclude that weekly oral etoposide can be safely administered to patients with AIDS and KS. The observed antitumor effects over a wide range of doses support further studies with very low and minimally toxic etoposide doses, alone or in combination with other agents.

  13. SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.

    PubMed

    Aissani, B; Boehme, A K; Wiener, H W; Shrestha, S; Jacobson, L P; Kaslow, R A

    2014-09-01

    The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

  14. Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-κB/IL-6/STAT3 signaling

    PubMed Central

    Qu, Zhaoxia

    2016-01-01

    The human oncogenic virus Kaposi's sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. KSHV possesses over hundred genes, including 25 microRNAs (miRNAs). The roles of these miRNAs and many other viral genes in KSHV biology and pathogenesis remain largely unknown. Accordingly, the molecular mechanisms by which KSHV induces tumorigenesis are still poorly defined. Here, we identify KSHV miRNA K12-1 (miR-K12-1) as a novel viral oncogene by activating two important transcription factors, nuclear factor-κb (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Interestingly, miR-K12-1 activates STAT3 indirectly through inducing NF-κB activation and NF-κB-dependent expression of the cytokine interleukin-6 (IL-6) by repressing the expression of the NF-κB inhibitor IκBα. Accordingly, expression of ectopic IκBα or knockdown of NF-κB RelA, IL-6 or STAT3 prevents expression of cell growth genes and suppresses the oncogenicities of both miR-K12-1 and KSHV. These data identify miR-K12-1/NF-κB/IL-6/STAT3 as a novel oncogenic signaling underlying KSHV tumorigenesis. These data also provide the first evidence showing that IL-6/STAT3 signaling acts as an essential mediator of NF-κB oncogenic actions. These findings significantly improve our understanding of KSHV pathogenesis and oncogenic interaction between NF-κB and STAT3. PMID:27166260

  15. Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latency-Associated Nuclear Antigen Regulates the KSHV Epigenome by Association with the Histone Demethylase KDM3A

    PubMed Central

    Kim, Kevin Y.; Huerta, Steve B.; Izumiya, Chie; Wang, Don-Hong; Martinez, Anthony; Shevchenko, Bogdan; Kung, Hsing-Jien; Campbell, Mel

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) latent genomes are tethered to host histones to form a minichromosome also known as an “episome.” Histones, which are core components of chromatin, are heavily modified by various histone-targeting enzymes. Posttranslational modifications of histones significantly influence accessibility of transcriptional factors and thus have profound effects on gene expression. Recent studies showed that epigenetic marks on the KSHV episome are well organized, exemplified by the absence of histone H3 lysine 9 (H3K9) methylation, a heterochromatic histone mark, from immediate early and latent gene promoters in naturally infected cells. The present study revealed a mechanistic insight into KSHV epigenome regulation via a complex consisting of LANA and the H3K9me1/2 histone demethylase JMJD1A/KDM3A. This complex was isolated from HeLa cell nuclear extracts stably expressing LANA and was verified by coimmunoprecipitation analyses and with purified proteins. LANA recruitment sites on the KSHV genome inversely correlated with H3K9me2 histone marks in naturally infected cells, and methylation of H3K9 significantly inhibited LANA binding to the histone H3 tail. Chromatin immunoprecipitation coupled with KSHV tiling arrays identified the recruitment sites of the complex, while depletion of LANA expression or overexpression of a KDM3A binding-deficient mutant decreased KDM3A recruitment to the KSHV genome. Finally, ablation of KDM3A expression from latently KSHV-infected cells significantly inhibited KSHV gene expression, leading to decreased KSHV replication during reactivation. Taken together, our results suggest that LANA may play a role in regulation of epigenetic marks on the KSHV genome, which is in part through association with the histone demethylase KDM3A. PMID:23576503

  16. Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma tumor formation in NOD/SCID mice is inhibited by neomycin and neamine blocking angiogenin's nuclear translocation.

    PubMed

    Bottero, Virginie; Sadagopan, Sathish; Johnson, Karen E; Dutta, Sujoy; Veettil, Mohanan Valiya; Chandran, Bala

    2013-11-01

    Angiogenin (ANG) is a 14-kDa multifunctional proangiogenic secreted protein whose expression level correlates with the aggressiveness of several tumors. We observed increased ANG expression and secretion in endothelial cells during de novo infection with Kaposi's sarcoma-associated herpesvirus (KSHV), in cells expressing only latency-associated nuclear antigen 1 (LANA-1) protein, and in KSHV latently infected primary effusion lymphoma (PEL) BCBL-1 and BC-3 cells. Inhibition of phospholipase Cγ (PLCγ) mediated ANG's nuclear translocation by neomycin, an aminoglycoside antibiotic (not G418-neomicin), resulted in reduced KSHV latent gene expression, increased lytic gene expression, and increased cell death of KSHV(+) PEL and endothelial cells. ANG detection in significant levels in KS and PEL lesions highlights its importance in KSHV pathogenesis. To assess the in vivo antitumor activity of neomycin and neamine (a nontoxic derivative of neomycin), BCBL-1 cells were injected intraperitoneally into NOD/SCID mice. We observed significant extended survival of mice treated with neomycin or neamine. Markers of lymphoma establishment, such as increases in animal body weight, spleen size, tumor cell spleen infiltration, and ascites volume, were observed in nontreated animals and were significantly diminished by neomycin or neamine treatments. A significant decrease in LANA-1 expression, an increase in lytic gene expression, and an increase in cleaved caspase-3 were also observed in neomycin- or neamine-treated animal ascitic cells. These studies demonstrated that ANG played an essential role in KSHV latency maintenance and BCBL-1 cell survival in vivo, and targeting ANG function by neomycin/neamine to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV-associated malignancies.

  17. High seroprevalence of antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) among HIV-1-infected children and adolescents in a non-endemic population.

    PubMed

    Feiterna-Sperling, Cornelia; Königs, Christoph; Notheis, Gundula; Buchholz, Bernd; Krüger, Renate; Weizsäcker, Katharina; Eberle, Josef; Hanhoff, Nikola; Gärtner, Barbara; Heider, Harald; Krüger, Detlev H; Hofmann, Jörg

    2016-10-01

    Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS), which primarily affects human immunodeficiency virus (HIV)-infected adults with advanced immunodeficiency. Currently, only limited prevalence data for HHV-8 infection in HIV-infected children living in non-endemic areas are available. This multicenter cross-sectional study was conducted in four university hospitals in Germany specializing in pediatric HIV care. Stored serum specimens obtained from 207 vertically HIV-1-infected children and adolescents were tested for antibodies against lytic and latent HHV-8 antigens. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall HHV-8 seroprevalence was 24.6 % (n = 51/207) without significant differences related to sex, age, or ethnicity. In univariate analysis, HHV-8 seropositivity was significantly associated with a child having being born outside Germany, maternal origin from sub-Saharan Africa, a history of breastfeeding, CDC immunologic category 3, and deferred initiation of antiretroviral therapy (>24 months of age). In multivariate analysis, a child's birth outside Germany was the only significant risk factor for HHV-8 seropositivity (odds ratio 3.98; 95 % confidence interval 1.27-12.42). HHV-8-associated malignancies were uncommon; only one patient had a history of KS. Serum specimen of vertically HIV-infected children and adolescents living in Germany showed a high HHV-8 seroprevalence. These findings suggest that primary HHV-8 infection-a risk factor for KS and other HHV-8-associated malignancies-occurs early in life. Thus, management of perinatally HIV-infected children should include testing for HHV-8 coinfection and should consider future risks of HHV-8-associated malignancies. PMID:27240652

  18. Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs.

    PubMed

    Bai, Zhiqiang; Huang, Yufei; Li, Wan; Zhu, Ying; Jung, Jae U; Lu, Chun; Gao, Shou-Jiang

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) encodes over 90 genes and 25 microRNAs (miRNAs). The KSHV life cycle is tightly regulated to ensure persistent infection in the host. In particular, miRNAs, which primarily exert their effects by binding to the 3' untranslated regions (3'UTRs) of target transcripts, have recently emerged as key regulators of KSHV life cycle. Although studies with RNA cross-linking immunoprecipitation approach have identified numerous targets of KSHV miRNAs, few of these targets are of viral origin because most KSHV 3'UTRs have not been characterized. Thus, the extents of viral genes targeted by KSHV miRNAs remain elusive. Here, we report the mapping of the 3'UTRs of 74 KSHV genes and the effects of KSHV miRNAs on the control of these 3'UTR-mediated gene expressions. This analysis reveals new bicistronic and polycistronic transcripts of KSHV genes. Due to the 5'-distal open reading frames (ORFs), KSHV bicistronic or polycistronic transcripts have significantly longer 3'UTRs than do KSHV monocistronic transcripts. Furthermore, screening of the 3'UTR reporters has identified 28 potential new targets of KSHV miRNAs, of which 11 (39%) are bicistronic or polycistronic transcripts. Reporter mutagenesis demonstrates that miR-K3 specifically targets ORF31-33 transcripts at the lytic locus via two binding sites in the ORF33 coding region, whereas miR-K10a-3p and miR-K10b-3p and their variants target ORF71-73 transcripts at the latent locus through distinct binding sites in both 5'-distal ORFs and intergenic regions. Our results indicate that KSHV miRNAs frequently target the 5'-distal coding regions of bicistronic or polycistronic transcripts and highlight the unique features of KSHV miRNAs in regulating gene expression and life cycle. PMID:24155407

  19. Interaction of Kaposi's sarcoma-associated herpesvirus ORF59 with oriLyt is dependent on binding with K-Rta.

    PubMed

    Rossetto, Cyprian C; Susilarini, Ni Ketut; Pari, Gregory S

    2011-04-01

    Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) displays two distinct life stages, latency and lytic reactivation. Progression through the lytic cycle and replication of the viral genome constitute an essential step toward the production of infectious virus and human disease. KSHV K-RTA has been shown to be the major transactivator required for the initiation of lytic reactivation. In the transient-cotransfection replication assay, K-Rta is the only noncore protein required for DNA synthesis. K-Rta was shown to interact with both C/EBPα binding motifs and the R response elements (RRE) within oriLyt. It is postulated that K-Rta acts in part to facilitate the recruitment of replication factors to oriLyt. In order to define the role of K-Rta in the initiation of lytic DNA synthesis, we show an interaction with ORF59, the DNA polymerase processivity factor (PF), one of the eight virally encoded proteins necessary for origin-dependent DNA replication. Using the chromatin immunoprecipitation (ChIP) assay, both K-Rta and ORF59 interact with the RRE and C/EBPα binding motifs within oriLyt in cells harboring the KSHV bacterial artificial chromosome (BAC). A transient-transfection ChIP assay demonstrated that the interaction of ORF59 with oriLyt is dependent on binding with K-Rta and that ORF59 fails to bind to oriLyt in the absence of K-Rta. Also, using the cotransfection replication assay, overexpression of the interaction domain of K-Rta with ORF59 has a dominant negative effect on oriLyt amplification, suggesting that the interaction of K-Rta with ORF59 is essential for DNA synthesis and supporting the hypothesis that K-Rta facilitates the formation of a replication complex at oriLyt. PMID:21289111

  20. Kaposi's sarcoma-associated herpesvirus noncoding polyadenylated nuclear RNA interacts with virus- and host cell-encoded proteins and suppresses expression of genes involved in immune modulation.

    PubMed

    Rossetto, Cyprian C; Pari, Gregory S

    2011-12-01

    During lytic infection, Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a polyadenylated nuclear RNA (PAN RNA). This noncoding RNA (ncRNA) is localized to the nucleus and is the most abundant viral RNA during lytic infection; however, to date, the role of PAN RNA in the virus life cycle is unknown. Many examples exist where ncRNAs have a defined key regulatory function controlling gene expression by various mechanisms. Our goal for this study was to identify putative binding partners for PAN RNA in an effort to elucidate a possible function for the transcript in KSHV infection. We employed an in vitro affinity protocol where PAN RNA was used as bait for factors present in BCBL-1 cell nuclear extract to show that PAN RNA interacts with several virus- and host cell-encoded factors, including histones H1 and H2A, mitochondrial and cellular single-stranded binding proteins (SSBPs), and interferon regulatory factor 4 (IRF4). RNA chromatin immunoprecipitation (ChIP) assays confirmed that PAN RNA interacted with these factors in the infected cell environment. A luciferase reporter assay showed that PAN RNA expression interfered with the ability of IRF4/PU.1 to activate the interleukin-4 (IL-4) promoter, strongly suggesting a role for PAN RNA in immune modulation. Since the proteomic screen and functional data suggested a role in immune responses, we investigated if constitutive PAN RNA expression could affect other genes involved in immune responses. PAN RNA expression decreased expression of gamma interferon, interleukin-18, alpha interferon 16, and RNase L. These data strongly suggest that PAN RNA interacts with viral and cellular proteins and can function as an immune modulator. PMID:21957289

  1. Kaposi Sarcoma Herpesvirus Induces HO-1 during De Novo Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms

    PubMed Central

    Botto, Sara; Totonchy, Jennifer E.; Gustin, Jean K.

    2015-01-01

    ABSTRACT Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype. PMID:26045540

  2. Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7.

    PubMed

    Chavoshi, Sara; Egorova, Olga; Lacdao, Ira Kay; Farhadi, Sahar; Sheng, Yi; Saridakis, Vivian

    2016-03-18

    Viral interferon regulatory factor 1 (vIRF1), a Kaposi sarcoma herpesvirus protein, destabilizes p53 by inhibiting p53 acetylation and Hdm2 phosphorylation. This leads to increased ubiquitination and degradation of p53 by Hdm2, which cripples the cellular p53-mediated antiviral response. Ubiquitin-specific protease 7 (USP7) deubiquitinates p53 and Hdm2 and regulates their stability. We identified an EGPS consensus sequence in vIRF1, which is identical to that found in Epstein-Barr virus nuclear antigen 1 (EBNA1) that interacts with the N-terminal domain of USP7 (USP7-NTD). GST pulldown assays demonstrated that vIRF1 interacts with USP7-NTD via its EGPS motif. NMR heteronuclear single quantum correlation (HSQC) analysis revealed chemical perturbations after titration of USP7-NTD with vIRF1 (44)SPGEGPSGTG(53) peptide. In contrast, these perturbations were reduced with a mutant vIRF1 peptide, (44)SPGEGPAGTG(53). Fluorescence polarization analysis indicated that the vIRF1 peptide interacted with USP7-NTD with a Kd of 2.0 μm. The crystal structure of the USP7-NTD·vIRF1 peptide complex revealed an identical mode of binding as that of the EBNA1 peptide to USP7-NTD. We also showed that USP7 interacts with vIRF1 in U2OS cells. Decreased levels of p53, but not Hdm2 or ataxia telangiectasia-mutated (ATM), were seen after expression of vIRF1, but not with a vIRF1 mutant protein. Our results support a new role for vIRF1 through deregulation of the deubiquitinating enzyme USP7 to inhibit p53-mediated antiviral responses.

  3. A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening.

    PubMed

    Shamay, Meir; Liu, Jianyong; Li, Renfeng; Liao, Gangling; Shen, Li; Greenway, Melanie; Hu, Shaohui; Zhu, Jian; Xie, Zhi; Ambinder, Richard F; Qian, Jiang; Zhu, Heng; Hayward, S Diane

    2012-05-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy. PMID:22379092

  4. Comparative study of Kaposi's sarcoma-associated herpesvirus serological assays using clinically and serologically defined reference standards and latent class analysis.

    PubMed

    Nascimento, Maria Claudia; de Souza, Vanda Akico; Sumita, Laura Masami; Freire, Wilton; Munoz, Fernando; Kim, Joseph; Pannuti, Claudio S; Mayaud, Philippe

    2007-03-01

    Accurate determination of infection with Kaposi's sarcoma-associated herpesvirus (KSHV) has been hindered by the lack of a "gold standard" for comparison of serological assays used to estimate KSHV prevalence in serosurveys conducted in different settings. We have evaluated the performance of five in-house (developed at University College London [UCL], United Kingdom, and at the virology laboratory of the Instituto de Medicine Tropical [IMT] in Sao Paulo, Brazil) and two commercial (ABI and DIAVIR) serological assays to detect antibodies to latency-associated nuclear antigen (LANA) and to lytic KSHV antigens. We used a variety of serum samples assembled to represent populations likely to be at high, intermediate, and low risk of KSHV infection in Brazil. Composite reference standard panels were prepared based on clinical and serological parameters, against which assay performances were assessed using conventional Bayesian statistics and latent class analysis (LCA). Against the clinical reference standard, in-house immunofluorescence assays to detect anti-LANA antibodies (IFA-LANA) produced at UCL and IMT had similar performances, with sensitivities of 61% (95% confidence interval [CI], 48% to 74%) and 72% (95% CI, 58% to 83%) and specificities of 99% (95% CI, 94% to 100%) and 100% (95% CI, 96% to 100%), respectively, and only the IMT IFA-LANA was included in LCA, together with the IMT IFA-lytic and four enzyme-linked immunosorbent assays (ELISAs). The LCA indicated that the IMT whole-virus ELISA performed best (sensitivity, 87% [95% CI, 81% to 91%]; and specificity, 100% [95% CI, 98% to 100%]), confirming the results obtained with the conventional statistical approach. Commercially available ELISA-based tests yielded the lowest specificities using a spectrum of serum samples. The evaluation of KSHV serological assays is warranted before planning serosurveys in various settings.

  5. The Minimal Replicator Element of the Kaposi's Sarcoma-Associated Herpesvirus Terminal Repeat Supports Replication in a Semiconservative and Cell-Cycle-Dependent Manner▿

    PubMed Central

    Verma, Subhash C.; Choudhuri, Tathagata; Robertson, Erle S.

    2007-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) persists as episomes in infected cells by circularizing at the terminal repeats (TRs). The KSHV episome carries multiple reiterated copies of the terminal repeat, and each copy is capable of supporting replication. Expression of the latency-associated nuclear antigen (LANA) is critical for the replication of TR-containing plasmids. A 32-bp sequence upstream of LANA binding site 1 (LBS1), referred to as RE (replication element), along with LANA binding sites 1 and 2 (RE-LBS1/2), is sufficient to support replication (J. Hu and R. Renne, J. Virol. 79:2637-2642, 2005). In this report we demonstrate that the minimal replicator element (RE-LBS1/2) replicates in synchrony with the host cellular DNA, and only once, in a cell-cycle-dependent manner. Overexpression of the mammalian replication inhibitor geminin blocked replication of the plasmid containing the minimal replicator element, confirming the involvement of the host cellular replication control mechanism, and prevented rereplication of the plasmid in the same cell cycle. Overexpression of Cdt1 also rescued the replicative ability of the RE-LBS1/2-containing plasmids. A chromatin immunoprecipitation assay performed using anti-origin recognition complex 2 (α-ORC2) and α-LANA antibodies from cells transfected with RE-LBS1/2, RE-LBS1, LBS1, or RE showed the association of ORC2 with the RE region. Expression of LANA increased the number of copies of chromatin-bound DNA of replication elements, suggesting that LANA is important for the recruitment of ORCs and may contribute to the stabilization of the replication protein complexes at the RE site. PMID:17151118

  6. Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

    PubMed Central

    Sun, Zhiguo; Jha, Hem Chandra

    2015-01-01

    ABSTRACT Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. IMPORTANCE During latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. PMID:26223641

  7. The clinical characteristics of 80 cases of acquired immunodeficiency syndrome-associated Kaposi's sarcoma in Xinjiang Autonomous Region and the effect of different treatments on the prognosis.

    PubMed

    Yang, Tongtong; He, Li; Wan, Xuefeng; Maimaitiaili, Wubuli; Song, Yuxia; Zhang, Yuexin; Lu, Xiaobo

    2015-01-01

    To analyze the clinical features of AIDS-related Kaposi's sarcoma (AIDS-KS) patients in Xinjiang Autonomous Region and the impact of CD4 (+)T lymphocyte count, highly active antiretroviral therapy (HAART) and systemic chemotherapy on the prognosis. The clinical information of 80 AIDS-KS patients admitted in Sixth People's Hospital of Xinjiang Autonomous Region from January 2008 to August 2014 was retrospectively reviewed. Population characteristics, extent of lesions, KS progress, CD4 (+)T lymphocyte count, combined opportunistic infections, treatment and prognosis of these patients were analyzed. The 80 patients were divided into five groups according to treatment methods, including HAART, HAART + chemotherapy, chemotherapy + HAART, chemotherapy, and untreated groups. The efficacy and prognosis of the five groups were compared. Among the 80 patients, 74 (92.50%) patients were Uygur. The average age was 39.5±9.9 years and male-to-female ratio was 3:1. The median of baseline CD4 (+)T lymphocyte count was 152.5 cells/μL and the interquartile was 233.25 cells/μL. CD4 (+)T lymphocyte counts were significantly increased after treatment in HAART, HAART + chemotherapy, and chemotherapy + HAART groups (P < 0.05). CD4 (+)T lymphocyte count in chemotherapy groups was significantly reduced after treatment (P < 0.05). The untreated group had the highest mortality rate (33.3%). In HAART group, KS-associated immune reconstitution inflammatory response syndrome (KS-IRIS) appeared in 45.5% cases and 2 death cases were caused by KS-IRIS. In Xinjiang Autonomous Region, the incidence of AIDS-KS is high in young Uygur male people. HAART followed by chemotherapy has ideal efficacy, reduces the incidence of KS-IRIS and improves the prognosis.

  8. Consensus-interferon and platelet-derived growth factor adversely regulate proliferation and migration of Kaposi's sarcoma cells by control of c-myc expression.

    PubMed Central

    Köster, R.; Blatt, L. M.; Streubert, M.; Zietz, C.; Hermeking, H.; Brysch, W.; Stürzl, M.

    1996-01-01

    Platelet-derived growth factor-B (PDGF-B) is a potent paracrine-acting mitogen in Kaposi's sarcoma (KS) lesions. Interferon-alpha is widely used for clinical treatment of KS. Here we show that platelet-derived growth factor-B activates proliferation and migration of cultivated AIDS-KS spindle cells whereas interferon-alpha acts as an inhibitor. At the molecular level, these opposite activities of platelet-derived growth factor-B and interferon-alpha converged onto the adverse regulation of the c-myc gene expression. Platelet-derived growth factor-B induced c-myc mRNA and protein synthesis in cultivated AIDS-KS spindle cells whereas interferon-alpha inhibited these processes. Using c-myc-specific phoshothioate antisense oligodeoxynucleotides, we demonstrated that down-regulation of c-myc expression is sufficient to inhibit proliferation and migration of KS spindle cells in vitro. This indicated that c-Myc protein may be an important regulatory molecule of KS spindle cell proliferation and migration. High amounts of the c-Myc protein were detected in the nuclei of KS spindle cells in histological sections of AIDS-KS biopsies. This suggested that the c-myc gene may also regulate proliferation and migration of AIDS-KS spindle cells in vivo. In this case, c-myc may play an important role in the focus of major pathogenic and therapeutic pathways of KS. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:8952524

  9. Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma-Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival

    PubMed Central

    Wang, Chong; Zhu, Caixia; Wei, Fang; Zhang, Liming; Mo, Xiaohui; Feng, Yanling; Xu, Jianqing; Yuan, Zhenghong; Robertson, Erle

    2015-01-01

    ABSTRACT Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been associated with numerous human malignancies, including primary effusion lymphomas (PELs). PEL, a cancerous proliferation of B cells, is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previously we identified constitutive phosphorylation of STAT6 on tyrosine 641 (p-STAT6C) in PEL cell lines BC3 and BCBL1; however, the molecular mechanism leading to this activation remains unclear. Here we demonstrate that STAT6 activation tightly correlates with interleukin-13 (IL-13) secretion, JAK1/2 tyrosine phosphorylation, and reduced expression of SHP1 due to KSHV infection. Moreover, p-STAT6C and reduction of SHP1 were also observed in KS patient tissue. Notably, blockade of IL-13 by antibody neutralization dramatically inhibits PEL cell proliferation and survival. Taken together, these results suggest that IL-13/STAT6 signaling is modulated by KSHV to promote host cell proliferation and viral pathogenesis. IMPORTANCE STAT6 is a member of signal transducer and activator of transcription (STAT) family, whose activation is linked to KSHV-associated cancers. The mechanism through which STAT6 is modulated by KSHV remains unclear. In this study, we demonstrated that constitutive activation of STAT6 in KSHV-associated PEL cells results from interleukin-13 (IL-13) secretion and reduced expression of SHP1. Importantly, we also found that depletion of IL-13 reduces PEL cell growth and survival. This discovery provides new insight that IL-13/STAT6 plays an essential role in KSHV pathogenesis. PMID:26246572

  10. Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells

    PubMed Central

    Nicol, Samantha M.; Sabbah, Shereen; Brulois, Kevin F.; Jung, Jae U.; Bell, Andrew I.

    2016-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4+ T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4+ T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8+ T cells, we suggest that CD4+ T cells are potentially important effectors for the in vivo control of KSHV-infected B lymphocytes. IMPORTANCE KSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that

  11. Kaposi's Sarcoma Associated Herpesvirus Tegument Protein ORF75 Is Essential for Viral Lytic Replication and Plays a Critical Role in the Antagonization of ND10-Instituted Intrinsic Immunity

    PubMed Central

    Full, Florian; Jungnickl, Doris; Reuter, Nina; Bogner, Elke; Brulois, Kevin; Scholz, Brigitte; Stürzl, Michael; Myoung, Jinjong; Jung, Jae U.; Stamminger, Thomas; Ensser, Armin

    2014-01-01

    Nuclear domain 10 (ND10) components are restriction factors that inhibit herpesviral replication. Effector proteins of different herpesviruses can antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. We investigated the interplay of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) infection and cellular defense by nuclear domain 10 (ND10) components. Knock-down experiments in primary human cells show that KSHV-infection is restricted by the ND10 components PML and Sp100, but not by ATRX. After KSHV infection, ATRX is efficiently depleted and Daxx is dispersed from ND10, indicating that these two ND10 components can be antagonized by KSHV. We then identified the ORF75 tegument protein of KSHV as the viral factor that induces the disappearance of ATRX and relocalization of Daxx. ORF75 belongs to a viral protein family (viral FGARATs) that has homologous proteins in all gamma-herpesviruses. Isolated expression of ORF75 in primary cells induces a relocalization of PML and dispersal of Sp100, indicating that this viral effector protein is able to influence multiple ND10 components. Moreover, by constructing a KSHV mutant harboring a stop codon at the beginning of ORF75, we could demonstrate that ORF75 is absolutely essential for viral replication and the initiation of viral immediate-early gene expression. Using recombinant viruses either carrying Flag- or YFP-tagged variants of ORF75, we could further corroborate the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity, and show that it is independent of the PML antagonist vIRF3. Members of the viral FGARAT family target different ND10 components, suggesting that the ND10 targets of viral FGARAT proteins have diversified during evolution. We assume that overcoming ND10 intrinsic defense constitutes a critical event in the replication of all herpesviruses; on the other hand, restriction of herpesviral replication by ND10 components may also

  12. Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation

    PubMed Central

    Izumiya, Yoshihiro; Kobayashi, Keisuke; Kim, Kevin Y.; Pochampalli, Mamata; Izumiya, Chie; Shevchenko, Bogdan; Wang, Don-Hong; Huerta, Steve B.; Martinez, Anthony; Campbell, Mel; Kung, Hsing-Jien

    2013-01-01

    The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene

  13. Kaposi sarcoma associated herpesvirus (KSHV) induces AKT hyperphosphorylation, bortezomib-resistance and GLUT-1 plasma membrane exposure in THP-1 monocytic cell line

    PubMed Central

    2013-01-01

    Background Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates multiple cellular processes such as cell proliferation, evasion from apoptosis, migration, glucose metabolism, protein synthesis and proper differentiation in immune cells. Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several human malignancies, expresses a variety of latent and lytic proteins able to activate PI3K/AKT pathway, promoting the growth of infected cells and a successful viral infection. Results We found that KSHV latent infection of THP-1 cells, a human monocytic cell line derived from an acute monocytic leukemia patient, resulted in an increase of AKT phoshorylation, not susceptible to bortezomib-induced dephosphorylation, compared to the mock-infected THP-1. Accordingly, THP-1-infected cells displayed increased resistance to the bortezomib cytotoxic effect in comparison to the uninfected cells, which was counteracted by pre-treatment with AKT-specific inhibitors. Finally, AKT hyperactivation by KSHV infection correlated with plasma membrane exposure of glucose transporter GLUT1, particularly evident during bortezomib treatment. GLUT1 membrane trafficking is a characteristic of malignant cells and underlies a change of glucose metabolism that ensures the survival to highly proliferating cells and render these cells highly dependent on glycolysis. GLUT1 membrane trafficking in KSHV-infected THP-1 cells indeed led to increased sensitivity to cell death induced by the glycolysis inhibitor 2-Deoxy-D-glucose (2DG), further potentiated by its combination with bortezomib. Conclusions KSHV confers to the THP-1 infected cells an oncogenic potential by altering the phosphorylation, expression and localization of key molecules that control cell survival and metabolism such as AKT and GLUT1. Such modifications in one hand lead to resistance to cell death induced by some chemotherapeutic drugs such as bortezomib

  14. Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

    PubMed Central

    Fu, Bishi; Kuang, Ersheng; Li, Wenwei; Avey, Denis; Li, Xiaojuan; Turpin, Zachary; Valdes, Ahmed; Brulois, Kevin; Myoung, Jinjong

    2014-01-01

    ABSTRACT We have previously shown that ORF45, an immediate-early and tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV), causes sustained activation of p90 ribosomal S6 kinases (RSKs) and extracellular regulated kinase (ERK) (E. Kuang, Q. Tang, G. G. Maul, and F. Zhu, J Virol 82:1838–1850, 2008, http://dx.doi.org/10.1128/JVI.02119-07). We now have identified the critical region of ORF45 that is involved in RSK interaction and activation. Alanine scanning mutagenesis of this region revealed that a single F66A point mutation abolished binding of ORF45 to RSK or ERK and, consequently, its ability to activate the kinases. We introduced the F66A mutation into BAC16 (a bacterial artificial chromosome clone containing the entire infectious KSHV genome), producing BAC16-45F66A. In parallel, we also repaired the mutation and obtained a revertant, BAC16-45A66F. The reconstitution of these mutants in iSLK cells demonstrated that the ORF45-F66A mutant failed to cause sustained ERK and RSK activation during lytic reactivation, resulting in dramatic differences in the phosphoproteomic profile between the wild-type virus-infected cells and the mutant virus-infected cells. ORF45 mutation or deletion also was accompanied by a noticeable decreased in viral gene expression during lytic reactivation. Consequently, the ORF45-F66A mutant produced significantly fewer infectious progeny virions than the wild type or the revertant. These results suggest a critical role for ORF45-mediated RSK activation in KSHV lytic replication. IMPORTANCE KSHV is the causative agent of three human malignancies. KSHV pathogenesis is intimately linked to its ability to modulate the host cell microenvironment and to facilitate efficient production of progeny viral particles. We previously described the mechanism by which the KSHV lytic protein ORF45 activates the cellular kinases ERK and RSK. We now have mapped the critical region of ORF45 responsible for binding and activation of ERK

  15. Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway.

    PubMed

    Wang, Shizhen Emily; Wu, Frederick Y; Chen, Honglin; Shamay, Meir; Zheng, Qizhi; Hayward, Gary S

    2004-04-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) maintains a latent infection in primary effusion lymphoma (PEL) cells, but treatment with tetradecanoyl phorbol acetate (TPA) can trigger the full lytic-cycle replication in some of these cells. During lytic-cycle replication, the KSHV-encoded replication and transcription activator (RTA or ORF50), the mRNA transport and accumulation protein (MTA), and the replication-associated protein (RAP) all play crucial roles in expression of downstream viral genes as well as in mediation of viral DNA replication. The cellular CCAAT/enhancer-binding protein alpha (C/EBP alpha) is induced in TPA-treated PEL cells and contributes to transactivation of the promoters for all of these genes through both direct binding and cooperative interactions with RTA and RAP targeted to upstream C/EBP sites. However, little is known about how RTA expression is triggered initially at the earliest stages after TPA induction when the C/EBP alpha levels are still limited. Treatment with TPA proved to significantly induce both AP1 DNA-binding activity and levels of activated phosphorylated cJUN in PEL cells and ectopic expression of cJUN-plus-cFOS-induced RTA protein expression in PEL cells. Cotransfected cJUN plus cFOS or TPA treatment transactivated the KSHV RTA, RAP, and MTA promoters in an AP1-binding site-dependent manner in all three promoters. Chromatin immunoprecipitation assays confirmed that cJUN associates with these KSHV target promoters in PEL cells as early as 4 h after TPA treatment. Furthermore, the KSHV RTA and RAP proteins both interact with cJUN or both cJUN and cFOS in vitro or by coimmunoprecipitation from induced PEL cells and enhance cJUN-plus-cFOS-mediated transactivation of these viral promoters. Both increased phosphorylated cJUN and AP1 DNA-binding activity was detected as early as 1 h after TPA treatment in PEL cells, suggesting that AP1 activity may be crucial for very early activation of the RAP, MTA, and RTA promoters

  16. Modulation of interferon regulatory factor 5 activities by the Kaposi sarcoma-associated herpesvirus-encoded viral interferon regulatory factor 3 contributes to immune evasion and lytic induction.

    PubMed

    Bi, Xiaohui; Yang, Lisong; Mancl, Margo E; Barnes, Betsy J

    2011-04-01

    Multiple Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded proteins with potential roles in KSHV-associated neoplasms have been identified. KSHV encodes 4 genes with homology to transcription factors of the interferon (IFN) regulatory factor (IRF) family. Viral IRF3 (vIRF3) is expressed in latently KSHV-infected primary effusion lymphoma (PEL) cells and was recently shown to be essential for the survival of PEL cells. The focus of this study was to determine the mechanism(s) of vIRF3 oncogenic activity contributing to KSHV-associated lymphoma. We report that vIRF3 interacts with the amino-terminal DNA binding domain of human IRF5, leading to a complex manipulation of IRF5 function. vIRF3 associated with both exogenous and endogenous IRF5, thereby inhibiting IRF5-mediated IFN promoter activation and the synthesis of biologically active type I IFNs by blocking its binding to endogenous IFNA promoters. The function of this interaction was not limited to the IFN system as IRF5-mediated cell growth regulation was significantly altered by overexpression of vIRF3 in B cells. vIRF3 prevented IRF5-mediated growth inhibition and G2/M cell cycle arrest. Important, IRF5 was upregulated by the protein kinase C agonist 12-O-tetradecanoyl-phorbol-13-acetate in BCBL1 PEL cells and interaction with vIRF3 was observed at the endogenous p21 promoter in response to 12-O-tetradecanoyl-phorbol-13-acetate, suggesting that these 2 proteins cooperate in the regulation of lytic cycle-induced G1 arrest, which is an important early step for the reactivation of KSHV. In conclusion, cellular IRF5 and vIRF3 interact, leading to the functional modulation of IRF5-mediated type I IFN expression and cell cycle regulation. These findings support an important role for vIRF3 in immune evasion and cell proliferation that likely contribute to the survival of PEL cells.

  17. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 1 Interacts with a Member of the Interferon-Stimulated Gene 15 Pathway

    PubMed Central

    Jacobs, Sarah R.; Stopford, Charles M.; West, John A.; Bennett, Christopher L.; Giffin, Louise

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus known to establish lifelong latency in the human host. We and others have previously shown that three KSHV homologs of cellular interferon regulatory factors (IRFs), known as viral IRFs (vIRFs), participate in evasion of the host interferon (IFN) response. We report that vIRF1 interacts with the cellular interferon-stimulated gene 15 (ISG15) E3 ligase, HERC5, in the context of Toll-like receptor 3 (TLR3) activation and IFN induction. The ISG15 protein is covalently conjugated to target proteins upon activation of the interferon response. Interaction between vIRF1 and HERC5 was confirmed by immunoprecipitation, and the region between amino acids 224 and 349 of vIRF1 was required for interaction with HERC5. We further report that expression of vIRF1 in the context of TLR3 activation results in decreased ISG15 conjugation of proteins. Specifically, TLR3-induced ISG15 conjugation and protein levels of cellular IRF3, a known ISG15 target, were decreased in the presence of vIRF1 compared to the control. vIRF1 itself was also identified as a target of ISG15 conjugation. KSHV-infected cells exhibited increased ISG15 conjugation upon reactivation from latency in coordination with increased IFN. Furthermore, knockdown of ISG15 in latently infected cells resulted in a higher level of KSHV reactivation and an increase in infectious virus. These data suggest that the KSHV vIRF1 protein affects ISG15 conjugation and interferon responses and may contribute to effective KSHV replication. IMPORTANCE The KSHV vIRF1 protein can inhibit interferon activation in response to viral infection. We identified a cellular protein named HERC5, which is the major ligase for ISG15, as a vIRF1 binding partner. vIRF1 association with HERC5 altered ISG15 modification of cellular proteins, and knockdown of ISG15 augmented reactivation of KSHV from latency. PMID:26355087

  18. Interleukin-4 receptor expression on AIDS-associated Kaposi's sarcoma cells and their targeting by a chimeric protein comprised of circularly permuted interleukin-4 and Pseudomonas exotoxin.

    PubMed Central

    Husain, S. R.; Gill, P.; Kreitman, R. J.; Pastan, I.; Puri, R. K.

    1997-01-01

    BACKGROUND: AIDS-associated Kaposi's sarcoma (AIDS-KS) represents one of the most common malignancies associated with human immunodeficiency virus infection. To target effective therapeutic agents to AIDS-KS, we have identified a new target in the form of interleukin-4 receptors (IL-4R). MATERIALS AND METHODS: The expression of IL-4R on AIDS-KS cells and their subunit structure was determined by radioligand receptor binding, cross-linking and Northern and RT-PCR analyses. The in vitro effect of IL-4 and recombinant fusion protein made up of circularly permuted IL-4 and a mutated form of Pseudomonas exotoxin, IL-4(38-37)-PE38KDEL, was examined by clonogenic and protein synthesis inhibition assays. RESULTS: Five AIDS-KS cell lines expressed high-affinity IL-4R with a Kd of 23.5-219 pM. IL-4 appeared to cross-link to one major protein corresponding to 140 kDa and a broad band corresponding to 60-70 kDa. Both cross-linked proteins were immunoprecipitated with an antibody to human IL-4R beta chain. AIDS-KS cells exhibited IL-4R beta-specific mRNA. IL-4 caused a modest inhibition (31-34%) of colony formation in two AIDS-KS cell lines tested. IL-4(38-37)-PE38KDEL was found to be highly effective in inhibiting the protein synthesis in all five AIDS-KS examined. The IC50 ranged from 32 to 1225 pM. The cytotoxic action of IL-4 toxin was blocked by an excess of IL-4, exhibiting the specificity of IL-4(38-37)-PE38KDEL. The cytotoxicity of IL-4 toxin observed by a clonogenic assay corroborated well with the IC50 obtained by protein synthesis inhibition assay. Normal human endothelial cells expressed a negligible number of IL-4R (< 50 sites/cell) and were less sensitive or not sensitive to IL-4(38-37)-PE38KDEL. CONCLUSION: The presence of a new plasma membrane protein in the form of IL-4R on AIDS-KS cells may be targeted by IL-4(38-37)-PE38KDEL for its potential implication in the treatment of AIDS-KS. Images FIG. 3 FIG. 4 FIG. 6 PMID:9205948

  19. Strong expression of kinase insert domain-containing receptor, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi's sarcoma and cutaneous angiosarcoma.

    PubMed Central

    Brown, L. F.; Tognazzi, K.; Dvorak, H. F.; Harrist, T. J.

    1996-01-01

    Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), plays an important role in the angiogenesis associated with the growth of many human and animal tumors. VPF/VEGF stimulates endothelial cell growth and increases microvascular permeability by interacting with two endothelial cell tyrosine kinase receptors, KDR and flt-1. We studied 16 cases of AIDS-associated Kaposi's sarcoma (KS), 2 cases of cutaneous angiosarcoma, and 6 cases of capillary hemangioma by in situ hybridization for expression of VPF/VEGF, KDR, and flt-1 mRNAs. We also performed immunohistochemical staining for VPF/VEGF protein in 15 cases. Tumor cells in KS and angiosarcoma strongly expressed KDR but not flt-1 mRNA. Endothelial cells in small stromal vessels in and around these tumors strongly expressed both KDR and flt-1 mRNAs. Tumor cells expressed VPF/VEGF mRNA strongly in only one case of KS, adjacent to an area of necrosis. This was also the only case in which the tumor cells stained substantially for VPF/VEGF protein. VPF/VEGF mRNA and protein were, however, strongly expressed by squamous epithelium in areas of hyperplasia and near areas of ulceration overlying tumors. VPF/VEGF mRNA was also expressed focally at lower levels by infiltrating inflammatory cells, probably macrophages. The strong expression of both KDR and flt-1 in small stromal vessels in and around tumors suggests that VPF/VEGF may be an important regulator of the edema and angiogenesis seen in these tumors. The strong expression of KDR by tumor cells in KS and angiosarcoma implies that VPF/VEGF may also have a direct effect on tumor cells. Tumor cells in four of six capillary hemangiomas strongly expressed both KDR and flt-1 mRNAs in contrast to the high level expression of only KDR observed in the malignant vascular tumors studied. Neither VPF/VEGF mRNA or protein were strongly expressed in capillary hemangiomas. VPF/VEGF and its receptors may play an important but as yet incompletely

  20. Activation of Mitogen-Activated Protein Kinase and NF-κB Pathways by a Kaposi's Sarcoma-Associated Herpesvirus K15 Membrane Protein

    PubMed Central

    Brinkmann, Melanie M.; Glenn, Mark; Rainbow, Lucille; Kieser, Arnd; Henke-Gendo, Cornelia; Schulz, Thomas F.

    2003-01-01

    The K15 gene of Kaposi's sarcoma-associated herpesvirus (also known as human herpesvirus 8) consists of eight alternatively spliced exons and has been predicted to encode membrane proteins with a variable number of transmembrane regions and a common C-terminal cytoplasmic domain with putative binding sites for SH2 and SH3 domains, as well as for tumor necrosis factor receptor-associated factors. These features are reminiscent of the latent membrane proteins LMP-1 and LMP2A of Epstein-Barr virus and, more distantly, of the STP, Tip, and Tio proteins of the related γ2-herpesviruses herpesvirus saimiri and herpesvirus ateles. These viral membrane proteins can activate a number of intracellular signaling pathways. We have therefore examined the abilities of different K15-encoded proteins to initiate intracellular signaling. We found that a 45-kDa K15 protein derived from all eight K15 exons and containing 12 predicted transmembrane domains in addition to the cytoplasmic domain activated the Ras/mitogen-activated protein kinase (MAPK) and NF-κB pathways, as well as (more weakly) the c-Jun N-terminal kinase/SAPK pathway. Activation of the MAPK and NF-κB pathways required phosphorylation of tyrosine residue 481 within a putative SH2-binding site (YEEVL). This motif was phosphorylated by the tyrosine kinases Src, Lck, Yes, Hck, and Fyn. The region containing the YEEVL motif interacted with tumor necrosis factor receptor-associated factor 2 (TRAF-2), and a dominant negative TRAF-2 mutant inhibited the K15-mediated activation of the Ras/MAPK pathway, suggesting the involvement of TRAF-2 in the initiation of these signaling routes. In contrast, several smaller K15 protein isoforms activated these pathways only weakly. All of the K15 isoforms tested were, however, localized in lipid rafts, suggesting that incorporation into lipid rafts is not sufficient to initiate signaling. Additional regions of K15, located presumably in exons 2 to 5, may therefore contribute to the

  1. Activation and repression of Epstein-Barr Virus and Kaposi's sarcoma-associated herpesvirus lytic cycles by short- and medium-chain fatty acids.

    PubMed

    Gorres, Kelly L; Daigle, Derek; Mohanram, Sudharshan; Miller, George

    2014-07-01

    The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. Importance: Lytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small

  2. The product of Kaposi's sarcoma-associated herpesvirus immediate early gene K4.2 regulates immunoglobulin secretion and calcium homeostasis by interacting with and inhibiting pERP1.

    PubMed

    Wong, Lai-Yee; Brulois, Kevin; Toth, Zsolt; Inn, Kyung-Soo; Lee, Sun-Hwa; O'Brien, Kathryn; Lee, Hyera; Gao, Shou-Jiang; Cesarman, Ethel; Ensser, Armin; Jung, Jae U

    2013-11-01

    Chaperones are proteins that assist the noncovalent folding and assembly of macromolecular polypeptide chains, ultimately preventing the formation of nonfunctional or potentially toxic protein aggregates. Plasma cell-induced-endoplasmic reticulum (ER)-resident protein 1 (pERP1) is a cellular chaperone that is preferentially expressed in marginal-zone B cells and is highly upregulated during plasma cell differentiation. While initially identified as a dedicated factor for the assembly of secreted IgM, pERP1 has since been implicated in suppressing calcium mobilization, and its expression is misregulated in multiple tumors. A number of herpesvirus immediate early gene products play important roles in the regulation of viral gene expression and/or evasion of host immune responses. Here, we report that the Kaposi's sarcoma-associated herpesvirus (KSHV) immediate early viral gene K4.2 encodes an endoplasmic reticulum-localized protein that interacts with and inhibits pERP1. Consequently, K4.2 expression interfered with immunoglobulin secretion by delaying the kinetics of immunoglobulin assembly and also led to increased responsiveness of B-cell receptor signal transduction by enhancing phosphotyrosine signals and intracellular calcium fluxes. Furthermore, K4.2 expression also appeared to contribute to maximal lytic replication by enhancing viral glycoprotein expression levels and ultimately promoting infectious-virus production. Finally, immunohistochemistry analysis showed that pERP1 expression was readily detected in KSHV-positive cells from multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS) lesions, suggesting that pERP1 may have potential roles in the KSHV life cycle and malignancy. In conclusion, our data suggest that K4.2 participates in lytic replication by enhancing calcium flux and viral glycoprotein expression, but also by interfering with immunoglobulin assembly to potentially dampen the adaptive immune response. PMID:23986581

  3. Next-generation sequence analysis of the genome of RFHVMn, the macaque homolog of Kaposi's sarcoma (KS)-associated herpesvirus, from a KS-like tumor of a pig-tailed macaque.

    PubMed

    Bruce, A Gregory; Ryan, Jonathan T; Thomas, Mathew J; Peng, Xinxia; Grundhoff, Adam; Tsai, Che-Chung; Rose, Timothy M

    2013-12-01

    The complete sequence of retroperitoneal fibromatosis-associated herpesvirus Macaca nemestrina (RFHVMn), the pig-tailed macaque homolog of Kaposi's sarcoma-associated herpesvirus (KSHV), was determined by next-generation sequence analysis of a Kaposi's sarcoma (KS)-like macaque tumor. Colinearity of genes was observed with the KSHV genome, and the core herpesvirus genes had strong sequence homology to the corresponding KSHV genes. RFHVMn lacked homologs of open reading frame 11 (ORF11) and KSHV ORFs K5 and K6, which appear to have been generated by duplication of ORFs K3 and K4 after the divergence of KSHV and RFHV. RFHVMn contained positional homologs of all other unique KSHV genes, although some showed limited sequence similarity. RFHVMn contained a number of candidate microRNA genes. Although there was little sequence similarity with KSHV microRNAs, one candidate contained the same seed sequence as the positional homolog, kshv-miR-K12-10a, suggesting functional overlap. RNA transcript splicing was highly conserved between RFHVMn and KSHV, and strong sequence conservation was noted in specific promoters and putative origins of replication, predicting important functional similarities. Sequence comparisons indicated that RFHVMn and KSHV developed in long-term synchrony with the evolution of their hosts, and both viruses phylogenetically group within the RV1 lineage of Old World primate rhadinoviruses. RFHVMn is the closest homolog of KSHV to be completely sequenced and the first sequenced RV1 rhadinovirus homolog of KSHV from a nonhuman Old World primate. The strong genetic and sequence similarity between RFHVMn and KSHV, coupled with similarities in biology and pathology, demonstrate that RFHVMn infection in macaques offers an important and relevant model for the study of KSHV in humans. PMID:24109218

  4. Fractionated doses of oral etoposide in the treatment of patients with aids-related kaposi sarcoma: a clinical and pharmacologic study to improve therapeutic index.

    PubMed

    Sprinz, E; Caldas, A P; Mans, D R; Cancela, A; DiLeone, L; Dalla Costa, T; Schwartsmann, G

    2001-04-01

    The purpose of this study was to examine the antitumor activity, toxic effects, and plasma pharmacokinetics of fractionated doses of oral etoposide aiming at the achievement of prolonged safe and active plasma drug levels in patients with AIDS-related Kaposi sarcoma (KS). This was designed as a phase II trial in which consecutive patients with progressing AIDS-KS after at least 3 months of active antiretroviral therapy received oral etoposide at the dose of 20 mg/m2 every 8 hours daily for 7 days every 21 days, with the study of its plasma pharmacokinetics. Eligible patients were 18 to 60 years old, with a histopathologically confirmed diagnosis of AIDS-related KS, human immunodeficiency virus-positive test, progressing after at least 3 months of active antiretroviral therapy, World Health Organization (WHO) performance status 0 to 3, New York University staging IIA or greater, no active infection except oral candidiasis, normal bone marrow, liver, and renal function, and who signed an informed consent. Objective tumor responses were evaluated after at least one full treatment course according to a modified WHO criteria, and toxicity was evaluated weekly and graded using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria. For the pharmacokinetic study, plasma was obtained from patients during the first drug administration immediately before and at various time points thereafter. Etoposide was measured after extraction from plasma by a standard high-performance liquid chromatography. Twenty-one patients were accrued for the study, and 18 of them met the eligibility criteria. They were all men, with median age of 36 years old (range: 25-50 years), median WHO performance status 0 (range: 0-3) median CD4+ count (cells/mm3) 67 (range: 8-443), prior AIDS diagnosis in 10 of 18 cases, NYU staging IIA (1 patient), IIB (1), IIIA (7), IIIB (1), IVA (4), and IVB (4) sites of disease: mucocutaneous only (5), mucocutaneous/lymph nodes (5), mucocutaneous

  5. How Is Kaposi Sarcoma Staged?

    MedlinePlus

    ... the lungs is a particularly bad sign. I (immune system) status The immune status is assessed using a ... in healthy people but affect people with suppressed immune systems) or thrush (a fungal infection in the mouth). ...

  6. How Is Kaposi Sarcoma Diagnosed?

    MedlinePlus

    ... thin, flexible lighted tube with a small video camera on the end) through the mouth, down the ... thin, flexible, lighted tube with a small video camera on the end) through the mouth and esophagus ...

  7. Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

    PubMed Central

    Hu, Haidai; Dong, Jiazhen; Liang, Deguang; Gao, Zengqiang; Bai, Lei; Sun, Rui; Hu, Hao; Zhang, Heng

    2015-01-01

    ABSTRACT The oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is known to encode four viral interferon regulatory factors (vIRF1 to -4) to subvert the host antiviral immune response, but their detailed DNA-binding profiles as transcription factors in the host remain uncharacterized. Here, we first performed genome-wide vIRF2-binding site mapping in the human genome using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). vIRF2 was capable of binding to the promoter regions of 100 putative target genes. Importantly, we confirmed that vIRF2 can specifically interact with the promoters of the genes encoding PIK3C3, HMGCR, and HMGCL, which are associated with autophagosome formation or tumor progression and metastasis, and regulate their transcription in vivo. The crystal structure of the vIRF2 DNA-binding domain (DBD) (referred to here as vIRF2DBD) showed variable loop conformations and positive-charge distributions different from those of vIRF1 and cellular IRFs that are associated with DNA-binding specificities. Structure-based mutagenesis revealed that Arg82 and Arg85 are required for the in vitro DNA-binding activity of vIRF2DBD and can abolish the transcription regulation function of vIRF2 on the promoter reporter activity of PIK3C3, HMGCR, and HMGCL. Collectively, our study provided unique insights into the DNA-binding potency of vIRF2 and suggested that vIRF2 could act as a transcription factor of its target genes in the host antiviral immune response. IMPORTANCE The oncogenic herpesvirus KSHV is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV has developed a unique mechanism to subvert the host antiviral immune responses by encoding four homologues of cellular interferon regulatory factors (vIRF1 to -4). However, none of their DNA-binding profiles in the human genome have been characterized until now, and the structural basis for their diverse

  8. Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

    ClinicalTrials.gov

    2016-06-09

    Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Unclassified Pleomorphic Sarcoma; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Conjunctival Kaposi Sarcoma; Dermatofibrosarcoma Protuberans; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Unclassified Pleomorphic Sarcoma of Bone; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Kaposi Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Corpus Sarcoma; Small Intestine Leiomyosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Unclassified Pleomorphic Sarcoma of Bone

  9. Oncovirus Kaposi sarcoma herpesvirus (KSHV) represses tumor suppressor PDLIM2 to persistently activate nuclear factor κB (NF-κB) and STAT3 transcription factors for tumorigenesis and tumor maintenance.

    PubMed

    Sun, Fan; Xiao, Yadong; Qu, Zhaoxia

    2015-03-20

    Kaposi sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. However, how KSHV induces tumorigenesis remains largely unknown. Here, we demonstrate that one important mechanism underlying the tumorigenesis of KSHV is through transcriptional repression of the tumor suppressor gene PDZ-LIM domain-containing protein 2 (PDLIM2). PDLIM2 expression is repressed in KSHV-transformed human umbilical vascular endothelial cells as well as in KSHV-associated cancer cell lines and primary tumors. Importantly, PDLIM2 repression is essential for KSHV-induced persistent activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and subsequent tumorigenesis and tumor maintenance. Our mechanistic studies indicate that PDLIM2 repression by KSHV involves DNA methylation. Notably, the epigenetic repression of PDLIM2 can be reversed by 5-aza-2-deoxycytidine and vitamin D to suppress KSHV-associated cancer cell growth. These studies not only improve our understanding of KSHV pathogenesis but also provide immediate therapeutic strategies for KSHV-mediated cancers, particularly those associated with AIDS.

  10. HIV-1 Tat promotes Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6-induced angiogenesis and tumorigenesis by regulating PI3K/PTEN/AKT/GSK-3β signaling pathway.

    PubMed

    Zhou, Feng; Xue, Min; Qin, Di; Zhu, Xiaofei; Wang, Cong; Zhu, Jianzhong; Hao, Tingting; Cheng, Lin; Chen, Xiuying; Bai, Zhiqiang; Feng, Ninghan; Gao, Shou-Jiang; Lu, Chun

    2013-01-01

    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM) model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. LY294002, a specific inhibitor of PI3K, effectively impaired Tat's promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients.

  11. IFN-gamma induces endothelial cells to proliferate and to invade the extracellular matrix in response to the HIV-1 Tat protein: implications for AIDS-Kaposi's sarcoma pathogenesis.

    PubMed

    Fiorelli, V; Barillari, G; Toschi, E; Sgadari, C; Monini, P; Stürzl, M; Ensoli, B

    1999-01-15

    Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi's sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-gamma alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-gamma up-regulates the expression and activity of the receptors for Tat identified as the integrins alpha5beta1 and alpha(v)beta3. These results suggest that, by triggering Tat effects, IFN-gamma plays a major role in AIDS-KS pathogenesis.

  12. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4/K10) is a novel interaction partner of CSL/CBF1, the major downstream effector of Notch signaling.

    PubMed

    Heinzelmann, Katharina; Scholz, Barbara A; Nowak, Agnes; Fossum, Even; Kremmer, Elisabeth; Haas, Juergen; Frank, Ronald; Kempkes, Bettina

    2010-12-01

    In cells infected with the Kaposi's sarcoma-associated herpesvirus (KSHV), CSL/CBF1 signaling is essential for viral replication and promotes the survival of KSHV-infected cells. CSL/CBF1 is a DNA adaptor molecule which recruits coactivator and corepressor complexes to regulate viral and cellular gene transcription and which is a major downstream effector molecule of activated Notch. The interaction of KSHV RTA and LANA with CSL/CBF1 has been shown to balance the lytic and latent viral life cycle. Here we report that a third KSHV protein, viral interferon regulatory factor 4 (vIRF4/K10), but none of the three other KSHV-encoded vIRFs, interacts with CSL/CBF1. Two regions of vIRF4 with dissimilar affinities contribute to CSL/CBF1 binding. Similar to Notch, vIRF4 targets the hydrophobic pocket in the beta trefoil domain of CSL/CBF1 through a short peptide motif which closely resembles a motif found in Notch but does not strictly follow the ΦWΦP consensus conserved in human and mouse Notch proteins. Our results suggest that vIRF4 might compete with Notch for CSL/CBF1 binding and signaling. PMID:20861242

  13. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4/K10) Is a Novel Interaction Partner of CSL/CBF1, the Major Downstream Effector of Notch Signaling▿

    PubMed Central

    Heinzelmann, Katharina; Scholz, Barbara A.; Nowak, Agnes; Fossum, Even; Kremmer, Elisabeth; Haas, Juergen; Frank, Ronald; Kempkes, Bettina

    2010-01-01

    In cells infected with the Kaposi's sarcoma-associated herpesvirus (KSHV), CSL/CBF1 signaling is essential for viral replication and promotes the survival of KSHV-infected cells. CSL/CBF1 is a DNA adaptor molecule which recruits coactivator and corepressor complexes to regulate viral and cellular gene transcription and which is a major downstream effector molecule of activated Notch. The interaction of KSHV RTA and LANA with CSL/CBF1 has been shown to balance the lytic and latent viral life cycle. Here we report that a third KSHV protein, viral interferon regulatory factor 4 (vIRF4/K10), but none of the three other KSHV-encoded vIRFs, interacts with CSL/CBF1. Two regions of vIRF4 with dissimilar affinities contribute to CSL/CBF1 binding. Similar to Notch, vIRF4 targets the hydrophobic pocket in the beta trefoil domain of CSL/CBF1 through a short peptide motif which closely resembles a motif found in Notch but does not strictly follow the ΦWΦP consensus conserved in human and mouse Notch proteins. Our results suggest that vIRF4 might compete with Notch for CSL/CBF1 binding and signaling. PMID:20861242

  14. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence.

    PubMed Central

    Barillari, G; Gendelman, R; Gallo, R C; Ensoli, B

    1993-01-01

    Spindle-shaped cells of vascular origin are the probable tumor cells of Kaposi sarcoma (KS). These cells, derived from patients with KS and AIDS, proliferate in response to extracellular Tat protein of human immunodeficiency virus type 1. Normal vascular cells, believed to be the progenitors of AIDS-KS cells, acquire spindle morphology and become responsive to the mitogenic effect of Tat after culture with inflammatory cytokines. Such cytokines are increased in human immunodeficiency virus type 1-infected people, suggesting that immune stimulation (rather than immune deficiency) is a component of AIDS-KS pathogenesis. Here we show that (i) Tat promotes adhesion of AIDS-KS and normal vascular cells; (ii) adhesion of normal vascular cells to Tat is induced by exposure of the cells to the same cytokines; (iii) adhesion is associated with the amino acid sequence RGD of Tat through a specific interaction with the integrin receptors alpha 5 beta 1 and alpha v beta 3, although it is augmented by the basic region; and (iv) the expression of both integrins is increased by the same cytokines that promote these cells to acquire spindle morphology and become responsive to the adhesion and growth effects of Tat. The results also suggest that RGD-recognizing integrins mediate the vascular cell-growth-promoting effect of Tat. Images Fig. 1 Fig. 5 PMID:7690138

  15. Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA, of the Viral Co-Receptor EphA2 as well as Other Client Proteins

    PubMed Central

    Chen, Wuguo; Sin, Sang-Hoon; Wen, Kwun Wah; Damania, Blossom; Dittmer, Dirk P.

    2012-01-01

    Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers. We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC50 in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs. PMID:23209418

  16. Making sense of antisense: seemingly noncoding RNAs antisense to the master regulator of Kaposi's sarcoma-associated herpesvirus lytic replication do not regulate that transcript but serve as mRNAs encoding small peptides.

    PubMed

    Xu, Yiyang; Ganem, Don

    2010-06-01

    The mammalian transcriptome is studded with putative noncoding RNAs, many of which are antisense to known open reading frames (ORFs). Roles in the regulation of their complementary mRNAs are often imputed to these antisense transcripts, but few have been experimentally examined, and such functions remain largely conjectural. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes two transcripts that lack obvious ORFs and are complementary to the gene (RTA) encoding the master regulator of the latent/lytic switch. Here, we show that, contrary to expectation, these RNAs do not regulate RTA expression. Rather, they are found on polysomes, and genetic analysis indicates that translational initiation occurs at several AUG codons in the RNA, leading to the presumptive synthesis of peptides of 17 to 48 amino acids. These findings underscore the need for circumspection in the computational assessment of coding potential and raise the possibility that the mammalian proteome may contain many previously unsuspected peptides generated from seemingly noncoding RNAs, some of which could have important biological functions. Irrespective of their function, such peptides could also contribute substantially to the repertoire of T cell epitopes generated in both uninfected and infected cells. PMID:20357088

  17. Kaposi's sarcoma-associated herpesvirus ORF57 functions as a viral splicing factor and promotes expression of intron-containing viral lytic genes in spliceosome-mediated RNA splicing.

    PubMed

    Majerciak, Vladimir; Yamanegi, Koji; Allemand, Eric; Kruhlak, Michael; Krainer, Adrian R; Zheng, Zhi-Ming

    2008-03-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 facilitates the expression of both intronless viral ORF59 genes and intron-containing viral K8 and K8.1 genes (V. Majerciak, N. Pripuzova, J. P. McCoy, S. J. Gao, and Z. M. Zheng, J. Virol. 81:1062-1071, 2007). In this study, we showed that disruption of ORF57 in a KSHV genome led to increased accumulation of ORF50 and K8 pre-mRNAs and reduced expression of ORF50 and K-bZIP proteins but had no effect on latency-associated nuclear antigen (LANA). Cotransfection of ORF57 and K8beta cDNA, which retains a suboptimal intron of K8 pre-mRNA due to alternative splicing, promoted RNA splicing of K8beta and production of K8alpha (K-bZIP). Although Epstein-Barr virus EB2, a closely related homolog of ORF57, had a similar activity in the cotransfection assays, herpes simplex virus type 1 ICP27 was inactive. This enhancement of RNA splicing by ORF57 correlates with the intact N-terminal nuclear localization signal motifs of ORF57 and takes place in the absence of other viral proteins. In activated KSHV-infected B cells, KSHV ORF57 partially colocalizes with splicing factors in nuclear speckles and assembles into spliceosomal complexes in association with low-abundance viral ORF50 and K8 pre-mRNAs and essential splicing components. The association of ORF57 with snRNAs occurs by ORF57-Sm protein interaction. We also found that ORF57 binds K8beta pre-mRNAs in vitro in the presence of nuclear extracts. Collectively our data indicate that KSHV ORF57 functions as a novel splicing factor in the spliceosome-mediated splicing of viral RNA transcripts.

  18. Detection and titration of human herpesvirus-8-specific antibodies in sera from blood donors, acquired immunodeficiency syndrome patients, and Kaposi's sarcoma patients using a whole virus enzyme-linked immunosorbent assay.

    PubMed

    Chatlynne, L G; Lapps, W; Handy, M; Huang, Y Q; Masood, R; Hamilton, A S; Said, J W; Koeffler, H P; Kaplan, M H; Friedman-Kien, A; Gill, P S; Whitman, J E; Ablashi, D V

    1998-07-01

    A human herpesvirus-8 (HHV-8) enzyme-linked immunosorbent assay (ELISA) with a whole virus lysate as antigen was developed and used to measure the seroprevalence rate and levels of IgG antibodies to HHV-8 in sera/plasma of various patient groups and blood donors. The virus antigen was prepared from the KS-1 cell line, which produces lytic virus, and therefore contains a broad array of viral proteins. Seroprevalence studies using this ELISA showed the following: 10 of 91 blood donors (11%) had an average HHV-8 antibody titer of 118; 67 of 72 (93%) classic Kaposi's sarcoma (KS) patients were positive with an average titer of 14,111; and 57 of 62 (92%) KS/human immunodeficiency virus (HIV) patients were positive with an average titer of 4,000. A study on a very limited number of serial serum samples from patients before and after diagnosis with KS showed highly elevated antibody titers to HHV-8 virus after KS lesions developed. Preliminary data show that 50% of the sera from HIV-1(+) homosexual patients contain IgG antibodies to HHV-8 suggesting that this population is at high risk for developing KS. Antibody results correlated well with the confirmatory immunofluorescent assays (IFA) using KS-1 cells as the substrate. This HHV-8 IgG antibody detection ELISA is sensitive and specific and does not cross-react with Epstein-Barr virus (EBV) or other human herpesviruses. The results of this HHV-8 antibody survey suggest that this rapid ELISA assay can be used to screen large numbers of sera to find those at risk for developing KS.

  19. Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development.

    PubMed Central

    Samaniego, F.; Markham, P. D.; Gendelman, R.; Watanabe, Y.; Kao, V.; Kowalski, K.; Sonnabend, J. A.; Pintus, A.; Gallo, R. C.; Ensoli, B.

    1998-01-01

    All forms of Kaposi's sarcoma (KS) are characterized by spindle cell proliferation, angiogenesis, inflammatory cell infiltration, and edema. We have previously reported that spindle cells of primary KS lesions and KS-derived spindle cell cultures express high levels of basic fibroblast growth factor (bFGF), which is promoted by the inflammatory cytokines identified in these lesions. These cytokines, namely, tumor necrosis factor, interleukin-1, and interferon-gamma, induce production and release of bFGF, which stimulates angiogenesis and spindle cell growth in an autocrine fashion. Here we show that both AIDS-KS and classical KS lesions co-express vascular endothelial growth factor (VEGF) and bFGF. VEGF production by KS cells is promoted synergistically by inflammatory cytokines present in conditioned media from activated T cells and in KS lesions. KS cells show synthesis of VEGF isoforms that are mitogenic to endothelial cells but not to KS spindle cells, suggesting a prevailing paracrine effect of this cytokine. This may be due to the level of expression of the flt-1-VEGF receptor that is down-regulated in KS cells as compared with endothelial cells. KS-derived bFGF and VEGF synergize in inducing endothelial cell growth as shown by studies using both neutralizing antibodies and antisense oligodeoxynucleotides directed against these cytokines. In addition, VEGF and bFGF synergize to induce angiogenic KS-like lesions in nude mice and vascular permeability and edema in guinea pigs. These results indicate that inflammatory cytokines present in KS lesions stimulate the production of bFGF and VEGF, which, in turn, cooperate to induce angiogenesis, edema, and KS lesion formation. Images Figure 1 Figure 3 PMID:9626048

  20. Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and Its Interaction with Kaposi Sarcoma-associated Herpes Virus Flice-interacting Protein and IKK Subunit β by EPR Spectroscopy.

    PubMed

    Bagnéris, Claire; Rogala, Kacper B; Baratchian, Mehdi; Zamfir, Vlad; Kunze, Micha B A; Dagless, Selina; Pirker, Katharina F; Collins, Mary K; Hall, Benjamin A; Barrett, Tracey E; Kay, Christopher W M

    2015-07-01

    Viral flice-interacting protein (vFLIP), encoded by the oncogenic Kaposi sarcoma-associated herpes virus (KSHV), constitutively activates the canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway. This is achieved through subversion of the IκB kinase (IKK) complex (or signalosome), which involves a physical interaction between vFLIP and the modulatory subunit IKKγ. Although this interaction has been examined both in vivo and in vitro, the mechanism by which vFLIP activates the kinase remains to be determined. Because IKKγ functions as a scaffold, recruiting both vFLIP and the IKKα/β subunits, it has been proposed that binding of vFLIP could trigger a structural rearrangement in IKKγ conducive to activation. To investigate this hypothesis we engineered a series of mutants along the length of the IKKγ molecule that could be individually modified with nitroxide spin labels. Subsequent distance measurements using electron paramagnetic resonance spectroscopy combined with molecular modeling and molecular dynamics simulations revealed that IKKγ is a parallel coiled-coil whose response to binding of vFLIP or IKKβ is localized twisting/stiffening and not large-scale rearrangements. The coiled-coil comprises N- and C-terminal regions with distinct registers accommodated by a twist: this structural motif is exploited by vFLIP, allowing it to bind and subsequently activate the NF-κB pathway. In vivo assays confirm that NF-κB activation by vFLIP only requires the N-terminal region up to the transition between the registers, which is located directly C-terminal of the vFLIP binding site. PMID:25979343

  1. The proapoptotic protein Bim is up regulated by 1α,25-dihydroxyvitamin D3 and its receptor agonist in endothelial cells and transformed by viral GPCR associated to Kaposi sarcoma.

    PubMed

    Suares, Alejandra; Russo de Boland, Ana; Verstuyf, Annemieke; Boland, Ricardo; González-Pardo, Verónica

    2015-10-01

    We have previously shown that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] and its less calcemic analog TX 527 induce apoptosis via caspase-3 activation in endothelial cells (SVEC) and endothelial cells transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (vGPCR). In this work, we studied whether intrinsic apoptotic pathway could be activated by changing the balance between anti and pro-apoptotic proteins. Time response qRT-PCR analysis demonstrated that the mRNA level of anti-apoptotic gene Bcl-2 decreased after 12h and increased after 48h treatment with 1α,25(OH)2D3 or TX 527 in SVEC and vGPCR cells, whereas its protein level remained unchanged through time. mRNA levels of pro-apoptotic gene Bax significantly increased only in SVEC after 24 and 48h treatment with 1α,25(OH)2D3 and TX 527 although its protein levels remained unchanged in both cell lines. Bim mRNA and protein levels increased in SVEC and vGPCR cells. Bim protein increase by 1α,25(OH)2D3 and TX 527 was abolished when the expression of vitamin D receptor (VDR) was suppressed. On the other hand, Bortezomib (0.25-1nM), an inhibitor of NF-κB pathway highly activated in vGPCR cells, increased Bim protein levels and induced caspase-3 cleavage. Altogether, these results indicate that 1α,25(OH)2D3 and TX 527 trigger apoptosis by Bim protein increase which turns into the activation of caspase-3 in SVEC and vGPCR cells. Moreover, this effect is mediated by VDR and involves NF-κB pathway inhibition in vGPCR.

  2. Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study

    PubMed Central

    El-Mallawany, Nader Kim; Kamiyango, William; Slone, Jeremy S.; Villiera, Jimmy; Kovarik, Carrie L.; Cox, Carrie M.; Dittmer, Dirk P.; Ahmed, Saeed; Schutze, Gordon E.; Scheurer, Michael E.; Kazembe, Peter N.; Mehta, Parth S.

    2016-01-01

    Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7–17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15–50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22–163.90 and 1.60–83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01–90.99 and 1.00–524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84–33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08–0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according

  3. Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression.

    PubMed

    Sadagopan, Sathish; Sharma-Walia, Neelam; Veettil, Mohanan Valiya; Raghu, Hari; Sivakumar, Ramu; Bottero, Virginie; Chandran, Bala

    2007-04-01

    In vitro Kaposi's sarcoma-associated herpesvirus (KSHV) infection of primary human dermal microvascular endothelial (HMVEC-d) cells and human foreskin fibroblast (HFF) cells is characterized by the induction of preexisting host signal cascades, sustained expression of latency-associated genes, transient expression of a limited number of lytic genes, and induction of several cytokines, growth factors, and angiogenic factors. Since NF-kappaB is a key molecule involved in the regulation of several of these factors, here, we examined NF-kappaB induction during de novo infection of HMVEC-d and HFF cells. Activation of NF-kappaB was observed as early as 5 to 15 min postinfection by KSHV, and translocation of p65-NF-kappaB into nuclei was detected by immunofluorescence assay, electrophoretic mobility shift assay, and p65 enzyme-linked immunosorbent assay. IkappaB phosphorylation inhibitor (Bay11-7082) reduced this activation significantly. A sustained moderate level of NF-kappaB induction was seen during the observed 72 h of in vitro KSHV latency. In contrast, high levels of ERK1/2 activation at earlier time points and a moderate level of activation at later times were observed. p38 mitogen-activated protein kinase was activated only at later time points, and AKT was activated in a cyclic manner. Studies with UV-inactivated KSHV suggested a role for virus entry stages in NF-kappaB induction and a requirement for KSHV viral gene expression in sustained induction. Inhibition of NF-kappaB did not affect target cell entry by KSHV but significantly reduced the expression of viral latent open reading frame 73 and lytic genes. KSHV infection induced the activation of several host transcription factors, including AP-1 family members, as well as several cytokines, growth factors, and angiogenic factors, which were significantly affected by NF-kappaB inhibition. These results suggest that during de novo infection, KSHV induces sustained levels of NF-kappaB to regulate viral and

  4. Origin-Independent Assembly of Kaposi's Sarcoma-Associated Herpesvirus DNA Replication Compartments in Transient Cotransfection Assays and Association with the ORF-K8 Protein and Cellular PML

    PubMed Central

    Wu, Frederick Y.; Ahn, Jin-Hyun; Alcendor, Donald J.; Jang, Won-Jong; Xiao, Jinsong; Hayward, S. Diane; Hayward, Gary S.

    2001-01-01

    Six predicted Kaposi's sarcoma virus herpesvirus (KSHV) proteins have homology with other well-characterized herpesvirus core DNA replication proteins and are expected to be essential for viral DNA synthesis. Intact Flag-tagged protein products from all six were produced from genomic expression vectors, although the ORF40/41 transcript encoding a primase-helicase component proved to be spliced with a 127-bp intron. The intracellular localization of these six KSHV replication proteins and the mechanism of their nuclear translocation were investigated. SSB (single-stranded DNA binding protein, ORF6) and PPF (polymerase processivity factor, ORF59) were found to be intrinsic nuclear proteins, whereas POL (polymerase, ORF9), which localized in the cytoplasm on its own, was translocated to the nucleus when cotransfected with PPF. PAF (primase-associated factor, ORF40/41), a component of the primase-helicase tripartite subcomplex together with PRI (primase, ORF56) and HEL (helicase, ORF44), required the presence of all five other replication proteins for efficient nuclear translocation. Surprisingly, even in the absence of a lytic cycle replication origin (ori-Lyt) and any known initiator or origin binding protein, the protein products of all six KSHV core replication genes cooperated in a transient cotransfection assay to form large globular shaped pseudo-replication compartments (pseudo-RC), which excluded cellular DNA. These pseudo-RC structures were confirmed to include POL, SSB, PRI, and PAF but did not contain any newly synthesized DNA. Similar to the human cytomegalovirus system, the peripheries of these KSHV pre-RC were also found to be surrounded by punctate PML oncogenic domains (PODs). Furthermore, by transient cotransfection, the six KSHV core replication machinery proteins successfully replicated a plasmid containing EBV ori-Lyt in the presence of the Epstein-Barr virus-encoded DNA binding initiator protein, ZTA. The KSHV-encoded K8 (ORF-K8) protein, which is

  5. Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

    PubMed

    El-Mallawany, Nader Kim; Kamiyango, William; Slone, Jeremy S; Villiera, Jimmy; Kovarik, Carrie L; Cox, Carrie M; Dittmer, Dirk P; Ahmed, Saeed; Schutze, Gordon E; Scheurer, Michael E; Kazembe, Peter N; Mehta, Parth S

    2016-01-01

    Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk

  6. Blood vessel growth blocker may treat AIDS-related Kaposi’s sarcoma

    Cancer.gov

    Patients with an AIDS-associated cancer, Kaposi's sarcoma (KS), showed improvement after receiving the combination of bevacizumab, a cancer drug that blocks the growth of new blood vessels, and highly active antiretroviral therapy (HAART).

  7. Pediatric Sarcomas.

    PubMed

    Williams, Regan F; Fernandez-Pineda, Israel; Gosain, Ankush

    2016-10-01

    Pediatric sarcomas are a heterogeneous group of tumors accounting for approximately 10% of childhood solid tumors. Treatment is focused on multimodality therapy, which has improved the prognosis over the past two decades. Current regimens focus on decreasing treatment for low-risk patients to decrease the long-term side effects while maximizing therapy for patients with metastatic disease to improve survival. Pediatric sarcomas can be divided into soft tissue sarcomas and osseous tumors. Soft tissue sarcomas are further delineated into rhabdomyosarcomas, which affect young children and nonrhabdomyosarcomas, which are most common in adolescents. The most common bone sarcomas are osteosarcomas and Ewing's sarcoma. PMID:27542645

  8. Ewing sarcoma

    MedlinePlus

    Bone cancer - Ewing sarcoma; Ewing family of tumors; Primitive neuroectodermal tumors (PNET); Bone neoplasm - Ewing sarcoma ... NCCN clinical practice guidelines in oncology (NCCN guidelines): bone cancer. Updated 2016. www.nccn.org/professionals/physician_gls/ ...

  9. Overview of CSR codes

    NASA Astrophysics Data System (ADS)

    Bassi, G.; Agoh, T.; Dohlus, M.; Giannessi, L.; Hajima, R.; Kabel, A.; Limberg, T.; Quattromini, M.

    2006-02-01

    Coherent synchrotron radiation (CSR) effects play an important role in accelerator physics. CSR effects can be negative (emittance growth in bunch compressors and microbunching instability) or positive (production of CSR in a controlled way). Moreover, CSR is of interest in other fields such as astrophysics. Only a few simple models have been solved analytically. This motivates the development of numerical procedures. In this review article we overview different numerical methods to study CSR effects.

  10. Retroperitoneal Sarcomas.

    PubMed

    Porpiglia, Andrea S; Reddy, Sanjay S; Farma, Jeffrey M

    2016-10-01

    Retroperitoneal sarcomas are rare tumors, representing only 15% of all sarcomas. The mainstay of therapy is surgical resection with negative margins. However, this is challenging because of the late presentation of many of these tumors and involvement with adjacent structures. Decisions on radiation therapy and chemotherapy should be made in a multidisciplinary setting at a tertiary referral center.

  11. Histiocytic sarcoma

    PubMed Central

    Machado, Eduardo Silva; de Miranda, Ana Carolina; Escopelli, Ticiane; Caron, Ruggero; Escopelli, Alessandra Cristhina

    2011-01-01

    A 59-year-old white woman, SC, after being treated for pneumonia, presented with an increase in the size of lymph nodes. The immunohistochemical examination diagnosed histiocytic sarcoma. Relapse occurred 12 months after starting chemotherapy. The patient evolved with febrile neutropenia, septic shock and death. PMID:23284265

  12. The ribonucleoprotein Csr network.

    PubMed

    Seyll, Ethel; Van Melderen, Laurence

    2013-11-08

    Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA binds to mRNA targets and regulates translation either negatively or positively. Binding to small non-coding RNAs controls activity of this protein. Expression of these regulators is tightly regulated at the level of transcription and stability by various global regulators (RNAses, two-component systems, alarmone). We discuss the implications of these complex regulations in bacterial adaptation.

  13. The Ribonucleoprotein Csr Network

    PubMed Central

    Seyll, Ethel; Van Melderen, Laurence

    2013-01-01

    Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA binds to mRNA targets and regulates translation either negatively or positively. Binding to small non-coding RNAs controls activity of this protein. Expression of these regulators is tightly regulated at the level of transcription and stability by various global regulators (RNAses, two-component systems, alarmone). We discuss the implications of these complex regulations in bacterial adaptation. PMID:24217225

  14. HIRFL-CSR project

    NASA Astrophysics Data System (ADS)

    Zhan, W. L.; Xia, J. W.; Wei, B. W.; Yuan, Y. J.; Zhao, H. W.; Man, K. T.; Dang, J. R.; Yuan, P.; Gao, D. Q.; Yang, X. T.; Song, M. T.; Zhang, W. Z.; Xiao, G. Q.; Cai, X. H.; Tang, J. Y.; Qiao, W. M.; Yang, X. D.; Wang, Y. F.

    2001-12-01

    HIRFL-CSR, the project that was proposed to upgrade the HIRFL facility, is a multifunctional Cooling Storage Ring (CSR) system, consisting of a main ring (CSRm) and an experimental ring (CSRe). The heavy ion beams from the HIRFL will be injected, accumulated, cooled and accelerated to high energy in the CSRm, then fast-extracted to produce radioactive ion beams (RIB), highly-charged stage ions, or slow-extracted to do experiment. The secondary beams will be accepted by CSRe and used for internal-target experiments of the high sensitive and high precision spectroscopy with cool beam. CSR project was started in end of 1999 and finish in the end of 2004. The period from beginning of 2000 to the summer of 2001 is the time for the building construction, fabrication design, prototype experiments. In this paper, the outline and status of the project will be reported.

  15. CSR Model Implementation from School Stakeholder Perspectives

    ERIC Educational Resources Information Center

    Herrmann, Suzannah

    2006-01-01

    Despite comprehensive school reform (CSR) model developers' best intentions to make school stakeholders adhere strictly to the implementation of model components, school stakeholders implementing CSR models inevitably make adaptations to the CSR model. Adaptations are made to CSR models because school stakeholders internalize CSR model practices…

  16. Sarcoma Foundation of America

    MedlinePlus

    ... Make a Donation Matching Gifts Sarcoma Dedication Page Stocks and Securities Workplace Giving Year-End Giving FAQ's ... Make a Donation Matching Gifts Sarcoma Dedication Page Stocks and Securities Workplace Giving Year-End Giving

  17. Targeted therapy for sarcomas

    PubMed Central

    Forscher, Charles; Mita, Monica; Figlin, Robert

    2014-01-01

    Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing’s sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing’s sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. PMID:24669185

  18. Lattice of the CSR

    NASA Astrophysics Data System (ADS)

    Xia, J. W.; Yuan, Y. J.; Song, M. T.; Zhang, W. Z.; Yang, X. D.; He, Y.; Mao, L. Z.; Xia, G. X.; Yang, J. C.; Wu, J. X.; Liu, W.

    2001-12-01

    CSR, a new Cooler-Storage-Ring project, is the post-acceleration system of the Heavy Ion Research Facility in Lanzhou (HIRFL). It consists of a main ring (CSRm) and an experimental ring (CSRe). From the HIRFL cyclotron system the heavy ions will be accumulated, cooled and accelerated in the CSRm, then extracted fast and injected into the CSRe for many internal-target experiments with electron cooling. The experimental ring (CSRe) will be operated with three lattice modes for different experiments. The details of the lattice for the two rings will be described in this paper.

  19. CSR-1 Slices a Balance.

    PubMed

    Yu, Ruby; Moazed, Danesh

    2016-04-01

    CSR-1 is a germline-expressed C. elegans Argonaute protein essential for viability. In this issue of Cell, Gerson-Gurwitz et al. now demonstrate a role for CSR-1 and its slicer activity in downregulating the levels of maternally deposited mRNAs to fine-tune the expression of proteins with critical roles in embryonic cell divisions.

  20. Head and Neck Sarcomas: Analysis of the SEER Database

    PubMed Central

    Peng, Kevin A.; Grogan, Tristan; Wang, Marilene B.

    2015-01-01

    Objective To summarize the epidemiology of sarcomas occurring in the head and neck and identify prognostic factors for patient survival. Study Design and Setting Cross-sectional analysis of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program. Methods The SEER 18 registries, comprising sarcoma diagnoses made from 1973 to 2010, were queried for sarcomas arising in the head and neck. Pediatric and adult patients were analyzed separately, and multivariate and propensity-matched analyses were performed to identify predictors of disease-specific survival. Results In all, 11,481 adult cases and 1244 pediatric cases were identified. In adults, the most common histologic subtypes were malignant fibrous histiocytoma (MFH), Kaposi sarcoma, and hemangiosarcoma, while in the pediatric cohort, the most common histologic subtypes were rhabdomyosar-coma, MFH, and osteosarcoma. Cause-specific 2-, 5-, and 10-year survival rates were 76%, 66%, and 61% for adults and 84%, 73%, and 71% for pediatric patients. Multivariate analysis performed for adults revealed that male gender, absence of radiation therapy, and stage I disease were associated with improved cause-specific survival reaching statistical significance. However, a propensity-matched model demonstrated no significant difference in cause-specific survival between patients who received radiation and those who did not. Conclusion Sarcomas, a heterogeneous group of malignant mesenchymal tumors, are uncommonly found in the head and neck. This study represents the largest analysis of patients with head and neck sarcomas in the literature and demonstrates the impact of age, gender, primary site, histology, and radiation status on overall prognosis. PMID:25135525

  1. The soft tissue sarcomas

    SciTech Connect

    Eilber, F.R.; Morton, D.L.; Sondak, V.K.; Economou, J.S.

    1987-01-01

    New advances in multimodality therapy of sarcomas in all anatomic sites are thoroughly described. Multimodality therapy with limb-salvage surgery for extremity tumors, sarcomas of the head and neck, trunk, intraabdominal, visceral, and genitourinary tract and cardiopulmonary system are presented. Separate sections are devoted to the management of pediatric sarcomas, pulmonary metastasis and to the pathology and radiobiology, chemotherapy, and immunotherapy of sarcomas. The text also stresses the philosophy of achieving adequate local control without radical amputation by combined surgery and chemo/radiotherapy.

  2. Trial of Dasatinib in Advanced Sarcomas

    ClinicalTrials.gov

    2016-10-12

    Rhabdomyosarcoma; Malignant Peripheral Nerve Sheath Tumors; Chondrosarcoma; Sarcoma, Ewing's; Sarcoma, Alveolar Soft Part; Chordoma; Epithelioid Sarcoma; Giant Cell Tumor of Bone; Hemangiopericytoma; Gastrointestinal Stromal Tumor (GIST)

  3. Management of Breast Sarcoma.

    PubMed

    Hsu, Cary; McCloskey, Susan A; Peddi, Parvin F

    2016-10-01

    Breast sarcomas are exceptionally rare mesenchymal neoplasms composed of many histologic subtypes. Therapy is guided by principles established in the management of extremity sarcomas. The anatomic site does influence treatment decisions, particularly the surgical management. Surgery should be undertaken with the aim of achieving a widely negative margin. Selected patients can be managed with breast-conserving surgery. Breast reconstruction is increasingly being undertaken for selected patients. Radiation therapy and chemotherapy are used selectively for large, high-grade sarcomas for which there is significant concern for local and distant recurrence. PMID:27542642

  4. What Is Uterine Sarcoma?

    MedlinePlus

    ... supporting tissues of the uterus (womb). About the uterus The uterus is a hollow organ, about the ... a baby out during childbirth. Cancers of the uterus and endometrium Sarcomas are cancers that start from ...

  5. Requirements management: A CSR's perspective

    NASA Technical Reports Server (NTRS)

    Thompson, Joanie

    1991-01-01

    The following subject areas are covered: customer service overview of network service request processing; Customer Service Representative (CSR) responsibility matrix; extract from a sample Memorandum of Understanding; Network Service Request Form and its instructions sample notification of receipt; and requirements management in the NASA Science Internet.

  6. General Information about Ewing Sarcoma

    MedlinePlus

    ... Research Ewing Sarcoma Treatment (PDQ®)–Patient Version General Information About Ewing Sarcoma Go to Health Professional Version ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  7. General Information About Uterine Sarcoma

    MedlinePlus

    ... Research Uterine Sarcoma Treatment (PDQ®)–Patient Version General Information About Uterine Sarcoma Go to Health Professional Version ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  8. Identification of a Csr system in Serratia marcescens 2170.

    PubMed

    Ito, Manabu; Nomura, Kazuki; Sugimoto, Hayuki; Watanabe, Takeshi; Suzuki, Kazushi

    2014-01-01

    The carbon storage regulator (Csr) global regulatory system is conserved in many eubacteria and coordinates the expression of various genes that facilitate adaptation during the major physiological growth phase. The Csr system in Escherichia coli comprises an RNA-binding protein, CsrA; small non-coding RNAs, CsrB and CsrC; and a decay factor for small RNAs, CsrD. In this study, we identified the Csr system in Serratia marcescens 2170. S. marcescens CsrA was 97% identical to E. coli CsrA. CsrB and CsrC RNAs had typical stem-loop structures, including a GGA motif that is the CsrA binding site. CsrD was composed of N-terminal two times transmembrane region and HAMP-like, GGDEF, and EAL domains. Overexpression of S. marcescens csr genes complemented the phenotype of E. coli csr mutants. S. marcescens CsrD affected the decay of CsrB and CsrC RNAs in E. coli. These results suggest that the Csr system in S. marcescens is composed of an RNA-binding protein, two Csr small RNAs, and a decay factor for Csr small RNAs.

  9. Sarcomas and pharmacogenetics.

    PubMed

    Biason, Paola; Toffoli, Giuseppe

    2005-09-01

    Sarcomas are a heterogeneous group of tumors, requiring different chemotherapeutic approaches. Recently, several regimens for metastatic tumors were evaluated with respect to the different responses to conventional chemotherapy of the various histologic subtypes of sarcomas. The impact of pharmacogenetics in the progress of chemotherapy appears to be crucial in defining the clinical response to many drugs, such as anthracycline or alkylating agents, that are widely used in treatment regimens for soft tissue sarcomas (STS) or sarcomas of the bone. Polymorphisms of metabolizing enzymes (e.g., cytochrome P450 and glutathione-S-transferase), transporter proteins (reduced folate carrier and P-glycoprotein) or target proteins (thymidylate synthase, methylenetetrahydrofolate reductase, dihydrofolate reductase, and c-KIT) may be responsible for an altered clinical outcome, in terms of both response and toxicity. The administration of new chemotherapeutic agents, such as imatinib for gastrointestinal tumors (GIST), requires the study of genetic polymorphisms possibly affecting the integrity of the target (c-KIT), which may provide valid information regarding possible developments of therapy. For STS and sarcoma of the bone, the genetic markers, which could be unambiguously predictive of the phenotypic profile of patients, are as yet undetermined.

  10. Primary pleuropulmonary synovial sarcoma.

    PubMed

    Mirzoyan, Michael; Muslimani, Ala'a; Setrakian, Sebouh; Swedeh, Mohamed; Daw, Hamed A

    2008-09-01

    Pleuropulmonary synovial sarcoma (PPSS) is increasingly recognized as a subtype of sarcoma because of the recent identification of a distinctive chromosomal translocation specific to synovial sarcoma. Soft-tissue synovial sarcoma is far more common than PPSS and typically develops in para-articular locations of the extremities, affects young and middle-aged adults, with no difference in distribution between the sexes, and has well-documented radiologic manifestations. Pleuropulmonary synovial sarcoma can arise in the chest wall, heart, mediastinum, pleura, or lung, and it shares patient demographics and several imaging features with its soft-tissue counterpart. Patients present with a cough, chest pain, or dyspnea. On chest radiographs, PPSS typically appears as a sharply marginated mass with uniform opacity, based in the pleura or in the lung, and often accompanied by an ipsilateral pleural effusion. Computed tomographic images show a well-circumscribed, heterogeneously enhanced lesion without associated involvement of bone and without calcifications (except in the case of a chest wall primary tumor). Magnetic resonance imaging provides superior demonstration of nodular soft tissue and multilocular fluid-filled internal components of PPSS, in addition to peripheral rim enhancement after the intravenous administration of a gadoliniumbased contrast material such as gadopentetate dimeglumine. Current treatment consists of surgical resection followed by chemotherapy, radiation therapy, or both. PMID:18824448

  11. Primary Intracranial Synovial Sarcoma

    PubMed Central

    Li, Luyuan; Sinson, Grant; Mueller, Wade

    2016-01-01

    Background. Synovial sarcoma is an aggressive soft tissue sarcoma with uncertain histological origin. The pathology frequently presents as a localized disease, especially near large joints around the knee and thigh. Intracranial disease, which is rare, has been reported as metastasis from synovial sarcoma. We report a case with no obvious primary extracranial pathology, suggesting primary intracranial disease; this has not been reported in the literature. Case Description. A 21-year-old male, with a prior right skull lesion resection for atypical spindle cell neoplasm, presented with headaches, gait instability, left arm weakness, and left homonymous hemianopsia. CT of head demonstrated a right parietal hemorrhagic lesion with mass effect, requiring surgical decompression. Histopathology revealed synovial sarcoma. FISH analysis noted the existence of the t(X;18)(p11.2;q11.2) chromosomal translocation. PET scan did not show other metastatic disease. He underwent stereotactic radiotherapy and adjuvant chemotherapy. At 2-year follow-up, he remained nonfocal without recurrence. Conclusion. We report the first known case of primary intracranial synovial sarcoma. Moreover, we stress that intracranial lesions may have a tendency for hemorrhage, requiring urgent lifesaving decompression. PMID:27247811

  12. Primary Intracranial Synovial Sarcoma.

    PubMed

    Patel, Mohit; Li, Luyuan; Nguyen, Ha Son; Doan, Ninh; Sinson, Grant; Mueller, Wade

    2016-01-01

    Background. Synovial sarcoma is an aggressive soft tissue sarcoma with uncertain histological origin. The pathology frequently presents as a localized disease, especially near large joints around the knee and thigh. Intracranial disease, which is rare, has been reported as metastasis from synovial sarcoma. We report a case with no obvious primary extracranial pathology, suggesting primary intracranial disease; this has not been reported in the literature. Case Description. A 21-year-old male, with a prior right skull lesion resection for atypical spindle cell neoplasm, presented with headaches, gait instability, left arm weakness, and left homonymous hemianopsia. CT of head demonstrated a right parietal hemorrhagic lesion with mass effect, requiring surgical decompression. Histopathology revealed synovial sarcoma. FISH analysis noted the existence of the t(X;18)(p11.2;q11.2) chromosomal translocation. PET scan did not show other metastatic disease. He underwent stereotactic radiotherapy and adjuvant chemotherapy. At 2-year follow-up, he remained nonfocal without recurrence. Conclusion. We report the first known case of primary intracranial synovial sarcoma. Moreover, we stress that intracranial lesions may have a tendency for hemorrhage, requiring urgent lifesaving decompression. PMID:27247811

  13. Multicentric myofibroblastic sarcoma

    PubMed Central

    Wechalekar, Mihir Dilip; Ayres, Oliver; Farshid, Gelareh; Clayer, Mark; Cleland, Leslie G

    2014-01-01

    We report a case of synchronous, multicentric low-grade myofibroblastic sarcoma presenting in a 62-year-old man. He initially presented with inflammatory symmetric polyarthritis and adhesive capsulitis of his shoulder and hips bilaterally and did not respond to a trial of disease modifying antirheumatic drugs. Over a period of several years he developed progressive restriction of both knees and nodules on his hands, both knees and back. A biopsy of the nodule on his back was inconclusive and subsequent biopsies on his left and then right knee revealed a spindle cell neoplasm with an infiltrative growth pattern, mitotic figures, positive immunostaining for smooth muscle actin and focal myxoid change consistent with myofibroblastic sarcoma. While myofibroblastic sarcoma has been known to metastasise, to our knowledge, a multifocal presentation of this tumour has not been described previously. PMID:25368122

  14. [Extraskeletal Ewing's sarcoma].

    PubMed

    Baram, J; Tichler, T; Nass, D; Brenner, H J

    1992-01-01

    5 patients diagnosed as having extraskeletal Ewing's sarcoma have been referred to our adult oncology unit since 1980. All were men, ranging in age from 18-57 (mean 32 years). The primary tumor was located on the trunk in 4 and in an extremity in 1. Wide tumor excision was feasible in only 2. 3 died within 27 months and 2 are alive, 13 and 67 months, respectively, following diagnosis. This study demonstrates the highly aggressive nature of extraskeletal Ewing's sarcoma and the need for early diagnosis and efficient chemotherapy.

  15. CSR Gravity Field Data Products

    NASA Astrophysics Data System (ADS)

    Bettadpur, Srinivas

    2014-05-01

    The joint NASA/DLR GRACE mission has successfully operated for nearly 12 years, and has provided a remarkable record of global mass flux due to a large variety of geophysical and climate processes at various spatio-temporal scales. The University of Texas Center for Space Research (CSR) hosts the mission PI, and is responsible for delivery of operational (presently denoted as Release-05 or RL05) gravity field data products. In addition, CSR generates and distributes a variety of other gravity field data products, including products generated from the use of satellite laser ranging data. This poster will provide an overview of all these data products, their relative quality, potential applications, and future plans for their development and delivery.

  16. Electron cooling experiments in CSR

    NASA Astrophysics Data System (ADS)

    Yang, XiaoDong; Li, Jie; Mao, LiJun; Li, GuoHong; Ma, XiaoMing; Yan, TaiLai; Mao, RuiShi; Yang, JianCheng; Yuan, YouJin; Parkhomchuk, Vasily; Reva, Vladimir

    2011-12-01

    The six species heavy ion beam was accumulated with the help of electron cooling in the main ring of Cooler Storage Ring of Heavy Ion Research Facility in Lanzhou (HIRFL-CSR). The ion beam accumulation dependence on the parameters of cooler was investigated experimentally. The 400 MeV/u 12C6+ and 200 MeV/u 129Xe54+ were stored and cooled in the experimental ring CSRe, and the cooling force was measured in different conditions.

  17. External ear nodule revealing a disseminated Kaposi disease.

    PubMed

    Rachadi, Hanane; Zemmez, Youssef; Znati, Kaoutar; Ismaili, Nadia; Hassam, Badreddine

    2016-01-01

    Kaposi disease (KD) is an angiogenetic tumor process, characterized by its various clinical aspects. Its pathogenesis is multifactorial and it was attributed to HHV-8 infection. We report an original case of disseminated KD revealed by solitary lesion of external ear in a patient treated by corticosteroids for bullous pemphigoid. PMID:27617947

  18. Antagonistic control of the turnover pathway for the global regulatory sRNA CsrB by the CsrA and CsrD proteins

    PubMed Central

    Vakulskas, Christopher A.; Leng, Yuanyuan; Abe, Hazuki; Amaki, Takumi; Okayama, Akihiro; Babitzke, Paul; Suzuki, Kazushi; Romeo, Tony

    2016-01-01

    The widely conserved protein CsrA (carbon storage regulator A) globally regulates bacterial gene expression at the post-transcriptional level. In many species, CsrA activity is governed by untranslated sRNAs, CsrB and CsrC in Escherichia coli, which bind to multiple CsrA dimers, sequestering them from lower affinity mRNA targets. Both the synthesis and turnover of CsrB/C are regulated. Their turnover requires the housekeeping endonuclease RNase E and is activated by the presence of a preferred carbon source via the binding of EIIAGlc of the glucose transport system to the GGDEF-EAL domain protein CsrD. We demonstrate that the CsrB 3′ segment contains the features necessary for CsrD-mediated decay. RNase E cleavage in an unstructured segment located immediately upstream from the intrinsic terminator is necessary for subsequent degradation to occur. CsrA stabilizes CsrB against RNase E cleavage by binding to two canonical sites adjacent to the necessary cleavage site, while CsrD acts by overcoming CsrA-mediated protection. Our genetic, biochemical and structural studies establish a molecular framework for sRNA turnover by the CsrD-RNase E pathway. We propose that CsrD evolution was driven by the selective advantage of decoupling Csr sRNA decay from CsrA binding, connecting it instead to the availability of a preferred carbon source. PMID:27235416

  19. CSR Impedance for Non-Ultrarelativistic Beams

    SciTech Connect

    Li, Rui; Tsai, Cheng Y.

    2015-09-01

    For the analysis of the coherent synchrotron radiation (CSR)-induced microbunching gain in the low energy regime, such as when a high-brightness electron beam is transported through a low-energy merger in an energy-recovery linac (ERL) design, it is necessary to extend the CSR impedance expression in the ultrarelativistic limit to the non-ultrarelativistic regime. This paper presents our analysis of CSR impedance for general beam energies.

  20. Management of Bone Sarcoma.

    PubMed

    Gutowski, Christina J; Basu-Mallick, Atrayee; Abraham, John A

    2016-10-01

    Treatment of bone sarcoma requires careful planning and involvement of an experienced multidisciplinary team. Significant advancements in systemic therapy, radiation, and surgery in recent years have contributed to improved functional and survival outcomes for patients with these difficult tumors, and emerging technologies hold promise for further advancement. PMID:27542644

  1. Leukosis/Sarcoma Group

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leukosis/sarcoma (L/S) group of diseases designates a variety of transmissible benign and malignant neoplasms of chickens caused by members that belong to the family Retroviridae. Because the expansion of the literature on this disease, it is no longer feasible to cite all relevant publications ...

  2. Leukosis/Sarcoma Group

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leukosis/sarcoma (L/S) group of diseases designates a variety of transmissible benign and malignant neoplasms of chickens caused by members that belong to the family Retroviridae. Lymphoid leukosis has been the most common form of L/S group of diseases seen in field flocks, although myeloid leuk...

  3. Immunotherapy of Childhood Sarcomas.

    PubMed

    Roberts, Stephen S; Chou, Alexander J; Cheung, Nai-Kong V

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed.

  4. Drugs Approved for Soft Tissue Sarcoma

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Soft Tissue Sarcoma This page lists ... soft tissue sarcoma that are not listed here. Drugs Approved for Soft Tissue Sarcoma Cosmegen (Dactinomycin) Dactinomycin ...

  5. Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-07-11

    Sarcoma, Soft Tissue; Soft Tissue Sarcoma; Undifferentiated Pleomorphic Sarcoma; Leiomyosarcoma; Liposarcoma; Synovial Sarcoma; Myxofibrosarcoma; Angiosarcoma; Fibrosarcoma; Malignant Peripheral Nerve Sheath Tumor; Epithelioid Sarcoma

  6. Renal metastases from osteogenic sarcoma

    SciTech Connect

    Ayres, R.; Curry, N.S.; Gordon, L.; Bradford, B.F.

    1985-01-01

    A clinically and radiographically unsuspected ossified renal metastasis from a primary osteogenic sarcoma was identified by computed tomography (CT) and radionuclide bone scan. These imaging modalities play an important adjunctive role in the evaluation and follow-up of patients with primary osteogenic sarcoma.

  7. Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)

    ClinicalTrials.gov

    2014-04-01

    Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  8. Diagnostic Study of Tumor Characteristics in Patients With Ewing's Sarcoma

    ClinicalTrials.gov

    2013-06-20

    Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  9. Collecting and Storing Biological Samples From Patients With Ewing Sarcoma

    ClinicalTrials.gov

    2016-05-16

    Askin Tumor; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  10. Matching modes between HIRFL and CSR

    NASA Astrophysics Data System (ADS)

    Tang, J. Y.; Li, H. H.; Yuan, Y. J.

    2001-12-01

    National key scientific project "HIRFL-CSR Cooler Storage Ring" makes use of existing HIRFL as its pre-accelerator. In order to take the full capability of HIRFL, we have studied in detailed the matching modes between HIRFL and CSR. It is proposed to use two matching modes: direct matching between SFC (HIRFL injector cyclotron) and CSRm (CSR main ring), three-cascade matching of SFC, SSC (HIRFL main cyclotron) and CSRm. With these combinations, better beam transmission efficiency, better beam utilization efficiency of HIRFL-CSR accelerator complex and better operation efficiency of HIRFL can be obtained. In the first case, SSC can be used simultaneously in other purposes, either to accelerate medium energy heavy ions or to accelerate protons combined with another small cyclotron.

  11. Stable CSR in storage rings: A model

    SciTech Connect

    Sannibale, Fernando; Byrd, John M.; Loftsdottir, Agusta; Venturini, Marco; Abo-Bakr, Michael; Feikes, Jorge; Holldack, Karsten; Kuske, Peter; Wustefeld, Godehart; Hubers, Heinz-Willerm; Warnock, Robert

    2005-01-03

    A comprehensive historical view of the work done on coherent synchrotron radiation (CSR) in storage rings is given in reference [1]. Here we want just to point out that even if the issue of CSR in storage rings was already discussed over 50 years ago, it is only recently that a considerable number of observations have been reported. In fact, intense bursts of coherent synchrotron radiation with a stochastic character were measured in the terahertz frequency range, at several synchrotron light source storage rings [2-8]. It has been shown [8-11], that this bursting emission of CSR is associated with a single bunch instability, usually referred as microbunching instability (MBI), driven by the fields of the synchrotron radiation emitted by the bunch itself. Of remarkably different characteristics was the CSR emission observed at BESSY II in Berlin, when the storage ring was tuned into a special low momentum compaction mode [12, 13]. In fact, the emitted radiation was not the quasi-random bursting observed in the other machines, but a powerful and stable flux of broadband CSR in the terahertz range. This was an important result, because it experimentally demonstrated the concrete possibility of constructing a stable broadband source with extremely high power in the terahertz region. Since the publication of the first successful experiment using the ring as a CSR source [14], BESSY II has regular scheduled user s shifts dedicated to CSR experiments. At the present time, several other laboratories are investigating the possibility of a CSR mode of operation [15-17] and a design for a new ring optimized for CSR is at an advanced stage [18]. In what follows, we describe a model that first accounts for the BESSY II observations and then indicates that the special case of BESSY II is actually quite general and typical when relativistic electron storage rings are tuned for short bunches. The model provides a scheme for predicting and optimizing the performance of ring

  12. Kaposi`s sarcoma associated herpesvirus infection among female sex workers and general population women in Shanghai, China: a cross-sectional study

    PubMed Central

    2014-01-01

    Background Limited information on epidemiologic patterns of KSHV, with none focusing on heterosexual transmission, is available in mainland China. To clarify this, a cross-sectional study was conducted among a group of female sex workers (FSW) and general population women (GW) in Shanghai, China. Methods An anonymous questionnaire interview was administrated among 600 FSW and 600 GW. Blood samples were collected and tested for antibodies to KSHV, HSV-2, HIV, syphilis and HBsAg. Correlates of KSHV and HSV-2 were examined using multiple logistic regression analysis. Results None of the study participants were tested positive for HIV. The seroprevalence of KSHV, HSV-2 , HBV and syphilis was 10.0%, 52.2%, 12.3% and 10.5%, respectively for FSW, and was 11.0%, 15.3%, 9.8% and 2.8%, respectively for GW. KSHV seropositivity was not associated with syphilis and HSV-2 infection as well as sexual practices among either FSW or GW. Nevertheless, HSV-2 infection among FSW was independently associated with being ever married (OR = 1.59; 95%CI: 1.04-2.45), >5 years of prostitution (OR = 2.06; 95%CI: 1.16-3.68) and being syphilis positive (OR = 2.65; 95%CI: 1.43-4.93). HSV-2 infection among GW was independently associated with an age of >35 years (OR = 2.29; 95%CI: 1.07-4.93), having had more than 2 sex partners in the prior 12 months (OR = 6.44; 95%CI: 1.67-24.93) and being syphilis positive (OR = 3.94; 95%CI: 1.38-11.23). A gradual increase of prevalence with the prostitution time group was also detected for HSV-2 and syphilis, but not for KSHV. Conclusions KSHV is moderately and equivalently prevalent among FSW and GW. Heterosexual contact is not a predominant route for KSHV transmission among Chinese women. PMID:24498947

  13. Adoptive cell therapy for sarcoma

    PubMed Central

    Mata, Melinda; Gottschalk, Stephen

    2015-01-01

    Current therapy for sarcomas, though effective in treating local disease, is often ineffective for patients with recurrent or metastatic disease. To improve outcomes, novel approaches are needed and cell therapy has the potential to meet this need since it does not rely on the cytotoxic mechanisms of conventional therapies. The recent successes of T-cell therapies for hematological malignancies have led to renewed interest in exploring cell therapies for solid tumors such as sarcomas. In this review, we will discuss current cell therapies for sarcoma with special emphasis on genetic approaches to improve the effector function of adoptively transferred cells. PMID:25572477

  14. csrR, a Paralog and Direct Target of CsrA, Promotes Legionella pneumophila Resilience in Water

    PubMed Central

    Abbott, Zachary D.; Yakhnin, Helen; Babitzke, Paul

    2015-01-01

    ABSTRACT Critical to microbial versatility is the capacity to express the cohort of genes that increase fitness in different environments. Legionella pneumophila occupies extensive ecological space that includes diverse protists, pond water, engineered water systems, and mammalian lung macrophages. One mechanism that equips this opportunistic pathogen to adapt to fluctuating conditions is a switch between replicative and transmissive cell types that is controlled by the broadly conserved regulatory protein CsrA. A striking feature of the legionellae surveyed is that each of 14 strains encodes 4 to 7 csrA-like genes, candidate regulators of distinct fitness traits. Here we focus on the one csrA paralog (lpg1593) that, like the canonical csrA, is conserved in all 14 strains surveyed. Phenotypic analysis revealed that long-term survival in tap water is promoted by the lpg1593 locus, which we name csrR (for “CsrA-similar protein for resilience”). As predicted by its GGA motif, csrR mRNA was bound directly by the canonical CsrA protein, as judged by electromobility shift and RNA-footprinting assays. Furthermore, CsrA repressed translation of csrR mRNA in vivo, as determined by analysis of csrR-gfp reporters, csrR mRNA stability in the presence and absence of csrA expression, and mutation of the CsrA binding site identified on the csrR mRNA. Thus, CsrA not only governs the transition from replication to transmission but also represses translation of its paralog csrR when nutrients are available. We propose that, during prolonged starvation, relief of CsrA repression permits CsrR protein to coordinate L. pneumophila’s switch to a cell type that is resilient in water supplies. PMID:26060275

  15. Iatrogenic Kaposi’s sarcoma in nasal cavity: a case report

    PubMed Central

    2014-01-01

    Background Kaposi's sarcoma (KS) is an uncommon borderline vascular tumor involving mostly the cutaneous and mucosal sites of the body. Among the four distinctly clinicopathological presentations of KS, the iatrogenic form principally occurs in kidney transplant recipients receiving immunosuppressive therapy. It rarely occurs in the head and neck region as primary site or in other groups of patients under immunosuppressive therapy. Case presentation We present of the case of a patient with right nose KS. The patient had history of systemic lupus erythematosus (SLE) and was under immunosuppressive therapy. Conclusion Once we keep KS in mind, the definite diagnosis can be made using routine histological examination and immunohistochemical study despite the rarity of the disease in this site. PMID:24890473

  16. Alisertib in Treating Patients With Advanced or Metastatic Sarcoma

    ClinicalTrials.gov

    2016-02-02

    Myxofibrosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Leiomyosarcoma; Recurrent Liposarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Undifferentiated Pleomorphic Sarcoma; Stage III Soft Tissue Sarcoma; Stage IV Soft Tissue Sarcoma

  17. The cryogenic storage ring CSR.

    PubMed

    von Hahn, R; Becker, A; Berg, F; Blaum, K; Breitenfeldt, C; Fadil, H; Fellenberger, F; Froese, M; George, S; Göck, J; Grieser, M; Grussie, F; Guerin, E A; Heber, O; Herwig, P; Karthein, J; Krantz, C; Kreckel, H; Lange, M; Laux, F; Lohmann, S; Menk, S; Meyer, C; Mishra, P M; Novotný, O; O'Connor, A P; Orlov, D A; Rappaport, M L; Repnow, R; Saurabh, S; Schippers, S; Schröter, C D; Schwalm, D; Schweikhard, L; Sieber, T; Shornikov, A; Spruck, K; Sunil Kumar, S; Ullrich, J; Urbain, X; Vogel, S; Wilhelm, P; Wolf, A; Zajfman, D

    2016-06-01

    An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV. The ion-beam intensity, energy-dependent closed-orbit shifts (dispersion), and the focusing properties of the machine were studied by a system of capacitive pickups. The Schottky-noise spectrum of the stored ions revealed a broadening of the momentum distribution on a time scale of 1000 s. Photodetachment of stored anions was used in the beam lifetime measurements. The detachment rate by anion collisions with residual-gas molecules was found to be extremely low. A residual-gas density below 140 cm(-3) is derived, equivalent to a room-temperature pressure below 10(-14) mbar. Fast atomic, molecular, and cluster ion beams stored for long periods of time in a cryogenic environment will allow experiments on collision- and radiation-induced fragmentation processes of ions in known internal quantum states with merged and crossed photon and particle beams.

  18. The cryogenic storage ring CSR

    NASA Astrophysics Data System (ADS)

    von Hahn, R.; Becker, A.; Berg, F.; Blaum, K.; Breitenfeldt, C.; Fadil, H.; Fellenberger, F.; Froese, M.; George, S.; Göck, J.; Grieser, M.; Grussie, F.; Guerin, E. A.; Heber, O.; Herwig, P.; Karthein, J.; Krantz, C.; Kreckel, H.; Lange, M.; Laux, F.; Lohmann, S.; Menk, S.; Meyer, C.; Mishra, P. M.; Novotný, O.; O'Connor, A. P.; Orlov, D. A.; Rappaport, M. L.; Repnow, R.; Saurabh, S.; Schippers, S.; Schröter, C. D.; Schwalm, D.; Schweikhard, L.; Sieber, T.; Shornikov, A.; Spruck, K.; Sunil Kumar, S.; Ullrich, J.; Urbain, X.; Vogel, S.; Wilhelm, P.; Wolf, A.; Zajfman, D.

    2016-06-01

    An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV. The ion-beam intensity, energy-dependent closed-orbit shifts (dispersion), and the focusing properties of the machine were studied by a system of capacitive pickups. The Schottky-noise spectrum of the stored ions revealed a broadening of the momentum distribution on a time scale of 1000 s. Photodetachment of stored anions was used in the beam lifetime measurements. The detachment rate by anion collisions with residual-gas molecules was found to be extremely low. A residual-gas density below 140 cm-3 is derived, equivalent to a room-temperature pressure below 10-14 mbar. Fast atomic, molecular, and cluster ion beams stored for long periods of time in a cryogenic environment will allow experiments on collision- and radiation-induced fragmentation processes of ions in known internal quantum states with merged and crossed photon and particle beams.

  19. The cryogenic storage ring CSR.

    PubMed

    von Hahn, R; Becker, A; Berg, F; Blaum, K; Breitenfeldt, C; Fadil, H; Fellenberger, F; Froese, M; George, S; Göck, J; Grieser, M; Grussie, F; Guerin, E A; Heber, O; Herwig, P; Karthein, J; Krantz, C; Kreckel, H; Lange, M; Laux, F; Lohmann, S; Menk, S; Meyer, C; Mishra, P M; Novotný, O; O'Connor, A P; Orlov, D A; Rappaport, M L; Repnow, R; Saurabh, S; Schippers, S; Schröter, C D; Schwalm, D; Schweikhard, L; Sieber, T; Shornikov, A; Spruck, K; Sunil Kumar, S; Ullrich, J; Urbain, X; Vogel, S; Wilhelm, P; Wolf, A; Zajfman, D

    2016-06-01

    An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV. The ion-beam intensity, energy-dependent closed-orbit shifts (dispersion), and the focusing properties of the machine were studied by a system of capacitive pickups. The Schottky-noise spectrum of the stored ions revealed a broadening of the momentum distribution on a time scale of 1000 s. Photodetachment of stored anions was used in the beam lifetime measurements. The detachment rate by anion collisions with residual-gas molecules was found to be extremely low. A residual-gas density below 140 cm(-3) is derived, equivalent to a room-temperature pressure below 10(-14) mbar. Fast atomic, molecular, and cluster ion beams stored for long periods of time in a cryogenic environment will allow experiments on collision- and radiation-induced fragmentation processes of ions in known internal quantum states with merged and crossed photon and particle beams. PMID:27370434

  20. Circuitry linking the Csr and stringent response global regulatory systems.

    PubMed

    Edwards, Adrianne N; Patterson-Fortin, Laura M; Vakulskas, Christopher A; Mercante, Jeffrey W; Potrykus, Katarzyna; Vinella, Daniel; Camacho, Martha I; Fields, Joshua A; Thompson, Stuart A; Georgellis, Dimitris; Cashel, Michael; Babitzke, Paul; Romeo, Tony

    2011-06-01

    CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry.

  1. Circuitry Linking the Csr and Stringent Response Global Regulatory Systems

    PubMed Central

    Edwards, Adrianne N.; Patterson-Fortin, Laura M.; Vakulskas, Christopher A.; Mercante, Jeffrey W.; Potrykus, Katarzyna; Vinella, Daniel; Camacho, Martha I.; Fields, Joshua A.; Thompson, Stuart A.; Georgellis, Dimitris; Cashel, Michael; Babitzke, Paul; Romeo, Tony

    2011-01-01

    Summary CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR, and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry. PMID:21488981

  2. [Radiotherapy of adult soft tissue sarcoma].

    PubMed

    Le Péchoux, C; Moureau-Zabotto, L; Llacer, C; Ducassou, A; Sargos, P; Sunyach, M P; Thariat, J

    2016-09-01

    Incidence of soft tissue sarcoma is low and requires multidisciplinary treatment in specialized centers. The objective of this paper is to report the state of the art regarding indications and treatment techniques of main soft tissue sarcoma localisations.

  3. General Information about Adult Soft Tissue Sarcoma

    MedlinePlus

    ... Soft Tissue Sarcoma Treatment (PDQ®)–Patient Version General Information About Adult Soft Tissue Sarcoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  4. General Information about Childhood Soft Tissue Sarcoma

    MedlinePlus

    ... Soft Tissue Sarcoma Treatment (PDQ®)–Patient Version General Information About Childhood Soft Tissue Sarcoma Go to Health ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  5. Childhood Soft Tissue Sarcoma: Treatment Information

    MedlinePlus

    ... Germ Cell Tumors Kidney/Wilms Tumor Liver Cancer Neuroblastoma Osteosarcoma Rhabdomyosarcoma Skin Cancer Soft Tissue Sarcoma Thyroid ... Tumor Liver Cancer Lymphoma (Non-Hodgkin) Lymphoma (Hodgkin) Neuroblastoma Osteosarcoma Retinoblastoma Rhabdomyosarcoma Skin Cancer Soft Tissue Sarcoma ...

  6. [Radiotherapy of adult soft tissue sarcoma].

    PubMed

    Le Péchoux, C; Moureau-Zabotto, L; Llacer, C; Ducassou, A; Sargos, P; Sunyach, M P; Thariat, J

    2016-09-01

    Incidence of soft tissue sarcoma is low and requires multidisciplinary treatment in specialized centers. The objective of this paper is to report the state of the art regarding indications and treatment techniques of main soft tissue sarcoma localisations. PMID:27523415

  7. Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma

    ClinicalTrials.gov

    2014-05-07

    Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Leiomyosarcoma; Adult Malignant Fibrous Histiocytoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma

  8. Talimogene Laherparepvec and Radiation Therapy in Treating Patients With Newly Diagnosed Soft Tissue Sarcoma That Can Be Removed by Surgery

    ClinicalTrials.gov

    2016-10-04

    Leiomyosarcoma; Liposarcoma; Sarcoma Differentiation Score 2; Sarcoma Differentiation Score 3; Stage IA Soft Tissue Sarcoma; Stage IB Soft Tissue Sarcoma; Stage IIA Soft Tissue Sarcoma; Stage IIB Soft Tissue Sarcoma; Undifferentiated Pleomorphic Sarcoma

  9. Implementation: Measuring and Explaining the Fidelity of CSR Implementation

    ERIC Educational Resources Information Center

    Kurki, Anja; Boyle, Andrea; Aladjem, Daniel K.

    2006-01-01

    Comprehensive school reform (CSR) is only as effective as its implementation. By using data collected for the National Longitudinal Evaluation of Comprehensive School Reform (NLECSR), this article explores the factors that predict CSR model implementation and the ways that CSR model implementation varies. We found little difference in the fidelity…

  10. Status of the HIRFL-CSR complex

    NASA Astrophysics Data System (ADS)

    Yuan, Y. J.; Yang, J. C.; Xia, J. W.; Yuan, P.; Qiao, W. M.; Gao, D. Q.; Xiao, G. Q.; Zhao, H. W.; Xu, H. S.; Song, M. T.; Yang, X. D.; Cai, X. H.; Ma, L. Z.; Yang, X. T.; Man, K. T.; He, Y.; Zhou, Z. Z.; Zhang, J. H.; Xu, Z.; Liu, Y.; Mao, R. S.; Zhang, W.; Xie, D. Z.; Sun, L. T.; Yang, Y. Q.; Yin, D. Y.; Li, P.; Li, J.; Shi, J.; Chai, W. P.; Wei, B. W.; Zhan, W. L.

    2013-12-01

    The HIRFL-CSR, as an upgrade of the HIRFL, has been put into operation since 2008. Together with a series of improvements of injector cyclotrons, the HIRFL is in a very good state and can provide all ion species from proton to uranium with energy variable from ion source energy to 1 GeV/u (A/q = 2). Present status of the HIRFL-CSR complex is given. Main features realized during the commissioning and operation are described in detail. The progress on physics experiments and cancer therapy are also presented.

  11. HIRFL-CSR electron cooler commissioning

    NASA Astrophysics Data System (ADS)

    Bocharov, V.; Bubley, A.; Boimelstein, Yu.; Veremeenko, V.; Voskoboinikov, V.; Goncharov, A.; Grishanov, V.; Dranichnikov, A.; Evtushenko, Yu.; Zapiatkin, N.; Zakhvatkin, M.; Ivanov, A.; Kokoulin, V.; Kolmogorov, V.; Kondaurov, M.; Konstantinov, E.; Konstantinov, S.; Krainov, G.; Kriuchkov, A.; Kuper, E.; Medvedko, A.; Mironenko, L.; Panasiuk, V.; Parkhomchuk, V.; Petrov, S.; Reva, V.; Svischev, P.; Skarbo, B.; Smirnov, B.; Sukhina, B.; Tiunov, M.; Shirokov, V.; Shrainer, K.; Yang, X. D.; Zhao, H. W.; Wang, Z. X.; Li, J.; Zhang, J. H.; Zhang, W.; Yan, H. B.; Yan, H. H.; Xia, G. X.

    2004-10-01

    HIRFL-CSR, a new ion cooler-storage ring, is under construction at IMP. It is equipped with two electron cooling devices. The technical parameters of the project will be reviewed briefly. The HIRFL-CSR cooler could be a new generation cooler with some unique features such as a new electron gun capable to produce hollow electron beam, electrostatic bending plates and a new structure of solenoid coils at the cooling section. The commissioning of the first cooler with electron beam at IMP was completed. The second cooler with energy 300 keV is under final assembling.

  12. Synovial Sarcoma With Myoid Differentiation.

    PubMed

    Qassid, Omar; Ali, Ahmed; Thway, Khin

    2016-09-01

    Synovial sarcoma is a malignant mesenchymal tumor with variable epithelial differentiation, which is defined by the presence of a specific t(X;18)(p11.2;q11.2) chromosomal translocation that generates SS18-SSX fusion oncogenes. Synovial sarcoma typically arises within extremity deep soft tissue (particularly around large joints) of young adults, but has been shown to occur at almost any location. When it arises in more unusual sites, such as the abdomen, it can present a significant diagnostic challenge. We describe a case of intraabdominal monophasic synovial sarcoma that immunohistochemically showed strong expression of smooth muscle actin and calponin but only very scanty cytokeratin, and which showed morphologic and immunohistochemical overlap with other spindle cell neoplasms that can arise at this site, such as gastrointestinal stromal tumor and myofibrosarcoma. As correct diagnosis is of clinical and prognostic importance, surgical pathologists should be aware of the potential for synovial sarcoma to occur at a variety of anatomic sites and of its spectrum of immunoreactivity. Synovial sarcoma should be in the differential diagnosis of spindle cell neoplasms with myoid differentiation that do not fall into any definite tumor category, for which there should be a relatively low threshold for performing fluorescence in situ hybridization or reverse transcription-polymerase chain reaction to assess for the specific SS18 gene rearrangement or SS18-SSX fusion transcripts, which remain the diagnostic gold standard. PMID:27106779

  13. [Unusual lung localization of histiocytic sarcoma].

    PubMed

    Aichaouia, C; Daboussi, S; Haddaoui, A; Moatemri, Z; Farah, S; Khadraoui, M; Bouzaiene, A; Cheikh, R

    2012-10-01

    Histiocytic sarcoma, proliferation araising from immunoregulatory effector system cells, is a very rare and recently recognised tumor. Diagnosis is based on immunohistochemistry and molecular genetic techniques, which allow to distinguish histiocytic sarcoma from lymphocytic proliferation, such as non-Hodgkin's. We report this rare case of multivisceral histiocytic sarcoma revealed by lung localization and for which the evolution was fatal.

  14. Granulocytic sarcoma masquerading as Ewing's sarcoma: a diagnostic dilemma.

    PubMed

    Haresh, Kunhi Parambath; Joshi, Nikhil; Gupta, Chaitali; Prabhakar, Ramachandran; Sharma, Daya Nand; Julka, Pramod Kumar; Rath, Goura Kishor

    2008-01-01

    An eleven-year-old boy presented with a swelling in his left elbow. Radiologically the features were that of an Ewing's sarcoma involving the ulna. Histopathology showed small round cell tumor strongly positive for Monoclonal Imperial Cancer research fund 2 (MIC2) antigen. Similar cells in the bone marrow were involved with MIC2 positivity. The patient developed skin lesions, which on biopsy were found to be chloromas. The initial biopsies were reevaluated with special stains revealing granulocytic sarcomas in acute myeloid leukemia masquerading as Ewing's due to its MIC2 positivity. The possibility of myeloid neoplasms should be considered routinely with known MIC2 positive round cell tumors. PMID:18923208

  15. SYNOVIAL SARCOMA OF THE LARYNX.

    PubMed

    Javed, Nabila; Iqbal, Javed

    2015-01-01

    Synovial sarcoma is a mesenchymal spindle cell tumour that displays variable epithelial differentiation. It most commonly occurs in lower extremities. Head and neck is a rare site for synovial sarcoma accounting for less than 10%. Larynx is an extremely rare site and only 16 cases with laryngeal location have been reported. Immunohistochemistry is important for correct diagnosis. Surgical excision of the tumour with clear margins and local radiotherapy is effective in local control. Chemotherapy is indicated in the presence of distant metastasis. Case of a 16 years old female is presented with hoarseness of voice and mass in supraglottic region. Lateral pharangotomy and excision of mass revealed synovial sarcoma. She had been treated with adjuvant radiotherapy in September 2012. She was fine and coming for regular follow up.

  16. Testicular myeloid sarcoma: case report

    PubMed Central

    Zago, Luzia Beatriz Ribeiro; Ladeia, Antônio Alexandre Lisbôa; Etchebehere, Renata Margarida; de Oliveira, Leonardo Rodrigues

    2013-01-01

    Myeloid sarcomas are extramedullary solid tumors composed of immature granulocytic precursor cells. In association with acute myeloid leukemia and other myeloproliferative disorders, they may arise concurrently with compromised bone marrow related to acute myeloid leukemia, as a relapsed presentation, or occur as the first manifestation. The testicles are considered to be an uncommon site for myeloid sarcomas. No therapeutic strategy has been defined as best but may include chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation. This study reports the evolution of a patient with testicular myeloid sarcoma as the first manifestation of acute myeloid leukemia. The patient initially refused medical treatment and died five months after the clinical condition started. PMID:23580888

  17. CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas.

    PubMed

    Yoshida, Akihiko; Goto, Keisuke; Kodaira, Makoto; Kobayashi, Eisuke; Kawamoto, Hiroshi; Mori, Taisuke; Yoshimoto, Seiichi; Endo, Otone; Kodama, Narihito; Kushima, Ryoji; Hiraoka, Nobuyoshi; Motoi, Toru; Kawai, Akira

    2016-03-01

    The CIC gene rearrangement exists in a subset of small round cell sarcomas. As the nosologic relationship of these sarcomas to Ewing sarcomas remains undetermined, we examined 20 CIC-rearranged sarcomas to compare their clinicopathologic features with those of Ewing sarcomas. The CIC-rearranged sarcomas were from a group of 14 men and 6 women with a median age of 24.5 years. The primary tumor sites included the limbs, trunk wall, internal trunk, lung, cerebrum, and pharynx. A comparison of the demographic and clinical characteristics of the 20 patients with CIC-rearranged sarcomas with those of the 53 near-consecutive patients with EWSR1-rarranged Ewing sarcomas showed that there were no differences with respect to their ages and sexes. Although none of the CIC-rearranged sarcomas arose in the bone, 40% of the Ewing sarcomas primarily affected the skeleton. The overall survival of patients with Ewing sarcomas was significantly better than that for patients with CIC-rearranged sarcomas. A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas. Distinguishing immunohistochemical features included heterogenous CD99 reactivity, nuclear WT1 expression, and calretinin expression in the CIC-rearranged sarcomas and NKX2.2 expression in the Ewing sarcomas. CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors.

  18. Activation of DNA Damage Response Induced by the Kaposi’s Sarcoma-Associated Herpes Virus

    PubMed Central

    Di Domenico, Enea Gino; Toma, Luigi; Bordignon, Valentina; Trento, Elisabetta; D’Agosto, Giovanna; Cordiali-Fei, Paola; Ensoli, Fabrizio

    2016-01-01

    The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman’s disease. KSHV is prevalent in areas such as sub-Saharan Africa and the Mediterranean region presenting distinct genotypes, which appear to be associated with differences in disease manifestation, according to geographical areas. In infected cells, KSHV persists in a latent episomal form. However, in a limited number of cells, it undergoes spontaneous lytic reactivation to ensure the production of new virions. During both the latent and the lytic cycle, KSHV is programmed to express genes which selectively modulate the DNA damage response (DDR) through the activation of the ataxia telangiectasia mutated (ATM) pathway and by phosphorylating factors associated with the DDR, including the major tumor suppressor protein p53 tumor suppressor p53. This review will focus on the interplay between the KSHV and the DDR response pathway throughout the viral lifecycle, exploring the putative molecular mechanism/s that may contribute to malignant transformation of host cells. PMID:27258263

  19. Mast cell sarcoma: clinical management.

    PubMed

    Weiler, Catherine R; Butterfield, Joseph

    2014-05-01

    Mast cell sarcoma is a disorder that results in abnormal mast cells as identified by morphology, special stains, and in some publications, c-kit mutation analysis. It affects animal species such as canines more commonly than humans. In humans it is a very rare condition, with variable clinical presentation. There is no standard therapy for the disorder. It can affect any age group. It is occasionally associated with systemic mastocytosis and/or urticaria pigmentosa. The prognosis of mast cell sarcoma in published literature is very poor in humans.

  20. Extra osseous primary Ewing's sarcoma.

    PubMed

    Ali, Syed Asad; Muhammad, Agha Taj; Soomro, Abdul Ghani; Siddiqui, Akmal Jamal

    2010-01-01

    The case of 20 years old boy with an extra osseous Ewing's sarcoma is described. He was initially diagnosed as a case of infiltrative malignant tumour of left suprarenal gland on the basis of preoperative workup but postoperative biopsy of surgically excised specimen confirmed Extra-osseous Ewing's Sarcoma (EES) suprarenal gland with no evidence of malignancy on skeletal scintiscan, bone marrow aspirate and histopathology Suprarenal location of primary EES is unknown and probably has not been reported in literature. We report a unique case of EES.

  1. Prognostic features of renal sarcomas (Review)

    PubMed Central

    ÖZTÜRK, HAKAN

    2015-01-01

    The aim of the present review was to evaluate the prognostic features of primary sarcomas of the kidney. A literature review was conducted using a number of databases, including Medline (PubMed) and Scopus, for studies published between January 1992 and December 2013. Of the studies published in English, those describing the prognostic features of primary sarcomas of the kidney were recorded. The electronic search was limited to the following keywords: Sarcoma, renal sarcoma, prognosis, diagnosis, immunohistochemistry, genetic and survey. Subsequent to the search, no review articles and/or meta-analyses associated with the prognosis of primary sarcomas of the kidney were identified. In total, 31 studies, which consisted of case studies, case series and studies concerned with the overall prognosis of urological soft-tissue sarcomas, were reviewed. Primary sarcoma of the kidney has a poor prognosis compared with other sarcomas of the urogenital system. In addition to the surgical excision of renal sarcomas, pathological, molecular and genetic prognostic factors are also considered. Due to the small number of cases, previous studies have not randomized the prognostic features of primary sarcomas of the kidney. The elucidation of the so-called ‘chaotic’ genetic and molecular basis of renal sarcomas will help to predict patient prognoses. Surgical excision is the most significant parameter for determining the prognosis of sarcomas of the kidney. However, sarcomas also exhibit prognostic features that are based upon pathological, genetic and molecular factors. The present review suggests that additional factors may be important in predicting the prognosis of patients with renal sarcomas, and that clinicians should plan treatment and follow-up regimens according to these factors. PMID:25663853

  2. Gemcitabine Hydrochloride, Docetaxel, and Radiation Therapy in Treating Patients With Uterine Sarcoma That Has Been Removed By Surgery

    ClinicalTrials.gov

    2015-01-16

    Stage IA Uterine Sarcoma; Stage IB Uterine Sarcoma; Stage IC Uterine Sarcoma; Stage IIA Uterine Sarcoma; Stage IIB Uterine Sarcoma; Stage IIIA Uterine Sarcoma; Stage IIIB Uterine Sarcoma; Stage IIIC Uterine Sarcoma; Stage IVA Uterine Sarcoma; Stage IVB Uterine Sarcoma; Uterine Corpus Leiomyosarcoma

  3. Molecular Approaches to Sarcoma Therapy

    PubMed Central

    Olsen, R. J.; Tarantolo, S. R.

    2002-01-01

    Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed. PMID:18521343

  4. Functional characterization of Kaposi's sarcoma-associated herpesvirus small capsid protein by bacterial artificial chromosome-based mutagenesis

    SciTech Connect

    Sathish, Narayanan; Yuan Yan

    2010-11-25

    A systematic investigation of interactions amongst KSHV capsid proteins was undertaken in this study to comprehend lesser known KSHV capsid assembly mechanisms. Interestingly the interaction patterns of the KSHV small capsid protein, ORF65 suggested its plausible role in viral capsid assembly pathways. Towards further understanding this, ORF65-null recombinant mutants (BAC-{Delta}65 and BAC-stop65) employing a bacterial artificial chromosome (BAC) system were generated. No significant difference was found in both overall viral gene expression and lytic DNA replication between stable monolayers of 293T-BAC36 (wild-type) and 293T-BAC-ORF65-null upon induction with 12-O-tetradecanoylphorbol-13-acetate, though the latter released 30-fold fewer virions to the medium than 293T-BAC36 cells. Sedimentation profiles of capsid proteins of ORF65-null recombinant mutants were non-reflective of their organization into the KSHV capsids and were also undetectable in cytoplasmic extracts compared to noticeable levels in nuclear extracts. These observations collectively suggested the pivotal role of ORF65 in the KSHV capsid assembly processes.

  5. Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

    ClinicalTrials.gov

    2016-10-31

    High Grade Sarcoma; Metastatic Leiomyosarcoma; Metastatic Malignant Peripheral Nerve Sheath Tumor; Metastatic Synovial Sarcoma; Metastatic Undifferentiated Pleomorphic Sarcoma; Myxofibrosarcoma; Recurrent Leiomyosarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Synovial Sarcoma; Recurrent Undifferentiated Pleomorphic Sarcoma; Uterine Corpus Leiomyosarcoma

  6. HIRFL-CSR power supply system

    NASA Astrophysics Data System (ADS)

    Gao, Daqing; Zhou, Zhongzu; Chen, Youxin; Wu, Rong; Shangguan, Jingbin; Bai, Zhen

    2001-12-01

    There are more than 200 power supplies will be employed in CSR power supply system. These power supplies provide DC and pulsed exciting current for all magnets in main ring (CSRm), experiment ring (CSRe), injection line of CSRm and RIB line. Six small-scale prototypes have been designed and made before formal manufacture. One thyristor rectifier pulsed converter was delivered to Lanzhou in January and all measurement has been finished in April. The result is satisfied.

  7. What's New in Soft Tissue Sarcomas Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for soft tissue sarcoma What`s new in soft tissue sarcoma research and treatment? Research ... develop. This information is already being applied to new tests to diagnose and classify sarcomas. This is ...

  8. HIRFL-CSR internal cluster target

    NASA Astrophysics Data System (ADS)

    Shao, Caojie; Lu, Rongchun; Cai, Xiaohong; Yu, Deyang; Ruan, Fangfang; Xue, Yingli; Zhang, Jianming; Torpokov, D. K.; Nikolenko, D.

    2013-12-01

    Since HIRFL-CSR internal cluster target was built, it has played a key role in in-ring experiments at HIRFL-CSR. So far it have been operated with five gas species as targets for scattering experiments, i.e. hydrogen, nitrogen, argon, neon, and krypton. The obtained highest thickness for hydrogen target amounts up to 1012 atoms/cm2, and those of other targets are larger than 1013 atoms/cm2 with the background pressure of 10-11 mbar in CSR. The target thickness can be varied by regulating the nozzle temperature and pressure of the inlet gas. The first online internal target experiment dedicated to investigate radioactive electron capture (REC) process with Xe54+ ions colliding with the nitrogen target demonstrated the stability and reliability of the internal target system. In addition, hydrogen and krypton were also tested online in recent experiments, which indicate the target system can meet experimental requirements for the thickness of target, pressure in scattering chamber, and long-term stability.

  9. Study of CSR Effects in the Jefferson Laboratory FEL Driver

    SciTech Connect

    Hall, C. C.; Biedron, S.; Burleson, Theodore A.; Milton, Stephen V.; Morin, Auralee L.; Benson, Stephen V.; Douglas, David R.; Evtushenko, Pavel E.; Hannon, Fay E.; Li, Rui; Tennant, Christopher D.; Zhang, Shukui; Carlsten, Bruce E.; Lewellen, John W.

    2013-08-01

    In a recent experiment conducted on the Jefferson Laboratory IR FEL driver the effects of Coherent Synchrotron Radiation (CSR) on beam quality were studied. The primary goal of this work was to explore CSR output and effect on the beam with variation of the bunch compression in the IR chicane. This experiment also provides a valuable opportunity to benchmark existing CSR models in a system that may not be fully represented by a 1-D CSR model. Here we present results from this experiment and compare to initial simulations of CSR in the magnetic compression chicane of the machine. Finally, we touch upon the possibility for CSR induced microbunching gain in the magnetic compression chicane, and show that parameters in the machine are such that it should be thoroughly damped.

  10. Diagnosis and Management of Hereditary Sarcoma.

    PubMed

    Thomas, David M; Ballinger, Mandy L

    2016-01-01

    Sarcomas are rare and heterogeneous diseases that affect a younger population than most epithelial cancers. Epidemiologic studies suggest a strong genetic component to sarcomas, and many familial cancer syndromes have been described, in which sarcomas are a feature. The best known of these are the Li-Fraumeni and retinoblastoma syndromes, study of which has been pivotal to elucidating the molecular basis for the cell response to DNA damage and the cell division. Although much has been learnt about cancer biology from the study of sarcoma families, in general clinical management of increased sarcoma risk has lagged behind other cancer predisposition syndromes. With the advent of genomic tools for genetic testing, it is likely that a substantial fraction of sarcoma patients will be identified as carriers of known risk alleles. The translation of this knowledge into effective risk management programs and cancer treatments will be essential to changes in routine clinical practice. PMID:27075354

  11. Radiation-induced sarcoma of the thyroid

    SciTech Connect

    Griem, K.L.; Robb, P.K.; Caldarelli, D.D.; Templeton, A.C. )

    1989-08-01

    A 23-year-old white man presented with a thyroid mass 12 years after receiving high-dose radiotherapy for a T2 and N1 lymphoepithelioma of the nasopharynx. Following subtotal thyroidectomy, a histopathologic examination revealed liposarcoma of the thyroid gland. The relationship between sarcomas and irradiation is described and Cahan and colleagues' criteria for radiation-induced sarcomas are reviewed. To our knowledge, we are presenting the first such case of a radiation-induced sarcoma of the thyroid gland.

  12. [Breast hematoma masking a sarcoma].

    PubMed

    Relea Sarabia, A; Bahamonde Cabria, S; González Rebollo, M; Encinas Gaspar, M B

    2015-01-01

    Sarcomas account for less than 1% of malignant breast tumors. We present the case of a sarcoma (malignant fibrous histiocytoma) of the breast that debuted as a lump. The patient associated the lump with trauma, and the clinical, sonographic, and cytological findings were suggestive of a hematoma. The lump grew rapidly, and the follow-up sonogram one month later clearly revealed hypervascular solid poles. This atypical presentation is useful for reviewing the management of lesions suggestive of hematomas, which are often associated with nonspecific findings and occasionally with signs that raise suspicion of malignancy. The emergence of what appears to be a hematoma in the breast, even when accompanied by a history of trauma or a tendency toward bleeding, calls for prudence: very short-term follow-up and biopsy, even excisional biopsy, are recommended if the lesion does not evolve like a hematoma. PMID:26160042

  13. Ewing's sarcoma of proximal humeral epiphysis.

    PubMed

    Esmaili, Heydar Ali; Niknejad, Mohammad Taghi; Mohajeri, Shiva

    2015-02-01

    Ewing's sarcoma is one of the most common primary bone tumors of childhood. The tumor is almost always metaphyseal or diaphyseal, within long bones. In children, lesions of the epiphysis are often benign, with the most common diagnosis being chondroblastoma. Rarely, 1%-2% of Ewing sarcomas may involve epiphysis. We present a case of Ewing's sarcoma of the proximal humeral epiphysis in a 13-year-old boy. This case adds to previously reported cases of epiphyseal Ewing sarcoma and suggests that the diagnosis should be considered for pediatric epiphyseal lesions. PMID:25644805

  14. Ewing sarcoma: a chronicle of molecular pathogenesis.

    PubMed

    Kim, Sang Kyum; Park, Yong-Koo

    2016-09-01

    Sarcomas have traditionally been classified according to their chromosomal alterations regardless of whether they accompany simple or complex genetic changes. Ewing sarcoma, a classic small round cell bone tumor, is a well-known mesenchymal malignancy that results from simple sarcoma-specific genetic alterations. The genetic alterations are translocations between genes of the TET/FET family (TLS/FUS, EWSR1, and TAF15) and genes of the E26 transformation-specific (ETS) family. In this review, we intend to summarize a chronicle of molecular findings of Ewing sarcoma including recent advances and explain resultant molecular pathogenesis. PMID:27246176

  15. Primary pleuropulmonary synovial sarcoma: a case report.

    PubMed

    Yuan, Lianfang; Guan, Zhiyu; Dai, Xuan; Xu, Jie

    2015-01-01

    Pleuropulmonary synovial sarcoma (PPSS) is an extremely rare malignant tumor, which is increasingly recognized as a subtype of sarcoma with a distinctive chromosomal translocation specific to synovial sarcoma. It is often presents like any thoracic tumor with symptoms such as chest pain or cough. Here we report a case of PPSS in a 49-year-old woman presenting with cough, shortness of breath and chest pain. And who were found upon histologic examination of the resection specimen to have cystic primary pleuropulmonary synovial sarcoma. PMID:26823907

  16. [Molecular biology for sarcoma: useful or necessary?].

    PubMed

    Neuville, Agnès; Coindre, Jean-Michel; Chibon, Frédéric

    2015-01-01

    Sarcomas are a heterogeneous group of tumors. Their diagnosis is based on morphology and immunohistochemical profile, with categories of tumors according to the type of tissue that they resemble. Nevertheless, for several tumors, cellular origin is unknown. Molecular analysis performed in recent years allowed, combining histophenotype and genomics, better classifying such sarcomas, individualizing new entities and grouping some tumors. Simple and recurrent genetic alterations, such as translocation, mutation, amplification, can be identified in one of two sarcomas and appear as new diagnostic markers. Their identification in specialized laboratories in molecular pathology of sarcomas is often useful and sometimes necessary for a good diagnosis, leading to a heavy and multidisciplinary multi-step treatment.

  17. Synovial Sarcoma Mimicking Myositis Ossificans

    PubMed Central

    Erkut, Adem; Guvercin, Yılmaz; Bedir, Recep

    2016-01-01

    A calcification mass was incidentally found in the soft tissue of a patient who had a history of trauma to the extremity during examination. The patient had no symptom. The pathological analysis of the mass revealed it was an early-phase synovial sarcoma (SS). The diagnosis was made before the onset of symptoms and proper surgical intervention was performed. Therefore, in case of a <1 cm lesion clinically suspicious of myositis ossificans, SS should be taken into consideration as a possible diagnosis.

  18. Impaired class switch recombination (CSR) in Waldenstrom macroglobulinemia (WM) despite apparently normal CSR machinery.

    PubMed

    Kriangkum, Jitra; Taylor, Brian J; Strachan, Erin; Mant, Michael J; Reiman, Tony; Belch, Andrew R; Pilarski, Linda M

    2006-04-01

    Analysis of clonotypic isotype class switching (CSR) in Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) reveals a normal initial phase of B-cell activation as determined by constitutive and inducible expression of activation-induced cytidine deaminase (AID). Switch mu (Smu) analysis shows that large deletions are not common in WM or IgM MGUS. In CD40L/IL-4-stimulated WM cultures from 2 patients, we observed clonotypic IgG exhibiting intraclonal homogeneity associated with multiple hybrid Smu/Sgamma junctions. This suggests CSR had occurred within WM cells. Nevertheless, the estimated IgG/IgM-cell frequency was relatively low (1/1600 cells). Thus, for the majority of WM B cells, CSR does not occur even when stimulated in vitro, suggesting that the WM cell is constitutively unable to or being prevented from carrying out CSR. In contrast to WM, the majority of IgM MGUS clones exhibit intraclonal heterogeneity of IgH VDJ. Furthermore, most IgM MGUS accumulate more mutations in the upstream Smu region than do WM, making them unlikely WM progenitors. These observations suggest that switch sequence analysis may identify the subset of patients with IgM MGUS who are at risk of progression to WM.

  19. HIRFL-CSR electron cooling devices

    NASA Astrophysics Data System (ADS)

    Yang, X. D.; Zhao, H. W.; Xia, J. W.; Zhan, W. L.; Wei, B. W.; Parkhomchuk, V. V.

    2001-12-01

    Electron cooling devices for HIRFL-CSR were under construction through collaboration between BINP and IMP [1]. The main parameters, design points and progress of the cooler devices will be presented. The electron motions in the gun region, adiabatic expansion region, toroid region and collector region were simulated with the help of numerical calculation. Cooling times of the typical heavy ions with injection energy were calculated with aid of the code. The prototypes of solenoid coils at the cooling section were fabricated and measured, the results show that the transverse components of the magnetic field for single coil is less than 2×10-4.

  20. Targeting epigenetic misregulation in synovial sarcoma.

    PubMed

    Waterfall, Joshua J; Meltzer, Paul S

    2012-03-20

    Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis.

  1. AZD0530 in Treating Patients With Recurrent Locally Advanced or Metastatic Soft Tissue Sarcoma

    ClinicalTrials.gov

    2015-07-02

    Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Rhabdomyosarcoma; Dermatofibrosarcoma Protuberans; Endometrial Stromal Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma

  2. 5 CFR 847.503 - Transfers from the CSR Fund.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Transfers from the CSR Fund. 847.503 Section 847.503 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE... from the CSR Fund. For elections of NAFI retirement system coverage under § 847.441, the amount...

  3. 5 CFR 847.502 - Transfers to the CSR Fund.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Transfers to the CSR Fund. 847.502 Section 847.502 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE... to the CSR Fund. For elections of CSRS or FERS coverage under § 847.411 or FERS coverage and...

  4. Regulation of bacterial virulence by Csr (Rsm) systems.

    PubMed

    Vakulskas, Christopher A; Potts, Anastasia H; Babitzke, Paul; Ahmer, Brian M M; Romeo, Tony

    2015-06-01

    Most bacterial pathogens have the remarkable ability to flourish in the external environment and in specialized host niches. This ability requires their metabolism, physiology, and virulence factors to be responsive to changes in their surroundings. It is no surprise that the underlying genetic circuitry that supports this adaptability is multilayered and exceedingly complex. Studies over the past 2 decades have established that the CsrA/RsmA proteins, global regulators of posttranscriptional gene expression, play important roles in the expression of virulence factors of numerous proteobacterial pathogens. To accomplish these tasks, CsrA binds to the 5' untranslated and/or early coding regions of mRNAs and alters translation, mRNA turnover, and/or transcript elongation. CsrA activity is regulated by noncoding small RNAs (sRNAs) that contain multiple CsrA binding sites, which permit them to sequester multiple CsrA homodimers away from mRNA targets. Environmental cues sensed by two-component signal transduction systems and other regulatory factors govern the expression of the CsrA-binding sRNAs and, ultimately, the effects of CsrA on secretion systems, surface molecules and biofilm formation, quorum sensing, motility, pigmentation, siderophore production, and phagocytic avoidance. This review presents the workings of the Csr system, the paradigm shift that it generated for understanding posttranscriptional regulation, and its roles in virulence networks of animal and plant pathogens.

  5. Regulation of Bacterial Virulence by Csr (Rsm) Systems

    PubMed Central

    Vakulskas, Christopher A.; Potts, Anastasia H.; Babitzke, Paul; Ahmer, Brian M. M.

    2015-01-01

    SUMMARY Most bacterial pathogens have the remarkable ability to flourish in the external environment and in specialized host niches. This ability requires their metabolism, physiology, and virulence factors to be responsive to changes in their surroundings. It is no surprise that the underlying genetic circuitry that supports this adaptability is multilayered and exceedingly complex. Studies over the past 2 decades have established that the CsrA/RsmA proteins, global regulators of posttranscriptional gene expression, play important roles in the expression of virulence factors of numerous proteobacterial pathogens. To accomplish these tasks, CsrA binds to the 5′ untranslated and/or early coding regions of mRNAs and alters translation, mRNA turnover, and/or transcript elongation. CsrA activity is regulated by noncoding small RNAs (sRNAs) that contain multiple CsrA binding sites, which permit them to sequester multiple CsrA homodimers away from mRNA targets. Environmental cues sensed by two-component signal transduction systems and other regulatory factors govern the expression of the CsrA-binding sRNAs and, ultimately, the effects of CsrA on secretion systems, surface molecules and biofilm formation, quorum sensing, motility, pigmentation, siderophore production, and phagocytic avoidance. This review presents the workings of the Csr system, the paradigm shift that it generated for understanding posttranscriptional regulation, and its roles in virulence networks of animal and plant pathogens. PMID:25833324

  6. Ewing Sarcoma in the Right Ventricle

    PubMed Central

    Zhao, Bihong; Thangam, Manoj; Loyalka, Pranav; Buja, L. Maximilian; Kar, Biswajit; Gregoric, Igor D.

    2016-01-01

    Ewing sarcoma is the second most prevalent malignant primary bone tumor but constitutes only a small proportion of cardiac metastases. We present a case of asymptomatic Ewing sarcoma metastatic to the right ventricle. A 36-year-old man presented for evaluation and resection of a pedunculated right ventricular cardiac tumor. Three years before, he had been diagnosed with translocation-negative Ewing sarcoma, for which he had undergone chemotherapy and amputation of the left leg below the knee. We resected the right ventricular tumor. Analysis of the resected mass supported the diagnosis of metastatic Ewing sarcoma. Postoperative transthoracic echocardiograms showed normal biventricular size and function. One year later, the patient had no recurrence of the sarcoma. In addition to discussing this case, we review the relevant medical literature. PMID:27777536

  7. [Alveolar sarcoma. Report of a case].

    PubMed

    Devisme, L; Mensier, E; Bisiau, S; Bloget, F; Gosselin, B

    1996-01-01

    Alveolar soft part sarcoma occurs mostly in the deep soft tissues. An unusual case of primary pulmonary alveolar soft part sarcoma is reported. A 39-year-old woman presented with thoracic pain revealing the tumor. The left lower lobe was surgically resected. The microscopic features of this tumor, including characteristic alveolar pattern and the PAS-positive crystals were typical of alveolar soft part sarcoma. Immunohistochemically, granular cytoplasmic reactivities were observed with antibodies against vimentin, myoglobin, methionine-enkephalin, S100 protein and neuron-specific-enolase. Electron microscopic study demonstrated numerous crystallized structures in the tumor cell cytoplasm. This is the third case of pulmonary alveolar soft part sarcoma, one arising from the pulmonary vein. The histogenesis of alveolar soft part sarcoma is still debated. Our case does not allow distinction between myogenic or neural origin of this tumor.

  8. L'atteinte osseuse dans le sarcome de Kaposi classique et agressif: à propos d'un cas

    PubMed Central

    Sbiyaa, Mouhcine; El Alaoui, Adil; El Bardai, Mohammed; Mezzani, Amine; Lahrach, Kamal; Marzouki, Amine; Boutayeb, Fawzi

    2016-01-01

    Le sarcome de Kaposi classique est une tumeur rare multifocale d'origine des cellules endothéliales vasculaires à caractère évolutif progressif et peu maligne. L'atteinte viscérale dans le sarcome de kaposi est parfois observée chez les patients VIH positif par contre la dissémination tumorale dans les ganglions lymphatiques viscérales dans le SK classique reste très rare. On rapporte un cas rare de sarcome de kaposi classique agressif de la main avec une évolution rapide et destructive. PMID:27347285

  9. Synovial Sarcoma Mimicking Myositis Ossificans

    PubMed Central

    Erkut, Adem; Guvercin, Yılmaz; Bedir, Recep

    2016-01-01

    A calcification mass was incidentally found in the soft tissue of a patient who had a history of trauma to the extremity during examination. The patient had no symptom. The pathological analysis of the mass revealed it was an early-phase synovial sarcoma (SS). The diagnosis was made before the onset of symptoms and proper surgical intervention was performed. Therefore, in case of a <1 cm lesion clinically suspicious of myositis ossificans, SS should be taken into consideration as a possible diagnosis. PMID:27595081

  10. Synovial Sarcoma Mimicking Myositis Ossificans.

    PubMed

    Balik, Mehmet Sabri; Erkut, Adem; Guvercin, Yılmaz; Bedir, Recep

    2016-09-01

    A calcification mass was incidentally found in the soft tissue of a patient who had a history of trauma to the extremity during examination. The patient had no symptom. The pathological analysis of the mass revealed it was an early-phase synovial sarcoma (SS). The diagnosis was made before the onset of symptoms and proper surgical intervention was performed. Therefore, in case of a <1 cm lesion clinically suspicious of myositis ossificans, SS should be taken into consideration as a possible diagnosis. PMID:27595081

  11. Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

    ClinicalTrials.gov

    2015-12-01

    Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  12. Defining, Measuring and Supporting Success: Meeting the Challenges of Comprehensive School Reform Research. CSR Connection.

    ERIC Educational Resources Information Center

    Appelbaum, Deborah; Schwartzbeck, Terri Duggan

    Many educators believe that comprehensive school reform (CSR) holds real promise for improving schools, as many CSR programs are based in research and have documented success. However, in the past year, there has been increased emphasis on CSR programs' evidence of effectiveness and scrutiny of CSR evaluations' degree of rigor. Questions exist…

  13. Uterine sarcomas: clinical presentation and MRI features

    PubMed Central

    Santos, Pedro; Cunha, Teresa Margarida

    2015-01-01

    Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies. They comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and adenosarcoma. Compared with the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis. Due to their distinct clinical and biological behavior, the International Federation of Gynecology and Obstetrics introduced a new staging system for uterine sarcomas in 2009, categorizing uterine carcinosarcoma as a variant of endometrial carcinoma, rather than a pure sarcoma. Magnetic resonance imaging (MRI) has a developing role in the assessment of these malignancies. Features such as tumor localization, irregular or nodular margins, necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging can suggest the diagnosis and help differentiate from more common leiomyomas and endometrial carcinoma. MRI is therefore extremely useful in preoperative detection and staging and, consequently, in determination of appropriate management. This pictorial review aims to discuss the clinical features of uterine sarcomas, as well as their most common appearances and distinct characteristics in MRI. PMID:25347940

  14. Hypernucleus Production at RHIC and HIRFL-CSR Energy

    SciTech Connect

    Zhang, S.; Xu, Z.; Chen, J.H., Ma, Y.G., Tang, Z.B.

    2010-09-01

    We calculated the hypertriton production at RHIC-STAR and HIRFL-CSR acceptance, with a multi-phase transport model (AMPT) and a relativistic transport model (ART), respectively. In specific, we calculated the Strangeness Population Factor S{sub 3} = {sub {Lambda}}{sup 3}H/({sup 3}H{sub e} x {Lambda}/p) at different beam energy. Our results from AGS to RHIC energy indicated that the collision system may change from hadronic phase at AGS energies to partonic phase at RHIC energies. Our calculation at HIRFL-CSR energy supports the proposal to measure hypertriton at HIRFL-CSR.

  15. Therapeutic Angiotensin-(1-7) in Treating Patients With Metastatic Sarcoma That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2013-12-10

    Bone Cancer; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma

  16. ACCELERATORS: Timing system of HIRFL-CSR

    NASA Astrophysics Data System (ADS)

    Dong, Jin-Mei; Yuan, You-Jin; Qiao, Wei-Min; Jing, Lan; Zhang, Wei

    2009-05-01

    The national science project HIRFL-CSR has recently been officially accepted. As a cyclotron and synchrotron complex, it puts some particularly high demands on the control system. There are hundreds of pieces of equipment that need to be synchronized. An integrated timing control system is built to meet these demands. The output rate and the accuracy of the controller are 16 bit/μs. The accuracy of the time delay reaches 40 ns. The timing control system is based on a typical event distribution system, which adopts the new event generation and the distribution scheme. The scheme of the timing control system with innovation points, the architecture and the implemented method are presented in the paper.

  17. Ziv-aflibercept in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gynecologic Soft Tissue Sarcoma

    ClinicalTrials.gov

    2015-12-03

    Fallopian Tube Cancer; Female Reproductive Cancer; Ovarian Carcinosarcoma; Ovarian Sarcoma; Recurrent Ovarian Epithelial Cancer; Recurrent Uterine Sarcoma; Stage III Ovarian Epithelial Cancer; Stage III Uterine Sarcoma; Stage IV Ovarian Epithelial Cancer; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma

  18. [Grading of soft tissue and bone sarcomas].

    PubMed

    Petersen, I; Wardelmann, E

    2016-07-01

    Malignancy grading is an essential element in the classification of sarcomas. It correlates with the prognosis of the disease and the risk of metastasis. This article presents the grading schemes for soft tissue, bone and pediatric sarcomas. It summarizes the histological criteria of the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system and the Pediatric Oncology Group as well as the grading of bone tumors by the College of American Pathologists (CAP). Furthermore, the potential relevance of gene expression signatures, the complexity index in sarcoma (CINSARC) and single genetic alterations (p53, MDM2, p16, SWI/SNF, EWSR1 fusions and PAX3/PAX7-FOXO1 fusions) for the prognosis of sarcomas are discussed.

  19. [Grading of soft tissue and bone sarcomas].

    PubMed

    Petersen, I; Wardelmann, E

    2016-07-01

    Malignancy grading is an essential element in the classification of sarcomas. It correlates with the prognosis of the disease and the risk of metastasis. This article presents the grading schemes for soft tissue, bone and pediatric sarcomas. It summarizes the histological criteria of the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system and the Pediatric Oncology Group as well as the grading of bone tumors by the College of American Pathologists (CAP). Furthermore, the potential relevance of gene expression signatures, the complexity index in sarcoma (CINSARC) and single genetic alterations (p53, MDM2, p16, SWI/SNF, EWSR1 fusions and PAX3/PAX7-FOXO1 fusions) for the prognosis of sarcomas are discussed. PMID:27384333

  20. Penile Sarcoma: Report of a Rare Malignancy

    PubMed Central

    Kumar, Vijay; Chaturvedi, Arun; Vishnoi, Jeevan Ram; Dontula, Prashant

    2016-01-01

    Penile cancer is an uncommon malignancy. Squamous cell carcinoma constitutes approximately 95% of all histology. Non-squamous malignancies are rare in penis. Sarcomas of penis are rarer among them. Spindle cell sarcoma is one of the extremely rare sarcoma of penis. To best of our knowledge, only two cases have been reported so far, one in English literature and other in Japanese. We are presenting this uncommon case of spindle cell sarcoma of penis, which was diagnosed with microscopy with its characteristic immunohistochemistry. The disease had an aggressive course with multiple recurrences in a short duration despite margin negative resection. Disease responded poorly with the chemotherapy and patient succumbed to the disease. PMID:27630937

  1. Pulmonary Artery Intimal Sarcoma: A Case Report

    PubMed Central

    Kriz, Joseph P.; Munfakh, Nabil A.; King, Gregory S.; Carden, Juan O.

    2016-01-01

    Pulmonary artery intimal sarcomas are rare and lethal malignant tumors that typically affect larger vessels: the aorta, inferior vena cava, and pulmonary arteries. Since symptoms and imaging of pulmonary arterial intimal sarcomas mimic pulmonary thromboembolism, the differential diagnosis of a patient presenting with chest pain, dyspnea, and filling defect within the pulmonary arteries should include intimal sarcoma. Often right ventricular failure is observed due to pulmonary hypertension caused by the obstructive effect of the tumor and concomitant chronic thromboembolism. We report the case of a 72-year-old African-American male with arterial intimal sarcoma of the left and right pulmonary artery with extension through the right artery into the bronchus and right lung. PMID:27239183

  2. Soft Tissue Sarcomas and Agent Orange

    MedlinePlus

    ... survivors' benefits . Research on soft tissue sarcoma and herbicides The Health and Medicine Division (formally known as ... report " Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam " and other updates that there ...

  3. Solitary pulmonary nodule: pleuropulmonary synovial sarcoma.

    PubMed

    Ward, Robert C; Birnbaum, Ariel E; Aswad, Bassam I; Healey, Terrance T

    2014-05-01

    Pleuropulmonary synovial sarcoma (PPSS) is an extremely rare primary malignancy of the lung. We present a case of a middle-aged female with PPSS that was initially discovered as an incidental indeterminate nodule on chest radiograph. Following evaluation with computed tomography (CT), the patient went on to positron-emission tomography (PET)/CT for work-up of the solitary pulmonary nodule, which demonstrated mild FDG-avidity and no other evidence of FDG-avid disease. The patient then underwent thoracotomy and right upper lobectomy for definitive treatment. Only after evaluation of the gross pathology, histology, immunohistochemistry and cytogenetics was the diagnosis of synovial sarcoma made. Importantly, the preceding PET/CT, in addition to physical exam of the upper and lower extremities, helped exclude the more common extra-thoracic soft-tissue variety of synovial sarcoma, which frequently metastasizes to lung, carrying a worse prognosis. Discussion of synovial sarcoma and PPSS follows. PMID:24791267

  4. Sarcomas of Soft Tissue and Bone.

    PubMed

    Ferrari, Andrea; Dirksen, Uta; Bielack, Stefan

    2016-01-01

    The definition of soft tissue and bone sarcomas include a large group of several heterogeneous subtypes of mesenchymal origin that may occur at any age. Among the different sarcomas, rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma and osteosarcoma are aggressive high-grade malignancies that often arise in adolescents and young adults. Managing these malignancies in patients in this age bracket poses various clinical problems, also because different therapeutic approaches are sometimes adopted by pediatric and adult oncologists, even though they are dealing with the same condition. Cooperation between pediatric oncologists and adult medical oncologists is a key step in order to assure the best treatment to these patients, preferably through their inclusion into international clinical trials. PMID:27595362

  5. Penile Sarcoma: Report of a Rare Malignancy.

    PubMed

    Rajan, Shiv; Kumar, Vijay; Chaturvedi, Arun; Vishnoi, Jeevan Ram; Dontula, Prashant

    2016-07-01

    Penile cancer is an uncommon malignancy. Squamous cell carcinoma constitutes approximately 95% of all histology. Non-squamous malignancies are rare in penis. Sarcomas of penis are rarer among them. Spindle cell sarcoma is one of the extremely rare sarcoma of penis. To best of our knowledge, only two cases have been reported so far, one in English literature and other in Japanese. We are presenting this uncommon case of spindle cell sarcoma of penis, which was diagnosed with microscopy with its characteristic immunohistochemistry. The disease had an aggressive course with multiple recurrences in a short duration despite margin negative resection. Disease responded poorly with the chemotherapy and patient succumbed to the disease. PMID:27630937

  6. Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-09-12

    Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  7. Myeloid Sarcoma: Current Approach and Therapeutic Options

    PubMed Central

    Avni, Batia; Koren-Michowitz, Maya

    2011-01-01

    Myeloid sarcoma is a rare disease that can present as an isolated extramedullary leukemic tumor, concurrently with or at relapse of acute myeloid leukemia. Owing to the rarity of this disorder, most of the literature comprises small retrospective studies and case reports. The aim of this review is to summarize the current published data regarding the clinical presentation, morphological, cytogenetic and molecular features, prognosis and treatment of myeloid sarcoma. PMID:23556098

  8. Imaging spectrum in soft tissue sarcomas.

    PubMed

    Aga, Pallavi; Singh, Ragini; Parihar, Anit; Parashari, Umesh

    2011-12-01

    Imaging plays an important role in detection, diagnosis as well as pre and post operative management of patients with soft tissue sarcomas. Soft tissue sarcomas are generally a diagnostic dilemma needing the complimentary use of both radiology and pathology for their accurate diagnosis. In this review article, we have tried to highlight the important facts about the various imaging modalities available as well as the recent advances in the field of radiology. PMID:23204782

  9. Surgical management of soft tissue sarcomas

    SciTech Connect

    Arlen, M.; Marcove, R.C.

    1987-01-01

    This volume reflects the latest thinking in surgical and adjuvant forms of therapy that can be offered to the sarcoma patient. Based on their analysis of sarcoma patients, the authors stress management based on site of origin, and discuss tumors on and about the shoulder girdle, hip joint, extremity, retroperitoneum, etc. Coverage includes methods for limb preservation; techniques for regional node resection; indications and methods for arterial perfusion, cryosurgery and isotope implantation; pre- and post-operative immunotherapy chemotherapy and radiation therapy.

  10. Imaging in Soft Tissue Sarcomas: Current Updates.

    PubMed

    Jagannathan, Jyothi P; Tirumani, Sree Harsha; Ramaiya, Nikhil H

    2016-10-01

    Soft tissue sarcomas (STS) are heterogeneous malignant tumors that have nonspecific imaging features. A combination of clinical, demographic, and imaging characteristics can aid in the diagnosis. Imaging provides important information regarding the tumor extent, pretreatment planning, and surveillance of patients with STS. In this article, we illustrate the pertinent imaging characteristics of the commonly occurring STS and some uncommon sarcomas with unique imaging characteristics. PMID:27591491

  11. CSR-induced emittance growth in achromats: Linear formalism revisited

    NASA Astrophysics Data System (ADS)

    Venturini, M.

    2015-09-01

    We review the R-matrix formalism used to describe Coherent Synchrotron Radiation (CSR)-induced projected emittance growth in electron beam transport lines and establish the connection with a description in terms of the dispersion-invariant function.

  12. Potential Therapeutic Targets in Uterine Sarcomas

    PubMed Central

    Cuppens, Tine; Tuyaerts, Sandra; Amant, Frédéric

    2015-01-01

    Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach. PMID:26576131

  13. Low intensity argon laser coagulation in central serous retinopathy (csr).

    PubMed

    Greite, J H; Birngruber, R

    1975-01-01

    Mechanisms of light coagulation effects in RPE and detached retina are discussed. 25 cases of CSR are presented in which the leaking point in the RPE was coagulated with an argon laser coagulator, the exposure parameters being set to avoid a whitening of the retina. The results suggest that the retinal whitening and consequently retinal damage does not constitute a criterium for coagulation effectiveness in CSR.

  14. Studying Genes in Tissue Samples From Younger and Adolescent Patients With Soft Tissue Sarcomas

    ClinicalTrials.gov

    2016-05-13

    Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Chordoma; Desmoid Tumor; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Recurrent Childhood Soft Tissue Sarcoma

  15. Isolated Limb Perfusion of Melphalan With or Without Tumor Necrosis Factor in Treating Patients With Soft Tissue Sarcoma of the Arm or Leg

    ClinicalTrials.gov

    2012-03-14

    Stage IVB Adult Soft Tissue Sarcoma; Stage IIB Adult Soft Tissue Sarcoma; Stage IIC Adult Soft Tissue Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage IVA Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma

  16. In Silico Identification and Experimental Characterization of Regulatory Elements Controlling the Expression of the Salmonella csrB and csrC Genes

    PubMed Central

    Martínez, Luary C.; Martínez-Flores, Irma; Salgado, Heladia; Fernández-Mora, Marcos; Medina-Rivera, Alejandra; Puente, José L.; Collado-Vides, Julio

    2014-01-01

    The small RNAs CsrB and CsrC of Salmonella indirectly control the expression of numerous genes encoding widespread cellular functions, including virulence. The expression of csrB and csrC genes, which are located in different chromosomal regions, is coordinated by positive transcriptional control mediated by the two-component regulatory system BarA/SirA. Here, we identified by computational analysis an 18-bp inverted repeat (IR) sequence located far upstream from the promoter of Salmonella enterica serovar Typhimurium csrB and csrC genes. Deletion analysis and site-directed mutagenesis of the csrB and csrC regulatory regions revealed that this IR sequence is required for transcriptional activation of both genes. Protein-DNA and protein-protein interaction assays showed that the response regulator SirA specifically binds to the IR sequence and provide evidence that SirA acts as a dimer. Interestingly, whereas the IR sequence was essential for the SirA-mediated expression of csrB, our results revealed that SirA controls the expression of csrC not only by binding to the IR sequence but also by an indirect mode involving the Csr system. Additional computational, biochemical, and genetic analyses demonstrated that the integration host factor (IHF) global regulator positively controls the expression of csrB, but not of csrC, by interacting with a sequence located between the promoter and the SirA-binding site. These findings contribute to the better understanding of the regulatory mechanism controlling the expression of CsrB and CsrC. PMID:24187088

  17. In silico identification and experimental characterization of regulatory elements controlling the expression of the Salmonella csrB and csrC genes.

    PubMed

    Martínez, Luary C; Martínez-Flores, Irma; Salgado, Heladia; Fernández-Mora, Marcos; Medina-Rivera, Alejandra; Puente, José L; Collado-Vides, Julio; Bustamante, Víctor H

    2014-01-01

    The small RNAs CsrB and CsrC of Salmonella indirectly control the expression of numerous genes encoding widespread cellular functions, including virulence. The expression of csrB and csrC genes, which are located in different chromosomal regions, is coordinated by positive transcriptional control mediated by the two-component regulatory system BarA/SirA. Here, we identified by computational analysis an 18-bp inverted repeat (IR) sequence located far upstream from the promoter of Salmonella enterica serovar Typhimurium csrB and csrC genes. Deletion analysis and site-directed mutagenesis of the csrB and csrC regulatory regions revealed that this IR sequence is required for transcriptional activation of both genes. Protein-DNA and protein-protein interaction assays showed that the response regulator SirA specifically binds to the IR sequence and provide evidence that SirA acts as a dimer. Interestingly, whereas the IR sequence was essential for the SirA-mediated expression of csrB, our results revealed that SirA controls the expression of csrC not only by binding to the IR sequence but also by an indirect mode involving the Csr system. Additional computational, biochemical, and genetic analyses demonstrated that the integration host factor (IHF) global regulator positively controls the expression of csrB, but not of csrC, by interacting with a sequence located between the promoter and the SirA-binding site. These findings contribute to the better understanding of the regulatory mechanism controlling the expression of CsrB and CsrC.

  18. Explant culture of sarcoma patients' tissue.

    PubMed

    Muff, Roman; Botter, Sander M; Husmann, Knut; Tchinda, Joelle; Selvam, Philomina; Seeli-Maduz, Franziska; Fuchs, Bruno

    2016-07-01

    Human sarcomas comprise a heterogeneous group of rare tumors that affect soft tissues and bone. Due to the scarcity and heterogeneity of these diseases, patient-derived cells that can be used for preclinical research are limited. In this study, we investigated whether the tissue explant technique can be used to obtain sarcoma cell lines from fresh as well as viable frozen tissue obtained from 8 out of 12 soft tissue and 9 out of 13 bone tumor entities as defined by the World Health Organization. The success rate, defined as the percent of samples that yielded sufficient numbers of outgrowing cells to be frozen, and the time to freeze were determined for a total of 734 sarcoma tissue specimens. In 552 cases (75%) enough cells were obtained to be frozen at early passage. Success rates were higher in bone tumors (82%) compared with soft tissue tumors (68%), and the mean time to freezing was lower in bone tumors (65 days) compared with soft tissue tumors (84 days). Overall, from 40% of the tissues cells could be frozen at early passage within <2 month after tissue removal. Comparable results as with fresh tissue were obtained after explant of viable frozen patient-derived material. In a selected number of bone and soft tissue sarcoma entities, conventional karyotyping and/or FISH (fluorescence in situ hybridization) analysis revealed a high amount (>60%) of abnormal cells in 41% of analyzed samples, especially in bone sarcomas (osteosarcoma and Ewing sarcoma). In conclusion, the explant technique is well suited to establish patient-derived cell lines for a large majority of bone and soft tissue sarcoma entities with adequate speed. This procedure thus opens the possibility for molecular analysis and drug testing for therapeutic decision making even during patient treatment. PMID:27111283

  19. Intratumoral oxygen gradients mediate sarcoma cell invasion.

    PubMed

    Lewis, Daniel M; Park, Kyung Min; Tang, Vitor; Xu, Yu; Pak, Koreana; Eisinger-Mathason, T S Karin; Simon, M Celeste; Gerecht, Sharon

    2016-08-16

    Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets. PMID:27486245

  20. What's New in Uterine Sarcoma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for uterine sarcoma What`s new in uterine sarcoma research and treatment? Molecular pathology ... the chromosomes leads to the formation of a new gene, called JAZF1/JJAZ. This gene may help ...

  1. New Rebunchers for HIRFL-CSR

    NASA Astrophysics Data System (ADS)

    Tang, J. Y.; Li, Z. H.; Zheng, Q. W.; Zhou, X. H.; Yuan, Y. J.; Li, H. H.; Huang, T. Z.; Nie, Y. Z.; Zhang, B.

    2001-12-01

    Three almost-identical rebunchers have been designed for HIRFL-CSR. The first one B1 is going to be taken the off-line test and will be installed in place soon. The rebunchers B1 and B2 are in the BL1 beam line from the injector cyclotron SFC to the main cyclotron SSC, together for the longitudinal matching between the two cyclotrons. The rebuncher B3 is in the BL2 beam line from SSC to the main ring CSRm, either working at the stand-alone mode for the beam from SSC or at the combined mode together with B1 for the beam from SFC. They work at different harmonic modes depending on the beam energy to get the best matching effect. The rebunchers of 22˜54 MHz for B1 and B2 and 23.5˜56 MHz for B3 in frequency range and 20˜120 kV in amplitude use two tuning mechanisms, where the two movable capacitors are for low frequency end and the movable short-circuit panel is for high frequency end.

  2. Targeted Therapy of Ewing's Sarcoma

    PubMed Central

    Subbiah, Vivek; Anderson, Pete

    2011-01-01

    Refractory and/or recurrent Ewing's sarcoma (EWS) remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22) translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS. PMID:21052545

  3. Spinal intradural extraosseous Ewing's sarcoma.

    PubMed

    Mateen, Farrah J; Nassar, Aziza; Bardia, Aditya; Jatoi, Aminah; Haddock, Michael G; Buckner, Jan C; Lachance, Daniel H

    2011-03-30

    Extraosseous Ewing's sarcoma (EES) involving the central nervous system is rare, but can be diagnosed and distinguished from other primitive neuroectodermal tumors (PNET) by identification of the chromosomal translocation (11;22)(q24;q12). We report EES arising from the spinal intradural extramedullary space, based on imaging, histopathological, and molecular data in two men, ages 50 and 60 years old and a review of the literature using PubMed (1970-2009). Reverse transcriptase polymerase chain reaction (RT-PCR) identified the fusion product FL1-EWS. Multimodal therapy, including radiation and alternating chemotherapy including vincristine, cyclophosphamide, doxorubicin and ifosfamide and etoposide led to local tumor control and an initial, favorable therapeutic response. No systemic involvement was seen from the time of diagnosis to the time of last follow-up (26 months) or death (4 years). This report confirms that EES is not confined to the earliest decades of life, and like its rare occurrence as an extra-axial meningeal based mass intracranially, can occasionally present as an intradural mass in the spinal canal without evidence of systemic tumor. Gross total resection followed by multimodal therapy may provide for extended progression free and overall survival.

  4. Uterine sarcoma Part II-Uterine endometrial stromal sarcoma: The TAG systematic review.

    PubMed

    Horng, Huann-Cheng; Wen, Kuo-Chang; Wang, Peng-Hui; Chen, Yi-Jen; Yen, Ming-Shyen; Ng, Heung-Tat

    2016-08-01

    Endometrial stromal tumors are rare uterine tumors (<1%). Four main categories include endometrial stromal nodule, low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and uterine undifferentiated sarcoma (UUS). This review is a series of articles discussing the uterine sarcomas. LG-ESS, a hormone-dependent tumor harboring chromosomal rearrangement, is an indolent tumor with a favorable prognosis, but characterized by late recurrences even in patients with Stage I disease, suggesting the requirement of a long-term follow-up. Patients with HG-ESS, based on the identification of YWHAE-NUTM2A/B (YWHAE-FAM22A/B) gene fusion, typically present with advanced stage diseases and frequently have recurrences, usually within a few years after initial surgery. UUS is, a high-grade sarcoma, extremely rare, lacking a specific line of differentiation, which is a diagnosis of exclusion (the wastebasket category, which fails to fulfill the morphological and immunohistochemical criteria of translocation-positive ESS). Surgery is the main strategy in the management of uterine sarcoma. Due to rarity, complex biological characteristics, and unknown etiology and risk factors of uterine sarcomas, the role of adjuvant therapy is not clear. Only LG-ESS might respond to progestins or aromatase inhibitors. PMID:27590366

  5. Primary pulmonary synovial sarcoma: a rare neoplasm

    PubMed Central

    Ramos, Montserrat Blanco; Fontán, Eva María García; Carretero, Miguel Ángel Cańizares; Pińeiro, Ana González

    2016-01-01

    Primary pulmonary synovial sarcoma is an extremely rare tumor with an unknown cause. The diagnosis is established after other primary lung malignancies or metastatic extrathoracic sarcoma have been excluded. We report the case of a 69-year-old man who presented with a well-defined mass in the right upper lobe on a chest X-ray. A video-assisted thoracoscopic surgery (VATS) right upper lobectomy was performed. Immunohistochemically, neoplastic cells were positive for vimentin, CD56 and Bcl-2, and focally positive for CD99, epithelial membrane antigen and cytokeratin 7 and 19. The cytogenetic study revealed a SYT genetic reassortment. So, the final pathological diagnosis was primary pulmonary synovial sarcoma. PMID:27516790

  6. Primary pulmonary synovial sarcoma: a rare neoplasm.

    PubMed

    García, José Soro; Ramos, Montserrat Blanco; Fontán, Eva María García; Carretero, Miguel Ángel Cańizares; Pińeiro, Ana González

    2016-06-01

    Primary pulmonary synovial sarcoma is an extremely rare tumor with an unknown cause. The diagnosis is established after other primary lung malignancies or metastatic extrathoracic sarcoma have been excluded. We report the case of a 69-year-old man who presented with a well-defined mass in the right upper lobe on a chest X-ray. A video-assisted thoracoscopic surgery (VATS) right upper lobectomy was performed. Immunohistochemically, neoplastic cells were positive for vimentin, CD56 and Bcl-2, and focally positive for CD99, epithelial membrane antigen and cytokeratin 7 and 19. The cytogenetic study revealed a SYT genetic reassortment. So, the final pathological diagnosis was primary pulmonary synovial sarcoma. PMID:27516790

  7. Osteosarcoma With Apparent Ewing Sarcoma Gene Rearrangement.

    PubMed

    Mathias, Melissa D; Chou, Alexander J; Meyers, Paul; Shukla, Neerav; Hameed, Meera; Agaram, Narasimhan; Wang, Lu; Berger, Michael F; Walsh, Michael; Kentsis, Alex

    2016-07-01

    Poorly differentiated round cell sarcomas present diagnostic challenges because of their variable morphology and lack of specific immunophenotypic markers. We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene. Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma. This illustrates the potential of clinical genomic profiling to improve diagnosis and enable specifically targeted therapies for cancers with complex pathologies. PMID:27352193

  8. [Sarcomas, example of a pathologist network organization].

    PubMed

    Neuville, Agnes; Coindre, Jean-Michel

    2013-12-01

    Sarcomas are rare and heterogeneous with many subtypes explaining the high level of diagnostic difficulty with frequent important therapeutic consequences. In 2009, a national network of pathologists has been set up with the main objective to perform a systematic histological review of every new sarcoma, gastro-intestinal stromal tumor (GIST) and desmoid tumor. We describe the network organization and report the results of the first two years of activity. These results clearly show the interest of this organization for the patients as well as for all pathologists. Moreover, data and material collect allows a better knowledge of these tumors and an improvement of the rules for their diagnostic management.

  9. Retroperitoneal Sarcoma: Fact, Opinion, and Controversy.

    PubMed

    Gladdy, Rebecca A; Gupta, Abha; Catton, Charles N

    2016-10-01

    After diagnosis of retroperitoneal sarcoma (RPS), detailed imaging and multidisciplinary discussion should guide treatment including surgical resection and in select cases, neoadjuvant therapy. Local recurrence is common in RPS and is associated with grade, histologic subtype, completeness of resection, and size. As guidelines to standardize RPS patient management emerge, expert pathologic assessment and management in centers of excellence are benchmarks of quality of care. The efficacy of current chemotherapy is limited and there is a critical need to understand the molecular basis of sarcoma so that new drug therapies are developed. Multicenter clinical trials are needed to limit opinion and controversy in this complex and challenging disease. PMID:27591493

  10. Systemic Therapy for Advanced Soft Tissue Sarcoma.

    PubMed

    Sheng, Jennifer Y; Movva, Sujana

    2016-10-01

    Soft tissue sarcomas are rare tumors that present with distant metastasis in up to 10% of patients. Survival has improved significantly because of advancements in histologic classification and improved management approaches. Older agents such as doxorubicin, ifosfamide, gemcitabine, and paclitaxel continue to demonstrate objective response rates from 18% to 25%. Newer agents such as trabectedin, eribulin, aldoxorubicin, and olaratumab have demonstrated improvements in progression-free survival, overall survival, or toxicity profiles. Future studies on treatment of advanced soft tissue sarcoma will continue to concentrate on reducing toxicity, personalization of therapy, and targeting novel pathways. PMID:27542647

  11. Primary cutaneous Ewing sarcoma--case report.

    PubMed

    Oliveira Filho, Jayme de; Tebet, Ana Carolina Franco; Oliveira, Anna Rita Ferrante Mitidieri de; Nasser, Kassila

    2014-01-01

    Ewing sarcoma is a primitive neuroectodermal tumor rarely occurs in the skin and sobcutaneous tissues. Generally Ewing's sarcoma is a primary bone tumor, but when present in soft tissues it characterizes an extremely uncommon clinical picture. It usually involves the deep subcutaneous tissue or muscles, and more rarely occurs like a primary skin cancer. Most patients are white, women, and in the second decade of life. The clinical features are a superficial mass, in average measuring 2-3 cm, of soft consistency, freely mobile and sometimes painful. The more affected locations are upper and lower extremities, trunk, head, neck or multiple lesions. The presence of metastases is very rare. PMID:24937829

  12. State-of-the-art approach for bone sarcomas.

    PubMed

    Mavrogenis, Andreas F; Angelini, Andrea; Vottis, Christos; Palmerini, Emanuela; Rimondi, Eugenio; Rossi, Giuseppe; Papagelopoulos, Panayiotis J; Ruggieri, Pietro

    2015-01-01

    Bone sarcomas are a variety of non-epithelial, malignant neoplasms of bone. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The approach to a patient with a suspected bone sarcoma from initial examination to the histological diagnosis and classification is staging. Staging is of critical importance, in order to classify different treatment options and point out which combination of them is more suitable depending on the severity of the tumor in every individual patient. Staging should include medical history, physical and imaging examination, and biopsy. This article presents the current approach for staging, principles of biopsy, tumor classification, treatment, and follow-up of patients with bone sarcomas.

  13. Synovial sarcoma of kidney in a child: A rare presentation

    PubMed Central

    Radhakrishnan, Venkatraman; Dhanushkodi, Manikandan; Narayanswamy, Kathiresan; Raja, Anand; Sundersingh, Shirley; Sagar, Tenali

    2016-01-01

    There are no reported cases in the literature of primary renal synovial sarcoma in pediatric patients. The management of renal synovial sarcoma has been extrapolated from the management of soft tissue sarcomas at other sites. We present a 4-year-old female who was suspected to have Wilms’ tumor. The patient underwent guided biopsy as she did not respond to neoadjuvant chemotherapy for Wilms’ tumor. The biopsy was consistent with primary renal synovial sarcoma. The child was treated with change in her neoadjuvant chemotherapy regimen and surgery. The diagnosis of synovial sarcoma was confirmed by demonstrating the t (X, 18) translocation using polymerase chain reaction. PMID:27046979

  14. csrT Represents a New Class of csrA-Like Regulatory Genes Associated with Integrative Conjugative Elements of Legionella pneumophila

    PubMed Central

    Abbott, Zachary D.; Flynn, Kaitlin J.; Byrne, Brenda G.; Mukherjee, Sampriti; Kearns, Daniel B.

    2015-01-01

    ABSTRACT Bacterial evolution is accelerated by mobile genetic elements. To spread horizontally and to benefit the recipient bacteria, genes encoded on these elements must be properly regulated. Among the legionellae are multiple integrative conjugative elements (ICEs) that each encode a paralog of the broadly conserved regulator csrA. Using bioinformatic analyses, we deduced that specific csrA paralogs are coinherited with particular lineages of the type IV secretion system that mediates horizontal spread of its ICE, suggesting a conserved regulatory interaction. As a first step to investigate the contribution of csrA regulators to this class of mobile genetic elements, we analyzed here the activity of the csrA paralog encoded on Legionella pneumophila ICE-βox. Deletion of this gene, which we name csrT, had no observed effect under laboratory conditions. However, ectopic expression of csrT abrogated the protection to hydrogen peroxide and macrophage degradation that ICE-βox confers to L. pneumophila. When ectopically expressed, csrT also repressed L. pneumophila flagellin production and motility, a function similar to the core genome's canonical csrA. Moreover, csrT restored the repression of motility to csrA mutants of Bacillus subtilis, a finding consistent with the predicted function of CsrT as an mRNA binding protein. Since all known ICEs of legionellae encode coinherited csrA-type IV secretion system pairs, we postulate that CsrA superfamily proteins regulate ICE activity to increase their horizontal spread, thereby expanding L. pneumophila versatility. IMPORTANCE ICEs are mobile DNA elements whose type IV secretion machineries mediate spread among bacterial populations. All surveyed ICEs within the Legionella genus also carry paralogs of the essential life cycle regulator csrA. It is striking that the csrA loci could be classified into distinct families based on either their sequence or the subtype of the adjacent type IV secretion system locus. To

  15. Effects of Core-Shell Rubber (CSR) Nanoparticles on the Cryogenic Fracture Toughness of CSR Modified Epoxy

    NASA Technical Reports Server (NTRS)

    Wang, Jun; Magee, Daniel; Schneider, Judy; Cannon, Seth

    2009-01-01

    This study investigated the effects of core-shell rubber (CSR) nanoparticles on the mechanical properties and fracture toughness of an epoxy resin at ambient and liquid nitrogen (LN2) temperatures. Varying amounts of Kane Ace(Registered TradeMark) MX130 and Kane Ace(Registered TradeMark) MX960 toughening agent were added to a commercially available EPON 862/Epikure W epoxy resin. Elastic modulus was calculated using quasi-static tensile data. Fracture toughness was evaluated by the resulting breaking energy measured in Charpy impact tests conducted on an instrumented drop tower. The size and distribution of the CSR nanoparticles were characterized using Transmission Electron Microscopy (TEM) and Small Angle X-ray Scattering (SAXS). Scanning Electron Microscopy (SEM) was used to study the fracture surface morphology. The addition of the CSR nanoparticles increased the breaking energy with negligible change in elastic modulus and ultimate tensile stress (UTS). At ambient temperature the breaking energy increased with increasing additions of the CSR nanoparticles up to 13.8wt%, while at LN2 temperatures, it reached a plateau at much lower CSR concentration.

  16. Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma

    ClinicalTrials.gov

    2014-09-08

    Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  17. Commissioning of HIRFL-CSR and its Electron Coolers

    NASA Astrophysics Data System (ADS)

    Yang, Xiaodong; Parkhomchuk, Vasily; Zhan, Wenlong; Xia, Jiawen; Zhao, Hongwei; Yuan, Youjin; Song, Mingtao; Li, Jie; Mao, Lijun; Lu, Wang; Ibnp Electron Cooler Group

    2006-03-01

    The brief achievements of HIRFL-CSR commissioning and the achieved parameters of its coolers were presented. With the help of electron cooling code, the cooling time of ion beam were extensive simulated in various parameters of the ion beam in the HIRFL-CSR electron cooling storage rings respectively, such as ion beam energy, initial transverse emittance, and momentum spread. The influence of the machine lattice parameters-betatron function, and dispersion function on the cooling time was investigated. The parameters of electron beam and cooling devices were taken into account, such as effective cooling length, magnetic field strength and its parallelism in cooling section, electron beam size and density. As a result, the lattice parameters of HIRFL-CSR were optimal for electron cooling, and the parameters of electron beam can be optimized according to the parameters of heavy ion beam.

  18. Hyperthermia in soft tissue sarcoma.

    PubMed

    Lindner, Lars H; Issels, Rolf D

    2011-03-01

    Patients with high-risk soft tissue sarcomas (STS)-FNCLCC grade 2-3, size >5 cm, deep to the fascia-are at risk for developing local recurrence and distant metastasis despite surgical tumor resection. Therefore, the management of high-risk STS requires a multidisciplinary approach. Besides surgery, radiotherapy, and chemotherapy, regional hyperthermia (RHT) has the potential to become the fourth standard treatment modality for the treatment of these patients. RHT means non-invasive selective heating of the tumor area to temperatures within the range of 40-43°C for 60 min by the use of an electromagnetic heating device. Thereby RHT is always applied in addition to radiotherapy or chemotherapy or both but is not effective as a single treatment. Beside direct cytotoxicity, RHT in combination with chemotherapy enhances the drug cytotoxicity mainly by increased chemical reaction and intratumoral drug accumulation. For the neoadjuvant setting, RHT in combination with a doxorubicin- and ifosfamide-based chemotherapy has been shown to dramatically improve the tumor response rate but also prevents from early disease progression as compared to chemotherapy alone. The addition of RHT to a multimodal treatment of high-risk STS consisting of surgery, radiotherapy, and chemotherapy either in the neoadjuvant setting but also after incomplete or marginal tumor resection has been shown to significantly improve local recurrence- and disease-free survival. Based on these results and in conjunction with the low RHT-related toxicity, RHT combined with preoperative or postoperative chemotherapy should be considered as an additional standard treatment option for the multidisciplinary treatment of locally advanced high-grade STS.

  19. Promoting Reading Comprehension, Content Learning, and English Acquisition through Collaborative Strategic Reading (CSR).

    ERIC Educational Resources Information Center

    Klingner, Janette K.; Vaughn, Sharon

    1999-01-01

    Describes procedures for teaching Collaborative Strategic Reading (CSR), in which students of mixed reading and achievement levels work in small, cooperative groups to assist one another in applying reading strategies to facilitate their comprehension of content-area text. Discusses whole-class instruction of CSR strategies, implementing CSR in…

  20. The Csr system regulates genome-wide mRNA stability and transcription and thus gene expression in Escherichia coli.

    PubMed

    Esquerré, Thomas; Bouvier, Marie; Turlan, Catherine; Carpousis, Agamemnon J; Girbal, Laurence; Cocaign-Bousquet, Muriel

    2016-04-26

    Bacterial adaptation requires large-scale regulation of gene expression. We have performed a genome-wide analysis of the Csr system, which regulates many important cellular functions. The Csr system is involved in post-transcriptional regulation, but a role in transcriptional regulation has also been suggested. Two proteins, an RNA-binding protein CsrA and an atypical signaling protein CsrD, participate in the Csr system. Genome-wide transcript stabilities and levels were compared in wildtype E. coli (MG1655) and isogenic mutant strains deficient in CsrA or CsrD activity demonstrating for the first time that CsrA and CsrD are global negative and positive regulators of transcription, respectively. The role of CsrA in transcription regulation may be indirect due to the 4.6-fold increase in csrD mRNA concentration in the CsrA deficient strain. Transcriptional action of CsrA and CsrD on a few genes was validated by transcriptional fusions. In addition to an effect on transcription, CsrA stabilizes thousands of mRNAs. This is the first demonstration that CsrA is a global positive regulator of mRNA stability. For one hundred genes, we predict that direct control of mRNA stability by CsrA might contribute to metabolic adaptation by regulating expression of genes involved in carbon metabolism and transport independently of transcriptional regulation.

  1. The Csr system regulates genome-wide mRNA stability and transcription and thus gene expression in Escherichia coli

    PubMed Central

    Esquerré, Thomas; Bouvier, Marie; Turlan, Catherine; Carpousis, Agamemnon J.; Girbal, Laurence; Cocaign-Bousquet, Muriel

    2016-01-01

    Bacterial adaptation requires large-scale regulation of gene expression. We have performed a genome-wide analysis of the Csr system, which regulates many important cellular functions. The Csr system is involved in post-transcriptional regulation, but a role in transcriptional regulation has also been suggested. Two proteins, an RNA-binding protein CsrA and an atypical signaling protein CsrD, participate in the Csr system. Genome-wide transcript stabilities and levels were compared in wildtype E. coli (MG1655) and isogenic mutant strains deficient in CsrA or CsrD activity demonstrating for the first time that CsrA and CsrD are global negative and positive regulators of transcription, respectively. The role of CsrA in transcription regulation may be indirect due to the 4.6-fold increase in csrD mRNA concentration in the CsrA deficient strain. Transcriptional action of CsrA and CsrD on a few genes was validated by transcriptional fusions. In addition to an effect on transcription, CsrA stabilizes thousands of mRNAs. This is the first demonstration that CsrA is a global positive regulator of mRNA stability. For one hundred genes, we predict that direct control of mRNA stability by CsrA might contribute to metabolic adaptation by regulating expression of genes involved in carbon metabolism and transport independently of transcriptional regulation. PMID:27112822

  2. The Collectivity in Csr 129Xe+129Xe Collisions

    NASA Astrophysics Data System (ADS)

    Xie, Fei; Wu, Kejun; Liu, Feng

    The Heavy Ion Research Facility in Lanzhou (HIRFL) - Cooler Storage Ring (CSR), which can gather few hundreds MeV/nucleon for heavy ion beam energy in the external-target experiments, could make a significant contribution in studying the property of dense matter. By using a Relativistic Transport Model(ART1.0), we study the collectivity of identified hadrons in 129Xe+129Xe collisions in CSR energy regions. Our investigation indicates that the anisotropic flow reaches its extremum around 500 MeV/nucleon of beam energy. The system size and EOS dependence on anisotropic flow show that directed flow is very sensitive to the equation of state.

  3. Test results of the HIRFL-CSR cluster target

    NASA Astrophysics Data System (ADS)

    Cai, Xiaohong; Lu, Rongchun; Shao, Caojie; Ruan, Fangfang; Yu, Deyang; Li, Mingsheng; Zhan, Wenlong; Torpokov, D. K.; Nikolenko, D.

    2005-12-01

    The HIRFL-CSR internal target can operate in two modes: cluster target mode and polarized target mode. The cluster target may provide the gas target of H 2, N 2, inert gases and small molecular gases. The test experiments have been done for H 2, N 2 and Ar gases. The target thicknesses of 6.6×10 12, 1.2×10 13 and 1.0×10 13 atoms/cm 2 are obtained for H 2, N 2 and Ar gases, respectively. In this paper, the structure and the test results of the HIRFL-CSR cluster target system are reported.

  4. Impact on the magnetic compressor due to CSR

    NASA Astrophysics Data System (ADS)

    Liu, Chu-Yu; Wang, Fang; Wang, Er-Dong; Quan, Sheng-Wen; Hao, Jian-Kui; Lu, Xiang-Yang; Zhang, Bao-Cheng; Zhao, Kui

    2008-08-01

    When an electron bunch is compressed in a chicane compressor, the CSR (coherent synchrotron radiation) will induce energy redistribution along the bunch. Such energy redistribution will affect the longitudinal emittance as a direct consequence. It will also excite betatron oscillation due to the chromatic transfer functions, and hence a transverse emittance change. So, it is indispensable for us to find a way to alleviate the CSR-caused emittance dilution and the bad result of chicane compressor in PKU-FEL. Supported by National Nature Science Foundation of China (10276001)

  5. Theory and simulation of CSR microbunching in bunch compressors

    NASA Astrophysics Data System (ADS)

    Huang, Zhirong; Borland, Michael; Emma, Paul; Kim, Kwang-Je

    2003-07-01

    CSR microbunching instability in bunch compressors is studied both analytically and numerically. The iterative solutions of the integral equation for the instability provide approximate expressions of CSR microbunching due to initial density and energy modulation, and can be applied to a series of bending systems consisting of multiple compressor chicanes and transport lines. Two similar but independent simulation methods are developed and are compared to each other as well as with theory. We determine the total gain in density modulation for all bend systems of the Linac Coherent Light Source and discuss initial conditions that start the unstable process.

  6. Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

    ClinicalTrials.gov

    2016-05-26

    Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Gliosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma

  7. Spindle Cell Sarcoma Presenting as Pancoast Syndrome.

    PubMed

    Badshah, Aliena; Khan, Salman; Saeed, Usman

    2016-07-01

    This report describes a patient who presented with pancoast syndrome, secondary to spindle cell sarcoma of the lung. A 56-year man presented with dyspnea, engorged neck veins and bilateral upper limb pitting edema. The patient also had ptosis and miosis in the right eye. Right ulnar nerve palsy with atrophy of hand muscles was seen. His chest X-ray showed bilateral pleural effusion with an opacity involving the apex of the right lung along with mediastinal widening. Echocardiography revealed a pericardial effusion which was drained. The patient's CTscan of chest strongly suspected a malignant mass in right upper lobe with extensive mediastinal lymphadenopathy, pleural metastases and pericardial involvement. He was started on oxygen inhalation, dexamethasone, and clopidogrel. Bronchoscopic biopsy confirmed the diagnosis of spindle cell sarcoma. Meanwhile, he was advised radiotherapy. The tumour was not amenable to surgery. Spindle cell sarcoma is a rare connective tissue tumor that replicates rapidly. To the best of the authors' knowledge, it is hereby reported the first case of spindle cell sarcoma of the lung presenting as Pancoast syndrome. PMID:27504558

  8. Feline postvaccinal sarcoma: 20 years later

    PubMed Central

    Wilcock, Brian; Wilcock, Anne; Bottoms, Katherine

    2012-01-01

    Comparison of the annual prevalence of feline postvaccinal sarcomas among 11 609 feline skin mass submissions from 1992 to 2010 revealed no decrease in disease prevalence or increase in the age of affected cats in response to changes in vaccine formulation or recommended changes in feline vaccination protocols. PMID:23024394

  9. Instantánea del sarcoma

    Cancer.gov

    Información sobre las tendencias de incidencia, mortalidad y financiamiento del NCI sobre el sarcoma; así como ejemplos de actividades del NCI y adelantos en la investigación de este tipo de cáncer.

  10. Genipin Enhances Kaposi’s Sarcoma-Associated Herpesvirus Genome Maintenance

    PubMed Central

    Son, Kuwon; Park, Gyu Hwan; Jung, Jong-Wha; Shin, Yu Su; Seo, Taegun; Hyosun Cho; Kang, Hyojeung

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a Gammaherpesvirus that causes acute infection and establishes life-long latency. KSHV causes several human cancers, including Kaposi's sarcoma, an acquired immune deficiency syndrome (AIDS)-related form of non-Hodgkin lymphoma. Genipin, an aglycone derived from geniposide found in Gardenia jasminoides, is known to be an excellent natural cross-linker, strong apoptosis inducer, and antiviral agent. Although evidence suggests antiviral activity of genipin in several in vitro viral infection systems, no inhibitory effect of genipin on KSHV infection has been reported. Thus, our aim was to determine, using the iSLK-BAC16 KSHV infection system, whether genipin has inhibitory effects on KSHV infection. For this purpose, we evaluated biological effects of genipin on KSHV infection and finally determined the underlying mechanisms responsible for the bioactive effects of genipin. A cytotoxicity assay revealed that genipin caused 50% cytotoxicity at 49.5 μM in iSLK-puro (KSHV-negative) cells and at 72.5 μM in iSLK-BAC16 (KSHV-positive) cells. Caspase 3/7 activities were slightly suppressed by genipin treatment in iSLK-BAC16 cells while significantly induced in iSLK-puro cells. Production of the KSHV latency-associated nuclear antigen (LANA), but not that of the R-transactivator (RTA) protein, was significantly induced by genipin treatment at lower concentration. Consistent with the LANA upregulation, KSHV LANA transcripts, but not RTA transcripts, were expressed at a higher level. Furthermore, KSHV intracellular copy numbers were slightly increased at lower concentration of genipin, while KSHV extracellular copy numbers were significantly increased at higher concentration of genipin. Interestingly, genipin treatment at a lower concentration did induce the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1); however, a co-immunoprecipitation assay showed that the DNMT1 and LANA induced by genipin did not co

  11. Closing the Achievement Gap: Urban Schools. CSR Connection.

    ERIC Educational Resources Information Center

    Porter, Kathleen; Soper, Stephanie

    This report reviews efforts to reform urban schools, focusing on initiatives in Tennessee and California as examples from which distric leaders may draw useful lessons. The report suggests that comprehensive school reform (CSR) offers promise to struggling urban schools by focusing on transforming the academic climate, school culture, and…

  12. The Challenges of Detecting Circulating Tumor Cells in Sarcoma.

    PubMed

    Tellez-Gabriel, Marta; Brown, Hannah K; Young, Robin; Heymann, Marie-Françoise; Heymann, Dominique

    2016-01-01

    Sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin, many of which have a propensity to develop distant metastases. Cancer cells that have escaped from the primary tumor are able to invade into surrounding tissues, to intravasate into the bloodstream to become circulating tumor cells (CTCs), and are responsible for the generation of distant metastases. Due to the rarity of these tumors and the absence of specific markers expressed by sarcoma tumor cells, the characterization of sarcoma CTCs has to date been relatively limited. Current techniques for isolating sarcoma CTCs are based on size criteria, the identification of circulating cells that express either common mesenchymal markers, sarcoma-specific markers, such as CD99, CD81, or PAX3, and chromosomal translocations found in certain sarcoma subtypes, such as EWS-FLI1 in Ewing's sarcoma, detection of osteoblast-related genes, or measurement of the activity of specific metabolic enzymes. Further studies are needed to improve the isolation and characterization of sarcoma CTCs, to demonstrate their clinical significance as predictive and/or prognostic biomarkers, and to utilize CTCs as a tool for investigating the metastatic process in sarcoma and to identify novel therapeutic targets. The present review provides a short overview of the most recent literature on CTCs in sarcoma. PMID:27656422

  13. The Challenges of Detecting Circulating Tumor Cells in Sarcoma

    PubMed Central

    Tellez-Gabriel, Marta; Brown, Hannah K.; Young, Robin; Heymann, Marie-Françoise; Heymann, Dominique

    2016-01-01

    Sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin, many of which have a propensity to develop distant metastases. Cancer cells that have escaped from the primary tumor are able to invade into surrounding tissues, to intravasate into the bloodstream to become circulating tumor cells (CTCs), and are responsible for the generation of distant metastases. Due to the rarity of these tumors and the absence of specific markers expressed by sarcoma tumor cells, the characterization of sarcoma CTCs has to date been relatively limited. Current techniques for isolating sarcoma CTCs are based on size criteria, the identification of circulating cells that express either common mesenchymal markers, sarcoma-specific markers, such as CD99, CD81, or PAX3, and chromosomal translocations found in certain sarcoma subtypes, such as EWS-FLI1 in Ewing’s sarcoma, detection of osteoblast-related genes, or measurement of the activity of specific metabolic enzymes. Further studies are needed to improve the isolation and characterization of sarcoma CTCs, to demonstrate their clinical significance as predictive and/or prognostic biomarkers, and to utilize CTCs as a tool for investigating the metastatic process in sarcoma and to identify novel therapeutic targets. The present review provides a short overview of the most recent literature on CTCs in sarcoma. PMID:27656422

  14. The Challenges of Detecting Circulating Tumor Cells in Sarcoma

    PubMed Central

    Tellez-Gabriel, Marta; Brown, Hannah K.; Young, Robin; Heymann, Marie-Françoise; Heymann, Dominique

    2016-01-01

    Sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin, many of which have a propensity to develop distant metastases. Cancer cells that have escaped from the primary tumor are able to invade into surrounding tissues, to intravasate into the bloodstream to become circulating tumor cells (CTCs), and are responsible for the generation of distant metastases. Due to the rarity of these tumors and the absence of specific markers expressed by sarcoma tumor cells, the characterization of sarcoma CTCs has to date been relatively limited. Current techniques for isolating sarcoma CTCs are based on size criteria, the identification of circulating cells that express either common mesenchymal markers, sarcoma-specific markers, such as CD99, CD81, or PAX3, and chromosomal translocations found in certain sarcoma subtypes, such as EWS-FLI1 in Ewing’s sarcoma, detection of osteoblast-related genes, or measurement of the activity of specific metabolic enzymes. Further studies are needed to improve the isolation and characterization of sarcoma CTCs, to demonstrate their clinical significance as predictive and/or prognostic biomarkers, and to utilize CTCs as a tool for investigating the metastatic process in sarcoma and to identify novel therapeutic targets. The present review provides a short overview of the most recent literature on CTCs in sarcoma.

  15. The global regulatory system Csr senses glucose through the phosphoenolpyruvate: carbohydrate phosphotransferase system.

    PubMed

    Pérez-Morales, Deyanira; Bustamante, Víctor H

    2016-02-01

    A novel connection between two regulatory systems controlling crucial biological processes in bacteria, the carbon storage regulator (Csr) system and the glucose-specific phosphotransferase system (PTS), is reported by Leng et al. in this issue. This involves the interaction of unphosphorylated EIIA(Glc), a component of the glucose-specific PTS, with the CsrD protein, which accelerates the decay of the CsrB and CsrC small RNAs via RNase E in Escherichia coli. As unphosphorylated EIIA(G) (lc) is generated in the presence of glucose, the PTS thus acts as a sensor of glucose for the Csr system. Interestingly, another pathway can operate for communication between the Csr system and the glucose-specific PTS. The absence of glucose generates phosphorylated EIIA(Glc) , which activates the enzyme adenylate cyclase to produce cyclic adenosine monophosphate (cAMP) that, in turn, binds to the regulator cAMP receptor protein (CRP). Leng et al. show that the complex cAMP-CRP modestly reduces CsrB decay independently of CsrD. On the other hand, a previous study indicates that the complex cAMP-CRP positively regulates the transcription of CsrB and CsrC in Salmonella enterica. Therefore, EIIA(G) (lc) could work as a molecular switch that regulates the activity of the Csr system, in response to its phosphorylation state determined by the presence or absence of glucose, in order to control gene expression.

  16. Production of Virus by Mammalian Cells Transformed by Rous Sarcoma and Murine Sarcoma Viruses

    PubMed Central

    Valentine, Artrice F.; Bader, John P.

    1968-01-01

    Cultured cells of mammalian tumors induced by ribonucleic acid (RNA)-containing oncogenic viruses were examined for production of virus. The cell lines were established from tumors induced in rats and hamsters with either Rous sarcoma virus (Schmidt-Ruppin or Bryan strains) or murine sarcoma virus (Moloney strain). When culture fluids from each of the cell lines were examined for transforming activity or production of progeny virus, none of the cell lines was found to be infectious. However, electron microscopic examination of the various cell lines revealed the presence of particles in the rat cells transformed by either Rous sarcoma virus or murine sarcoma virus. These particles, morphologically similar to those associated with murine leukemias, were found both in the extracellular fluid concentrates and in whole-cell preparations. In the latter, they were seen budding from the cell membranes or lying in the intercellular spaces. No viruslike particles were seen in preparations from hamster tumors. Exposure of the rat cells to 3H-uridine resulted in the appearance of labeled particles with densities in sucrose gradients typical of virus (1.16 g/ml.). RNA of high molecular weight was extracted from these particles, and double-labeling experiments showed that this RNA sedimented at the same rate as RNA extracted from Rous sarcoma virus. None of the hamster cell lines gave radioactive peaks in the virus density range, and no extractable high molecular weight RNA was found. These studies suggest that the murine sarcoma virus produces an infection analogous to certain “defective” strains of Rous sarcoma virus, in that particles produced by infected cells have a low efficiency of infection. The control of the host cell over the production and properties of the RNA-containing tumorigenic viruses is discussed. Images PMID:4316021

  17. Collecting and Storing Tissue, Blood, and Bone Marrow Samples From Patients With Rhabdomyosarcoma or Other Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-09-23

    Adult Rhabdomyosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Chordoma; Desmoid Tumor; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Previously Untreated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  18. Treatment of early uterine sarcomas: disentangling adjuvant modalities.

    PubMed

    Zagouri, Flora; Dimopoulos, Athanasios-Meletios; Fotiou, Stelios; Kouloulias, Vassilios; Papadimitriou, Christos A

    2009-01-01

    Uterine sarcomas are a rare group of neoplasms with aggressive clinical course and poor prognosis. They are classified into four main histological subtypes in order of decreasing incidence: carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas and "other" sarcomas. The pathological subtype demands a tailored approach. Surgical resection is regarded as the mainstay of treatment. Total abdominal hysterectomy and bilateral salpingo-oophorectomy represents the standard treatment of uterine sarcomas. Pelvic and para-aortic lymph node dissection in carcinosarcomas is recommended, given their high incidence of lymph node metastases, and may have a role in endometrial stromal sarcomas. Adjuvant radiation therapy has historically been of little survival value, but it appears to improve local control and may delay recurrence. Regarding adjuvant chemotherapy, there is little evidence in the literature supporting its use except for carcinosarcomas. However, more trials are needed to address these issues, especially, their sequential application. Patients with uterine sarcomas should be referred to large academic centers for participation in clinical trials.

  19. Undifferentiated embryonal sarcoma of the liver in an adult patient

    PubMed Central

    Lee, Kyu Ho; Maratovich, Mussin Nadiar; Lee, Kyoung-Bun

    2016-01-01

    Undifferentiated embryonal sarcoma of the liver (UESL) is rare primary hepatic sarcoma and is known to occur in pediatric patients. This case is the UESL occurred in a 51-year old male patient. Multilocular cystic lesion was composed of primitive spindle cells without specific differentiation. This rare case would help to review differential diagnosis of primary sarcoma in liver and cystic neoplasm of the liver. PMID:27377912

  20. [Magnetic resonance imaging in the diagnosis of knee joint sarcomas].

    PubMed

    Shubkin, V N; Gunicheva, N V; Akhadov, T A; Puzhitskiĭ, L B; Keshishian, R A

    2007-01-01

    The purpose of the investigation was to study the potentialities of magnetic resonance imaging (MRI) in the diagnosis of knee joint sarcomas. The paper presents the results of examining 13 patients of different age, shows the potentialities of the technique in the identification of knee joint sarcomas, and describes the MRI semiotics of sarcomas in both the routine study and that using contrast enhancement in lesions of bone and soft tissue elements in the presence of regional metastases.

  1. Aortic intimal sarcoma with embolic metastases.

    PubMed

    Wright, E P; Glick, A D; Virmani, R; Page, D L

    1985-12-01

    A 46-year-old woman died from massive bowel infarction. At autopsy, a primary sarcoma was found growing along the intimal surface of the aorta at the level of the celiac axis. Tumor emboli were found in distal aortic branches and most abdominal organs. Immunoperoxidase for Factor VIII and electron microscopy (EM) did not support an endothelial origin. EM showed myofibroblastic differentiation. Review of the literature yields an array of diagnostic histologic terms for these tumors, hampering case comparison. The literature does suggest, however, that the clinical presentation of these rare neoplasms correlates nicely with the location and gross morphology of the lesion. We therefore propose a clinicopathologic classification, categorizing the lesions as intimal (obstructive and nonobstructive) and mural. The former are typically pleomorphic sarcomas and are probably of myofibroblastic origin, whereas the latter are usually leiomyosarcomas or fibrosarcomas that probably originate in the media or adventitia. PMID:3000205

  2. Bone Sarcomas: From Biology to Targeted Therapies

    PubMed Central

    Gaspar, Nathalie; Di Giannatale, Angela; Geoerger, Birgit; Redini, Françoise; Corradini, Nadège; Enz-Werle, Natacha; Tirode, Franck; Marec-Berard, Perrine; Gentet, Jean-Claude; Laurence, Valérie; Piperno-Neumann, Sophie; Oberlin, Odile; Brugieres, Laurence

    2012-01-01

    Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival. PMID:23226965

  3. Recent advances in targeted therapy for Ewing sarcoma.

    PubMed

    Pishas, Kathleen I; Lessnick, Stephen L

    2016-01-01

    Ewing sarcoma is an aggressive, poorly differentiated neoplasm of solid bone that disproportionally afflicts the young. Despite intensive multi-modal therapy and valiant efforts, 70% of patients with relapsed and metastatic Ewing sarcoma will succumb to their disease. The persistent failure to improve overall survival for this subset of patients highlights the urgent need for rapid translation of novel therapeutic strategies. As Ewing sarcoma is associated with a paucity of mutations in readily targetable signal transduction pathways, targeting the key genetic aberration and master regulator of Ewing sarcoma, the EWS/ETS fusion, remains an important goal. PMID:27635231

  4. Recent advances in targeted therapy for Ewing sarcoma

    PubMed Central

    Pishas, Kathleen I.; Lessnick, Stephen L.

    2016-01-01

    Ewing sarcoma is an aggressive, poorly differentiated neoplasm of solid bone that disproportionally afflicts the young. Despite intensive multi-modal therapy and valiant efforts, 70% of patients with relapsed and metastatic Ewing sarcoma will succumb to their disease. The persistent failure to improve overall survival for this subset of patients highlights the urgent need for rapid translation of novel therapeutic strategies. As Ewing sarcoma is associated with a paucity of mutations in readily targetable signal transduction pathways, targeting the key genetic aberration and master regulator of Ewing sarcoma, the EWS/ETS fusion, remains an important goal. PMID:27635231

  5. Recent advances in targeted therapy for Ewing sarcoma

    PubMed Central

    Pishas, Kathleen I.; Lessnick, Stephen L.

    2016-01-01

    Ewing sarcoma is an aggressive, poorly differentiated neoplasm of solid bone that disproportionally afflicts the young. Despite intensive multi-modal therapy and valiant efforts, 70% of patients with relapsed and metastatic Ewing sarcoma will succumb to their disease. The persistent failure to improve overall survival for this subset of patients highlights the urgent need for rapid translation of novel therapeutic strategies. As Ewing sarcoma is associated with a paucity of mutations in readily targetable signal transduction pathways, targeting the key genetic aberration and master regulator of Ewing sarcoma, the EWS/ETS fusion, remains an important goal.

  6. Current Immunotherapies for Sarcoma: Clinical Trials and Rationale

    PubMed Central

    Mitsis, Demytra; Francescutti, Valerie

    2016-01-01

    Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality. PMID:27703409

  7. Primary Thyroid Sarcoma: A Systematic Review.

    PubMed

    Surov, Alexey; Gottschling, Sebastian; Wienke, Andreas; Meyer, Hans Jonas; Spielmann, Rolf Peter; Dralle, Henning

    2015-10-01

    Different types of malignant tumors can occur within the thyroid. Primary cancer is the most common type of thyroid malignancy. Non-epithelial malignancies can also arise within the thyroid. The aim of the present study was to analyze clinical and radiological characteristics of reported primary thyroid sarcomas (PTS), based on a large sample of cases. The PubMed database was screened for articles from between 1990 and 2014. Overall, 86 articles with 142 patients were identified. Ultrasound evaluation was reported for 36 patients. Data regarding computed tomography of the neck were available for 29 cases. Magnetic resonance imaging was performed for eight patients. The following data were retrieved for the identified sarcomas: localization, size, homogeneity, internal texture, and margin characteristics. In most cases, PTS occurred in patients over 40 years of age, with a peak incidence for the group aged 60-79 years. Angiosarcoma was diagnosed in 29 cases (20.4%), followed by malignant hemangioendothelioma (n=23, 16.3%), malignant fibrous histiocytoma (n=20, 14.1%), leiomyosarcoma (n=16, 11.3%), and fibrosarcoma (n=13, 9.2%). In most patients (n=113, 79.6%), PTS manifested clinically as a painless goiter. On ultrasound, PTS were predominantly mixed hypo-to-hyperechoic in comparison to the normal thyroid tissue. On non-contrast computed tomography, most sarcomas were inhomogeneous hypo-to-hyperdense. On post-contrast magnetic resonance images, most sarcomas showed marked non-homogenous enhancement. In 26.8%, infiltration of the adjacent organs was seen. The trachea or esophagus was affected more frequently in patients with malignant histiocytoma and liposarcoma. Different strategies were used in the treatment of PTS. Our analysis provides clinical and radiological characteristics of PTS. The described features should be taken into consideration in the differential diagnosis of thyroid tumors. PMID:26408676

  8. Multimodality Local Therapy for Retroperitoneal Sarcoma

    SciTech Connect

    Paryani, Nitesh N.; Zlotecki, Robert A.; Swanson, Erika L.; Morris, Christopher G.; Grobmyer, Stephen R.; Hochwald, Steven N.; Marcus, Robert B.; Indelicato, Daniel J.

    2012-03-01

    Purpose: Soft-tissue sarcomas of the retroperitoneum are rare tumors comprising less than 1% of all malignancies. Although surgery continues as the mainstay of treatment, the large size of these tumors coupled with their proximity to critical structures make resection with wide margins difficult to achieve. The role and timing of radiotherapy are controversial. This study updates our institutional experience using multimodality local therapy for resectable retroperitoneal sarcoma and identifies prognostic factors impacting disease control and survival. Methods and Materials: Between 1974 and 2007, 58 patients with nonmetastatic retroperitoneal sarcoma were treated with surgery and radiation at University of Florida. The median age at radiotherapy was 57 years old (range, 18-80 years). Forty-two patients received preoperative radiotherapy and 16 received postoperative radiotherapy. Nineteen patients received 1.8 Gy once daily and 39 patients received 1.2 Gy twice daily. Variables analyzed for prognostic value included age, grade, kidney involvement, histology, de novo versus recurrent presentation, tumor diameter, margin status, radiotherapy sequencing (preoperative vs. postoperative), total radiation dose, fractionation scheme, and treatment era. Results: The 5-year overall survival, cause-specific survival, and local control rates were 49%, 58%, and 62%, respectively. Nearly two-thirds of disease failures involved a component of local progression. On multivariate analysis, only margin status was significantly associated with improved 5-year local control (85%, negative margins; 63%, microscopic positive margins; 0%, gross positive margins; p < 0.0001) and 5-year overall survival (64%, negative margins; 56%, microscopic positive margins; 13%, gross positive margins; p = 0.0012). Thirty-one Grade 3 or greater toxicities were observed in 22 patients, including two treatment-related deaths (3%). Conclusion: For retroperitoneal sarcoma, local control remains a

  9. Primary pleuro-pulmonary synovial sarcoma.

    PubMed

    Shah, Unmil B; Joshi, S; Ghorpade, S V; Gaikwad, S N; Sundrani, R M

    2010-01-01

    Primary pleuro-pulmonary synovial sarcoma (PPSS) is a rare tumour and poses adiagnostic challenge particularly when unusual histological features are present. We report a case of a 30-year-old immunocompromised human immunodeficiency virus (HIV) sero-positive male who was referred to us with complaints of cough, breathlessness and left-sided chestpain for the past two months. The PPSS can be confirmed on tru-cut biopsy. PMID:20949738

  10. Extraskeletal Ewing's sarcoma mimicking traumatic hematoma.

    PubMed

    Ogose, A; Hotta, T; Yamamura, S; Shioya, Y; Yazawa, T

    1998-01-01

    We describe the clinical course of a 16-year-old baseball player with a history of recurrent hematoma of the thigh. The lesion was aspirated percutaneously several times and curetted under the diagnosis of traumatic hematoma. Microscopical examination revealed massive hemorrhage, necrosis, and a small number of Ewing's sarcoma cells. He died of multiple metastases. With recurrent hematoma in the soft tissue, neoplastic lesions should be ruled out.

  11. Granulocytic sarcoma with expression of CD30.

    PubMed Central

    Fickers, M; Theunissen, P

    1996-01-01

    A case of a young man with a spinal epidural tumour, initially diagnosed as large cell anaplastic malignant lymphoma, is reported. The tumour consisted of poorly differentiated cells showing immunoreactivity with antibodies directed against CD30 and CD45. Ten months later the patient developed acute myeloid leukaemia. The histological slides of the epidural tumour were reviewed, including additional enzymochemical and immunochemical stains. As the tumour showed immunoreactivity for myeloperoxidase and chloroacetate esterase, it was reclassified as a granulocytic sarcoma. Images PMID:9038763

  12. Management of soft tissue and bone sarcomas

    SciTech Connect

    Van Oosterom, A.T.; Van Unnik, J.A.M.

    1986-01-01

    This book contains 32 papers. Some of the titles are: Adjuvant Treatment for Osteosarcoma of the Limbs; Trial 20781 of the SIOP and the EORTC Radiotherapy/Chemotherapy; Application of Magnetic Resonance Imaging (MRI) in Diagnosis and Follow-up During Treatment of Bone Tumors; Radiological Assessment of Local Involvement in Bone Sarcomas; and Prevention of Lung Metastases by Irradiation Alone or Combined with Chemotherapy in an Animal Model.

  13. Post-transcriptional regulation on a global scale: form and function of Csr/Rsm systems.

    PubMed

    Romeo, Tony; Vakulskas, Christopher A; Babitzke, Paul

    2013-02-01

    Originally described as a repressor of gene expression in the stationary phase of growth, CsrA (RsmA) regulates primary and secondary metabolic pathways, biofilm formation, motility, virulence circuitry of pathogens, quorum sensing and stress response systems by binding to conserved sequences in its target mRNAs and altering their translation and/or turnover. While the binding of CsrA to RNA is understood at an atomic level, new mechanisms of gene activation and repression by this protein are still emerging. In the γ-proteobacteria, small non-coding RNAs (sRNAs) use molecular mimicry to sequester multiple CsrA dimers away from mRNA. In contrast, the FliW protein of Bacillus subtilis inhibits CsrA activity by binding to this protein, thereby establishing a checkpoint in flagellum morphogenesis. Turnover of CsrB and CsrC sRNAs in Escherichia coli requires a specificity protein of the GGDEF-EAL domain superfamily, CsrD, in addition to the housekeeping nucleases RNase E and PNPase. The Csr system of E. coli contains extensive autoregulatory circuitry, which governs the expression and activity of CsrA. Interaction of the Csr system with transcriptional regulatory networks results in a variety of complex response patterns. This minireview will highlight basic principles and new insights into the workings of these complex eubacterial regulatory systems.

  14. Posttranscriptional regulation on a global scale: Form and function of Csr/Rsm systems

    PubMed Central

    Romeo, Tony; Vakulskas, Christopher A.; Babitzke, Paul

    2012-01-01

    Summary Originally described as a repressor of gene expression in the stationary phase of growth, CsrA (RsmA) regulates primary and secondary metabolic pathways, biofilm formation, motility, virulence circuitry of pathogens, quorum sensing, and stress response systems by binding to conserved sequences in its target mRNAs and altering their translation and/or turnover. While the binding of CsrA to RNA is understood at an atomic level, new mechanisms of gene activation and repression by this protein are still emerging. In the γ-proteobacteria, small noncoding RNAs (sRNAs) use molecular mimicry to sequester multiple CsrA dimers away from mRNA. In contrast, the FliW protein of Bacillus subtilis inhibits CsrA activity by binding to this protein, thereby establishing a checkpoint in flagellum morphogenesis. Turnover of CsrB and CsrC sRNAs in Escherichia coli requires a specificity protein of the GGDEF-EAL domain superfamily, CsrD, in addition to the housekeeping nucleases RNase E and PNPase. The Csr system of E. coli contains extensive autoregulatory circuitry, which governs the expression and activity of CsrA. Interaction of the Csr system with transcriptional regulatory networks results in a variety of complex response patterns. This minireview will highlight basic principles and new insights into the workings of these complex eubacterial regulatory systems. PMID:22672726

  15. A direct link between the global regulator PhoP and the Csr regulon in Y. pseudotuberculosis through the small regulatory RNA CsrC.

    PubMed

    Nuss, Aaron M; Schuster, Franziska; Kathrin Heroven, Ann; Heine, Wiebke; Pisano, Fabio; Dersch, Petra

    2014-01-01

    In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrC(IP32953), which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs.

  16. Titration patterns of a murine sarcoma-leukemia virus complex: evidence for existence of competent sarcoma virions.

    PubMed

    O'Connor, T E; Fischinger, P J

    1968-01-19

    Stocks of inurine sarcoma virus show titration patterns ranging from one-to two-hit kinetics. The comparison of various titrations of this virus, both with and without added helper virus, to theoretical model systems composed of defined constituents, suggests the existence of a sarcoma virus that does not need coinfectinig murine leukemia virus to be manifested as a focus-forming unit. The behavior of such nondefective particles is compatible with a postulated leukemia-sarcoma virus hybrid.

  17. Cutaneous myeloid sarcoma of the penile foreskin.

    PubMed

    Afrose, Ruquiya; Nebhnani, Deepa; Wadhwa, Neelam

    2015-01-01

    Myeloid sarcoma, considered to herald the onset of a blast crisis in the setting of chronic myeloproliferative neoplasm/dysplasia, typically presents during the course of the disorder. Cutaneous involvement is uncommon and lesions on genital skin are seldom seen. We present a case of a well-differentiated myeloid sarcoma in the penile foreskin in an apparently healthy 29-year-old male presenting with phimosis. The unusual composition of the inflammatory cell infiltrate, and characteristic sparing of dermal blood vessels, nerves and smooth muscle fibres led to the correct diagnosis. Absence of commonly observed changes in the circumcision skin like those of balanitis xerotica was also helpful. Detailed hematological work up revealed a previously undiagnosed chronic myeloid leukemia in chronic phase. The patient also had simultaneous priapism, another rare presentation of chronic myeloid leukemia. One year hence, the patient is in hematological remission with no evidence of extramedullary disease. Although priapism has been described as a rare presenting symptom in chronic myeloid leukemia, the present case is unique as this is the first time a cutaneous myeloid sarcoma has been documented in the penile foreskin. PMID:24913300

  18. Sarcoma Immunotherapy: Past Approaches and Future Directions

    PubMed Central

    D'Angelo, S. P.; Tap, W. D.; Schwartz, G. K.; Carvajal, R. D.

    2014-01-01

    Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. PMID:24778572

  19. Potential molecular targets for Ewing's sarcoma therapy.

    PubMed

    Jully, Babu; Rajkumar, Thangarajan

    2012-10-01

    Ewing's sarcoma (ES) is a highly malignant tumor of children and young adults. Modern therapy for Ewing's sarcoma combines high-dose chemotherapy for systemic control of disease, with advanced surgical and/or radiation therapeutic approaches for local control. Despite optimal management, the cure rate for localized disease is only approximately 70%, whereas the cure rate for metastatic disease at presentation is less than 30%. Patients who experience long-term disease-free survival are at risk for significant side-effects of therapy, including infertility, limb dysfunction and an increased risk for second malignancies. The identification of new targets for innovative therapeutic approaches is, therefore, strongly needed for its treatment. Many new pharmaceutical agents have been tested in early phases of clinical trials in ES patients who have recurrent disease. While some agents led to partial response or stable disease, the percentages of drugs eliciting responses or causing an overall effect have been minimal. Furthermore, of the new pharmaceuticals being introduced to clinical practice, the most effective agents also have dose-limiting toxicities. Novel approaches are needed to minimize non-specific toxicity, both for patients with recurrence and at diagnosis. This report presents an overview of the potential molecular targets in ES and highlights the possibility that they may serve as therapeutic targets for the disease. Although additional investigations are required before most of these approaches can be assessed in the clinic, they provide a great deal of hope for patients with Ewing's sarcoma. PMID:23580819

  20. Diagnostic triage for sarcoma: an effective model for reducing referrals to the sarcoma multidisciplinary team

    PubMed Central

    Botchu, R; Ashford, R U; Rennie, W J

    2015-01-01

    Objective: Soft-tissue lesions are common and often benign. Owing to the rarity of soft-tissue sarcomas (STSs), evidence has shown that patients are increasingly referred urgently onto the 2-week wait pathway, which may have a detrimental impact on the management of patients with a proven STS. Imaging plays a vital role in lesion characterization and can be used to triage referrals to reduce the caseload of a sarcoma multidisciplinary team (MDT). In our institution, we established a sarcoma diagnostic triage meeting (SDTM). This study aimed to determine the effectiveness of the SDTM in reducing non-sarcomatous referrals to the main sarcoma MDT. Methods: A retrospective review of the SDTM minutes from July 2011 to June 2012 was performed. Data collected for each case included details of referrer, referral modality and referral outcome. Results: 165 cases were reviewed. 58% of referrals underwent a core biopsy or surgical excision with 85% benign pathology, the commonest being lipoma. 15% of referrals were sarcomatous lesions and were referred onwards to the main MDT. Conclusion: A total of 82% of the patients referred urgently with a suspicious soft-tissue mass was managed by the SDTM and hence not referred onwards to the East Midlands Sarcoma Service MDT. A diagnostic triage is effective in reducing the caseload burden of the main MDT and allowing it to be more effective. Advances in knowledge: Referrals based on imaging can be prioritized by diagnostic triage. Diagnostic triage established in our institution reduced 82% of MDT referrals allowing a more focused MDT discussion on patients with a proven sarcoma. PMID:25697295

  1. Status and Assessments of CSR GRACE Level-2 Data Products

    NASA Astrophysics Data System (ADS)

    Bettadpur, Srinivas; Kang, Zhigui; Nagel, Peter; Pastor, Rick; Poole, Steve; Ries, John; Save, Himanshu

    2015-04-01

    The joint NASA/DLR GRACE mission has successfully operated for more than 13 years, and has provided a remarkable record of global mass flux due to a large variety of geophysical and climate processes at various spatio-temporal scales. The University of Texas Center for Space Research (CSR) hosts the mission PI, and is responsible for delivery of operational (presently denoted as Release-05 or RL05) gravity field data products. In addition, CSR generates and distributes a variety of other gravity field data products, including products generated from the use of satellite laser ranging data. This poster will provide an overview of all these data products, their relative quality, potential applications, and future plans for their development and delivery.

  2. An untuned MA-loaded cavity for HIRFL-CSR

    NASA Astrophysics Data System (ADS)

    Mei, Li-Rong; Xu, Zhe; Yuan, You-Jin; Zhang, Sheng-Hu; Zhang, Zhou-Li; Zhang, Cong; Sun, Lie-Peng; Jin, Peng; Yue, Wei-Ming

    2010-08-01

    In order to realize high energy density physics and plasma physics research at HIRFL-CSR, a magnetic alloy (MA)-loaded cavity has been studied. According to the theoretical calculation and simulation for the MA-loaded cavity, we achieved a better result. The MA-loaded cavity had a higher μQf value, with a higher shunt impedance and a higher accelerating gradient. The accelerating gradient was about 95 kV/m at 1.8003 MHz, 130 kV/m at 0.9000 MHz. Compared with the ferrite-loaded cavities that are used at HIRFL-CSR, with about 10 kV/m accelerating gradient, the MA-loaded cavity obviously has an advantage. The results of the theoretical calculation and the simulation, which meet the design requirements are in good agreement.

  3. CSR GRACE Release-05 Data Products: Status & Assessments

    NASA Astrophysics Data System (ADS)

    Bettadpur, S. V.

    2013-12-01

    The joint NASA/DLR mission has provided a decade of ground-breaking insights into several aspects of the Earth system mass flux variability. The GRACE Science Data System has released the latest revision of the monthly gravity field time-series, dubbed Release-05 (RL05). Examination of this series shows a factor of two to three improvement, in terms of variance reduction, relative to the previous (RL04) release. In this paper, we provide a detailed assessment of the CSR RL05 time-series and describe the manner in which it improves upon the RL04 series. The focus of this paper is a characterization and detailed description of the errors in the CSR monthly gravity field time-series, including the changing character of the errors as the flight system passes through different stages in its 11 year lifetime.

  4. HADRON ACCELERATORS: HIRFL-CSR commissioning in 2006 and 2007

    NASA Astrophysics Data System (ADS)

    Xia, Jia-Wen; Yuan, You-Jin; Liu, Yong; Yang, Jian-Cheng; Xu, Hu-Shan; Xiao, Guo-Qing; Yang, Xiao-Dong; Zhang, Wei; Gao, Da-Qing; Zhou, Zhong-Zu; Mao, Rui-Shi; Mao, Li-Jun; He, Yuan; Xu, Zhe; Yang, Ya-Qing; Xiao, Chen; Yin, Da-Yu; Zhao, Tie-Cheng; Wu, Jun-Xia; Li, Guo-Hong; Li, Jie; Li, Peng; Li, Ke; Hu, Zheng-Guo

    2009-06-01

    HIRFL-CSR, a new heavy ion cooler-storage-ring system at IMP, had been in commissioning since the beginning of 2006. In the two years of 2006 and 2007 the CSR commissioning was finished, including the stripping injection (STI), electron-cooling with hollow electron beam, C-beam stacking with the combination of STI and e-cooling, the wide energy-range synchrotron ramping from 7 MeV/u to 1000 MeV/u by changing the RF harmonic-number at mid-energy, the multiple multi-turn injection (MMI), the beam accumulation with MMI and e-cooling for heavy-ion beams of Ar, Kr and Xe, the fast extraction from CSRm and single-turn injection to CSRe, beam stacking in CSRe and the RIBs mass-spectrometer test with the isochronous mode in CSRe by using the time-of-flight method.

  5. CsrA and Cra influence Shigella flexneri pathogenesis.

    PubMed

    Gore, Aja L; Payne, Shelley M

    2010-11-01

    Shigella flexneri is a facultative intracellular pathogen that invades and disrupts the colonic epithelium. In order to thrive in the host, S. flexneri must adapt to environmental conditions in the gut and within the eukaryotic cytosol, including variability in the available carbon sources and other nutrients. We examined the roles of the carbon consumption regulators CsrA and Cra in a cell culture model of S. flexneri virulence. CsrA is an activator of glycolysis and a repressor of gluconeogenesis, and a csrA mutant had decreased attachment and invasion of cultured cells. Conversely, Cra represses glycolysis and activates gluconeogenesis, and the cra mutant had an increase in both attachment and invasion compared to the wild-type strain. Both mutants were defective in plaque formation. The importance of the glycolytic pathway in invasion and plaque formation was confirmed by testing the effect of a mutation in the glycolysis gene pfkA. The pfkA mutant was noninvasive and had cell surface alterations as indicated by decreased sensitivity to SDS and an altered lipopolysaccharide profile. The loss of invasion by the csrA and pfkA mutants was due to decreased expression of the S. flexneri virulence factor regulators virF and virB, resulting in decreased production of Shigella invasion plasmid antigens (Ipa). These data indicate that regulation of carbon metabolism and expression of the glycolysis gene pfkA are critical for synthesis of the virulence gene regulators VirF and VirB, and both the glycolytic and gluconeogenic pathways influence steps in S. flexneri invasion and plaque formation. PMID:20713625

  6. Requirement of UAP56, URH49, RBM15, and OTT3 in the expression of Kaposi sarcoma-associated herpesvirus ORF57

    SciTech Connect

    Majerciak, Vladimir; Deng, Merlyn; Zheng Zhiming

    2010-11-25

    Transport of mRNA from the nucleus to the cytoplasm is mediated by cellular RNA export factors. In this report, we examined how RNA export factors UAP56 and URH49, and RNA export cofactors RBM15 and OTT3, function in modulating KSHV ORF57 expression. We found that knockdown of each factor by RNAi led to decreased ORF57 expression. Specifically, reduced expression of either UAP56 or RBM15 led to nuclear export deficiency of ORF57 RNA. In the context of the KSHV genome, the near absence of UAP56 or RBM15 reduced the expression of both ORF57 and ORF59 (an RNA target of ORF57), but not ORF50. Collectively, our data indicate that the expression of KSHV ORF57 is regulated by cellular RNA export factors and cofactors at the posttranscriptional level.

  7. The seroprevalence of Kaposi's sarcoma associated herpes virus and human herpes virus-6 in pediatric patients with cancer and healthy children in a Turkish pediatric oncology center

    PubMed Central

    Tacyildiz, Nurdan; Dincaslan, Handan Ugur; Ozdemir, Halil; Yavuz, Gulsan; Unal, Emel; Ikinciogullari, Aydan; Dogu, Figen; Guloglu, Deniz; Suskan, Emine; Kose, Kenan

    2014-01-01

    Background: Many studies have tried to be establish a pathogenic role for human herpesvirus-6 and -8 (HHV-6, HHV-8) in malignant diseases, but whether these viruses plays a role in these pathologies remains unclear. HHV-6 and HHV-8 seropositivity were shown in a healthy population. There is no published data in Turkey about seroprevalence of these viruses. We aimed to determine the seroprevalence of HHV-6 and HHV-8 in pediatric cancer patients and to compare with healthy Turkish children's viral seroprevalence. Patients and Methods: Ninety-three pediatric cancer patients and 43 age-matched healthy children were included in the study. All sera were screened for antibodies to HHV-6 and HHV-8 by ELISA. Results: HHV-8 immunoglobulin G (IgG) was positive in 3.3% of lymphoma patients, in 4.8% of acute lymphoblastic leukemia (ALL) patients, in 4.8% of retinoblastoma patients and in 7% of healthy children. There was no significant difference in HHV-8 seroprevelance between these groups. HHV-6 seroprevalence was 81% in ALL patients, 70% in lymphoma group, 81% in retinoblastoma patients and 69.8% in healthy children. Although there was no significant difference in HHV-6 prevalence between healthy children and pediatric cancer patients, HHV-6 seropositivity tended to be higher in retinoblastoma patients under age of 4 years (odds ratio: 2.925). Conclusion: HHV-6 seroprevalence was higher than HHV-8 seropositivity in our study. Viral studies related HHV-6 seroprevelance in retinoblastoma patients would be useful to clarify if there is any etiological association between HHV-6 and retinoblastoma. PMID:25336794

  8. The central repeat domain 1 of Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents cis MHC class I peptide presentation

    SciTech Connect

    Kwun, Hyun Jin; Ramos da Silva, Suzane; Qin Huilian; Ferris, Robert L.; Tan Rusung; Chang Yuan; Moore, Patrick S.

    2011-04-10

    KSHV LANA1, a latent protein expressed during chronic infection to maintain a viral genome, inhibits major histocompatibility complex class I (MHC I) peptide presentation in cis as a means of immune evasion. Through deletional cloning, we localized this function to the LANA1 central repeat 1 (CR1) subregion. Other CR subregions retard LANA1 translation and proteasomal processing but do not markedly inhibit LANA1 peptide processing by MHC I. Inhibition of proteasomal processing ablates LANA1 peptide presentation. Direct expression of LANA1 within the endoplasmic reticulum (ER) overcomes CR1 inhibition suggesting that CR1 acts prior to translocation of cytoplasmic peptides into the ER. By physically separating CR1 from other subdomains, we show that LANA1 evades MHC I peptide processing by a mechanism distinct from other herpesviruses including Epstein-Barr virus (EBV). Although LANA1 and EBV EBNA1 are functionally similar, they appear to use different mechanisms to evade host cytotoxic T lymphocyte surveillance.

  9. Vironome of Kaposi Sarcoma associated Herpesvirus-Inflammatory Cytokine Syndrome in an AIDS patient reveals co-infection of Human Herpesvirus 8 and Human Herpesvirus 6A

    PubMed Central

    Tamburro, Kristen M.; Yang, Dongmei; Poisson, Jessica; Fedoriw, Yuri; Roy, Debasmita; Lucas, Amy; Sin, Sang-Hoon; Malouf, Nadia; Moylan, Vincent; Damania, Blossom; Moll, Stephan; van der Horst, Charles; Dittmer, Dirk P.

    2012-01-01

    KSHV inflammatory cytokine syndrome (KICS) is a newly described condition characterized by systemic illness as a result of systemic, lytic KSHV infection. We used Illumina sequencing to establish the DNA vironome of blood from such a patient. It identified concurrent high-level viremia of human herpesvirus (HHV) 8 and 6a. The HHV8 plasma viral load was 5,300,000 copies/ml, which is the highest reported to date; this despite <5 skin lesions and no HHV8 associated lymphoma. This is the first report of systemic HHV6a/KSHV co-infection in a patient. It is the first whole genome KSHV sequence to be determined directly from patient plasma rather than cultured or biopsied tumor material. This case supports KICS as a new clinical entity associated with KSHV. PMID:22925337

  10. CSR: Constrained Selfish Routing in Ad-Hoc Networks

    NASA Astrophysics Data System (ADS)

    Bassem, Christine; Bestavros, Azer

    Routing protocols for ad-hoc networks assume that the nodes forming the network are either under a single authority, or else that they would be altruistically forwarding data for other nodes with no expectation of a return. These assumptions are unrealistic since in ad-hoc networks, nodes are likely to be autonomous and rational (selfish), and thus unwilling to help unless they have an incentive to do so. Providing such incentives is an important aspect that should be considered when designing ad-hoc routing protocols. In this paper, we propose a dynamic, decentralized routing protocol for ad-hoc networks that provides incentives in the form of payments to intermediate nodes used to forward data for others. In our Constrained Selfish Routing (CSR) protocol, game-theoretic approaches are used to calculate payments (incentives) that ensure both the truthfulness of participating nodes and the fairness of the CSR protocol. We show through simulations that CSR is an energy efficient protocol and that it provides lower communication overhead in the best and average cases compared to existing approaches.

  11. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma.

    PubMed

    Puls, Florian; Niblett, Angela; Marland, Gillian; Gaston, Czar Louie L; Douis, Hassan; Mangham, D Chas; Sumathi, Vaiyapuri P; Kindblom, Lars-Gunnar

    2014-10-01

    BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis. PMID:24805859

  12. The Limits of Corporate Social Responsibility: Techniques of Neutralization, Stakeholder Management and Political CSR.

    PubMed

    Fooks, Gary; Gilmore, Anna; Collin, Jeff; Holden, Chris; Lee, Kelley

    2013-01-01

    Since scholarly interest in corporate social responsibility (CSR) has primarily focused on the synergies between social and economic performance, our understanding of how (and the conditions under which) companies use CSR to produce policy outcomes that work against public welfare has remained comparatively under-developed. In particular, little is known about how corporate decision-makers privately reconcile the conflicts between public and private interests, even though this is likely to be relevant to understanding the limitations of CSR as a means of aligning business activity with the broader public interest. This study addresses this issue using internal tobacco industry documents to explore British-American Tobacco's (BAT) thinking on CSR and its effects on the company's CSR Programme. The article presents a three-stage model of CSR development, based on Sykes and Matza's theory of techniques of neutralization, which links together: how BAT managers made sense of the company's declining political authority in the mid-1990s; how they subsequently justified the use of CSR as a tool of stakeholder management aimed at diffusing the political impact of public health advocates by breaking up political constituencies working towards evidence-based tobacco regulation; and how CSR works ideologically to shape stakeholders' perceptions of the relative merits of competing approaches to tobacco control. Our analysis has three implications for research and practice. First, it underlines the importance of approaching corporate managers' public comments on CSR critically and situating them in their economic, political and historical contexts. Second, it illustrates the importance of focusing on the political aims and effects of CSR. Third, by showing how CSR practices are used to stymie evidence-based government regulation, the article underlines the importance of highlighting and developing matrices to assess the negative social impacts of CSR.

  13. The Limits of Corporate Social Responsibility: Techniques of Neutralization, Stakeholder Management and Political CSR.

    PubMed

    Fooks, Gary; Gilmore, Anna; Collin, Jeff; Holden, Chris; Lee, Kelley

    2013-01-01

    Since scholarly interest in corporate social responsibility (CSR) has primarily focused on the synergies between social and economic performance, our understanding of how (and the conditions under which) companies use CSR to produce policy outcomes that work against public welfare has remained comparatively under-developed. In particular, little is known about how corporate decision-makers privately reconcile the conflicts between public and private interests, even though this is likely to be relevant to understanding the limitations of CSR as a means of aligning business activity with the broader public interest. This study addresses this issue using internal tobacco industry documents to explore British-American Tobacco's (BAT) thinking on CSR and its effects on the company's CSR Programme. The article presents a three-stage model of CSR development, based on Sykes and Matza's theory of techniques of neutralization, which links together: how BAT managers made sense of the company's declining political authority in the mid-1990s; how they subsequently justified the use of CSR as a tool of stakeholder management aimed at diffusing the political impact of public health advocates by breaking up political constituencies working towards evidence-based tobacco regulation; and how CSR works ideologically to shape stakeholders' perceptions of the relative merits of competing approaches to tobacco control. Our analysis has three implications for research and practice. First, it underlines the importance of approaching corporate managers' public comments on CSR critically and situating them in their economic, political and historical contexts. Second, it illustrates the importance of focusing on the political aims and effects of CSR. Third, by showing how CSR practices are used to stymie evidence-based government regulation, the article underlines the importance of highlighting and developing matrices to assess the negative social impacts of CSR. PMID:23997379

  14. Synovial sarcoma presenting as iliotibial band friction syndrome.

    PubMed

    Mesiha, Mena; Bauer, Thomas; Andrish, Jack

    2009-10-01

    Iliotibial band friction syndrome is a common entity that is often quickly diagnosed in orthopedic clinics. However, synovial sarcoma is an elusive clinical entity that appears around many joints with variable presentations. This case report is an example of a patient with a classic presentation of iliotibial band friction syndrome that was diagnosed as a synovial sarcoma on further investigation.

  15. TAZ and YAP are frequently activated oncoproteins in sarcomas

    PubMed Central

    Fullenkamp, Colleen A.; Hall, Sarah L.; Jaber, Omar I.; Pakalniskis, Brittany L.; Savage, Erica C.; Savage, Johanna M.; Ofori-Amanfo, Georgina K.; Lambertz, Allyn M.; Ivins, Stephanie D.; Stipp, Christopher S.; Miller, Benjamin J.; Milhem, Mohammed M.; Tanas, Munir R.

    2016-01-01

    TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP. PMID:27129148

  16. Postradiation sarcoma of bone: review of 78 Mayo Clinic cases.

    PubMed

    Weatherby, R P; Dahlin, D C; Ivins, J C

    1981-05-01

    Postradiation sarcoma of bone is an uncommon but serious sequela of radiation therapy. Seventy-eight Mayo Clinic patients have been treated for sarcomas arising in irradiated bones. They received their initial radiotherapy for a wide variety of nonneoplastic and neoplastic conditions, both benign and malignant. Thirty-five sarcomas arose in bone that was normal at the time of radiotherapy, and 43 arose in irradiated preexisting osseous lesions. The latent period between radiotherapy and diagnosis of sarcoma averaged 14.3 years. Ninety percent of the postradiation sarcomas were either osteosarcomas or fibrosarcomas; chondrosarcoma, malignant (fibrous) histiocytoma, malignant lymphoma, Ewing's tumor, and metastasizing chondroblastoma also occurred. Prompt radical surgery, when feasible, is usually the treatment of choice for the sarcoma. About 30% of patients with sarcomas of the extremities or craniofacial bones survived 5 years without recurrence; there were no disease-free survivors among patients with tumors of the vertebral column, pelvis, or shoulder girdle. The low risk of sarcoma following radiotherapy for the treatment of cancer should not be a contraindication to its use in these patients; however, radiation therapy for benign bone tumors should be reserved for lesions that are not amenable to surgical treatment. An unusual case is also reported herein in which a fibrosarcoma was discovered in the humerus of a patient who had received radiotherapy 55 years previously for a verified osteosarcoma in the same site. PMID:6939953

  17. Pazopanib in the management of advanced soft tissue sarcomas

    PubMed Central

    Cranmer, Lee D; Loggers, Elizabeth T; Pollack, Seth M

    2016-01-01

    Therapy of soft tissue sarcomas represents an area of significant unmet need in oncology. Angiogenesis has been explored as a potential target both preclinically and clinically, with suggestions of activity. Pazopanib is a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects. In a Phase II study, pazopanib demonstrated activity in strata enrolling patients with leiomyosarcomas, synovial sarcomas, or other sarcomas but not those enrolling adipocytic sarcomas. PALETTE, the pivotal Phase III trial, demonstrated improved progression-free survival versus placebo in pazopanib-treated patients previously treated for advanced soft tissue sarcomas. No survival benefit was observed, and adipocytic sarcomas were excluded. Health-related quality-of-life assessments indicated significant decrements in several areas affected by pazopanib toxicities, but no global deterioration. Cost-effectiveness analyses indicate that pazopanib therapy may or may not be cost-effective in different geographic settings. Pazopanib provides important proof-of-concept for antiangiogenic therapy in soft tissue sarcomas. Its use can be improved by further biological studies of its activity profile in sarcomas, studies of biological rational combinations, and clinicopathologic/biological correlative studies of activity to allow better drug targeting. PMID:27354810

  18. Acute Myeloid Leukemia Presenting as Intracerebral Granulocytic Sarcoma.

    PubMed

    Dhandapani, E; Thirumavalavan; Sowrirajan

    2015-10-01

    The CNS involvement of acute myeloid leukemia (AML) is more commonly manifest as meningeal involvement. Rarely it may present as intravascular tumor aggregates called granulocytic sarcoma which presents as intracranial hemorrhage. We are presenting a case of intracranial, intra-parenchymal granulocytic sarcoma (other names: chloroma, extramedullary myeloblastoma), presenting as acute hemiplegia without cerebral hemorrhage. PMID:27608697

  19. An unusual pleomorphic sarcoma in a hybrid mallard

    USGS Publications Warehouse

    Roffe, Thomas J.

    1987-01-01

    An unusual pleomorphic sarcoma from a hybrid mallard (Anas platyrhynchos) is described. Rhabdomyosarcoma was considered in the original differential diagnoses but rejected due to lack of specific characteristics generally seen in these tumors. The histologic characteristics described are consistent with mammalian sarcomas recorded in the literature as malignant fibrous histiocytoma.

  20. Comparative functional characterization of the CSR-1 22G-RNA pathway in Caenorhabditis nematodes.

    PubMed

    Tu, Shikui; Wu, Monica Z; Wang, Jie; Cutter, Asher D; Weng, Zhiping; Claycomb, Julie M

    2015-01-01

    As a champion of small RNA research for two decades, Caenorhabditis elegans has revealed the essential Argonaute CSR-1 to play key nuclear roles in modulating chromatin, chromosome segregation and germline gene expression via 22G-small RNAs. Despite CSR-1 being preserved among diverse nematodes, the conservation and divergence in function of the targets of small RNA pathways remains poorly resolved. Here we apply comparative functional genomic analysis between C. elegans and Caenorhabditis briggsae to characterize the CSR-1 pathway, its targets and their evolution. C. briggsae CSR-1-associated small RNAs that we identified by immunoprecipitation-small RNA sequencing overlap with 22G-RNAs depleted in cbr-csr-1 RNAi-treated worms. By comparing 22G-RNAs and target genes between species, we defined a set of CSR-1 target genes with conserved germline expression, enrichment in operons and more slowly evolving coding sequences than other genes, along with a small group of evolutionarily labile targets. We demonstrate that the association of CSR-1 with chromatin is preserved, and show that depletion of cbr-csr-1 leads to chromosome segregation defects and embryonic lethality. This first comparative characterization of a small RNA pathway in Caenorhabditis establishes a conserved nuclear role for CSR-1 and highlights its key role in germline gene regulation across multiple animal species.