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Sample records for aggressive human malignancies

  1. Hyaluronan in human malignancies

    SciTech Connect

    Sironen, R.K.; Tammi, M.; Tammi, R.; Auvinen, P.K.; Anttila, M.; Kosma, V-M.

    2011-02-15

    Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

  2. Malignant transformation of aggressive osteoblastoma to ostesarcoma.

    PubMed

    Görgün, Ömer; Salduz, Ahmet; Kebudi, Rejin; Özger, Harzem; Bilgiç, Bilge

    2016-08-01

    Osteoblastoma is a rare, bone-forming tumor, characterized by osteoid and woven bone production. A 13-year-old boy patient presented to our clinic with complaint of pain in his left proximal tibia. We performed curettage and bone grafting for the lesion diagnosed as osteoblastoma. Two years later, the patient admitted to the hospital with a mass in the same region which was diagnosed by biopsy to be osteosarcoma. Patient was performed reconstruction operation with local resection and mega prosthesis. Fourteen months after termination of chemotherapy, lung metastasis developed and the patient died consequently. In this article, we reported a patient with aggressive osteoblastoma of the left proximal tibia which recurred as an osteosarcoma and discussed the difficulties in the histopathological diagnosis and management of these patients. As some other cases in the literature, our case indicates that osteoblastomas may undergo malignant transformation. PMID:27499324

  3. Human Aggression and Suicide

    ERIC Educational Resources Information Center

    Brown, Gerald L.; Goodwin, Frederick K

    1986-01-01

    The central nervous system transmitter serontonin may be altered in aggressive/impulsive and suicidal behaviors in humans. These reports are largely consistent with animal data, and constitute one of the most highly replicated set of findings in biological psychiatry. Suggests that some suicidal behavior may be a special kind of aggressive…

  4. Non-Hodgkin's Malignant Lymphoma with Aggressive Development

    PubMed Central

    DANCIU, Cezara Elisabeta; HEROIU (CATALOIU), Adriana-Daniela; POPESCU, Cristian Radu

    2014-01-01

    Non-Hodgkin's malignant lymphoma is a hematologic malignant disease which usually responds to the polychemotherapy. We present a clinical case report of a 50 years old patient who develops an aggressive type of lymphoma. Patient develops a nodal Non-Hodgkin's malignant lymphoma who present at hospital admission as a huge tumor at the right side of the neck. Any type of treatment was a failure, the patient having a particularly aggressive form of lymphoma, resistant to all three chemotherapy regimens tested. Death occurs quickly, about one year after diagnosis and initiation of therapy. PMID:25553129

  5. Psychological Research on Human Aggressiveness

    ERIC Educational Resources Information Center

    Hamburg, D. A.; Brodie, H. K. H.

    1973-01-01

    Discusses research relating to the effects of hormones, neurophysiology, and the environment on animal and human aggression. Indicates that the interactions of biological, psychological and social processes in the development of human aggressiveness should constitute one of the principal frontiers for science in the next two decades. (JR)

  6. The nature of human aggression.

    PubMed

    Archer, John

    2009-01-01

    Human aggression is viewed from four explanatory perspectives, derived from the ethological tradition. The first consists of its adaptive value, which can be seen throughout the animal kingdom, involving resource competition and protection of the self and offspring, which has been viewed from a cost-benefit perspective. The second concerns the phylogenetic origin of aggression, which in humans involves brain mechanisms that are associated with anger and inhibition, the emotional expression of anger, and how aggressive actions are manifest. The third concerns the origin of aggression in development and its subsequent modification through experience. An evolutionary approach to development yields conclusions that are contrary to the influential social learning perspective, notably that physical aggression occurs early in life, and its subsequent development is characterized by learned inhibition. The fourth explanation concerns the motivational mechanisms controlling aggression: approached from an evolutionary background, these mechanisms range from the inflexible reflex-like responses to those incorporating rational decision-making. PMID:19411108

  7. Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors

    PubMed Central

    Roche, Magali; Wierinckx, Anne; Croze, Séverine; Rey, Catherine; Legras-Lachuer, Catherine; Morel, Anne-Pierre; Fusco, Alfredo; Raverot, Gérald; Trouillas, Jacqueline; Lachuer, Joel

    2015-01-01

    Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients. PMID:26322309

  8. Human Aggression Linked to Chemical Balance

    ERIC Educational Resources Information Center

    Science News, 1978

    1978-01-01

    Recent studies done by federal researchers indicate that human aggression may be affected by a critical balance of two or three key brain chemical neurotransmitters. Results of this study with human beings are included in this article. (MA)

  9. Lunar Influences on Human Aggression.

    ERIC Educational Resources Information Center

    Russell, Gordon W.; Dua, Manjula

    1983-01-01

    Used league records of all Canadian hockey games (N=426) played during a season to test a lunar-aggression hypothesis. Despite the use of multiple measures of lunar phase and interpersonal aggression, support for lunar influence was not forthcoming. Supplemental data revealed that beliefs in lunar influence are fairly common. (JAC)

  10. MIB-1 labeling indices in benign, aggressive, and malignant meningiomas: a study of 90 tumors.

    PubMed

    Abramovich, C M; Prayson, R A

    1998-12-01

    Predicting tumor behavior in meningiomas based on histology alone has been problematic. This study retrospectively compares histology and MIB-1 (cell proliferation marker) labeling indices (LI) in benign, aggressive, and malignant meningiomas. Six histological features, including mitoses, necrosis, loss of pattern, hypervascularity/hemosiderin deposition, prominent nucleoli, and nuclear pleomorphism, were compared in 90 meningiomas (Fisher's exact test). Tumors with two or more of the above features were designated as aggressive meningiomas. Malignant meningiomas were characterized by brain invasion or metastasis. The MIB-1 LIs (% positive tumor cell nuclei) were compared between the three groups (Kruskal-Wallis test, Wilcoxon two-sample test). Of the benign meningiomas (n=37; mean age, 54 years), 41% had one of the six histological features, with nuclear pleomorphism (n=10) being the most frequent. The aggressive tumors (n=29; mean age, 61 years) were characterized by nuclear pleomorphism (n=28), mitoses (n=20), necrosis (n=16), loss of pattern (n=16), prominent nucleoli (n=6), and hypervascularity/hemosiderin deposition (n=5). Malignant tumors (n=24; mean age, 59 years) were characterized by nuclear pleomorphism (n=22), mitoses (n=21), loss of pattern (n=21), necrosis (n=21), nucleoli (n=17), and hypervascularity/hemosiderin deposition (n=3). Significant differences were found between the aggressive and malignant groups with regard to loss of pattern, necrosis, and nucleoli (P=.0043, .011, and .00029, respectively). Mean MIB-1 LIs for the benign, aggressive, and malignant groups were 1.0% (range, 0 to 5.5%),5.5% (range, 0.1 to 32.5%), and 12.0% (range, 0.3 to 32.5%), respectively. Differences in the mean MIB-1 LI between groups were statistically significant, with P values of <.0001 (benign v aggressive) and .0012 (aggressive v malignant). Mean MIB-1 LIs for recurrent versus nonrecurrent tumors were 7.1% (range, 0 to 32.5%) versus 3.8% (range, 0 to 20.9%) (P=.32

  11. Delay in treatment of primary malignant and aggressive musculoskeletal tumours.

    PubMed

    Pan, K L; Zolqarnain, A; Chia, Y Y

    2006-02-01

    Patients with aggressive musculoskeletal tumours often arrive at specialised treatment centres late. Such a delay could mean disfavour for potentially curable or long-term disease-free outcome of limb preserving surgery. This study was undertaken to identify the underlying problem-related delay with a view to propose solution for solving it. We reviewed 30 patients to determine the periods of delay between onset of the first symptom and the definitive treatment. The delays were categorized as 'patient' delay, 'referral' delay and 'treatment' delay. There was 'patient' delay in 57% of patients (n=17), ranging from 1 to 18 months; 'referral' delay in 67% of patients (n=20) ranging from 1 to 19 months and 23% of patients (n=7) had treatment delay (average 23 days) at the treatment centre. The causes of late arrival are not solely patient-related but are multifactorial. Measures to minimize such delays include enhancing awareness only with high index of suspicion among primary care practitioners, creating a special lane specialized imaging studies and establishing a dedicated musculoskeletal tumour unit. PMID:17042231

  12. IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer.

    PubMed

    Lee, Chia-Huei; Chang, Jeffrey Shu-Ming; Syu, Shih-Han; Wong, Thian-Sze; Chan, Jimmy Yu-Wai; Tang, Ya-Chu; Yang, Zhi-Ping; Yang, Wen-Chan; Chen, Chiung-Tong; Lu, Shao-Chun; Tang, Pei-Hua; Yang, Tzu-Ching; Chu, Pei-Yi; Hsiao, Jenn-Ren; Liu, Ko-Jiunn

    2015-04-01

    Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin-1 beta (IL-1β) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro-IL-1β expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4-Nitroquinolin-1-oxide (4-NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro-IL-1β was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine-derived nitrosamine ketone (NNK) and arecoline stimulated IL-1β secretion in an inflammasome-dependent manner. IL-1β treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL-6, IL-8, and growth-regulated oncogene-α following IL-1β stimulation. The conditioned medium of IL-1β-treated OSCC cells exerted significant proangiogenic effects. Crucially, IL-1β increased the invasiveness of OSCC cells through the epithelial-mesenchymal transition (EMT), characterized by downregulation of E-cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL-1β can be induced by tobacco and betel quid-related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC. PMID:25204733

  13. Oral malignant melanoma: An aggressive clinical entity - Report of a rare case with review of literature

    PubMed Central

    Hasan, Shamimul; Jamdar, Sami Faisal; Jangra, Jogender; Al Beaiji, Sadun Mohammad Al Ageel

    2016-01-01

    Melanomais one of the most dreaded and aggressive neoplasms, being derived from epidermal melanocytes. The majority of melanomas are seen to involve the skin, and primary mucosal melanomas account for less than 1% of all melanomas. Oral malignant melanomas (OMM) are asymptomatic at the initial presentation, but later they become painful with growth and expansion. In the late stages, the patient may present with ulceration, bleeding, tooth mobility, paresthesia, ill-fitting prosthesis, and delayed healing of the extraction sockets. Diagnosis is often delayed due to asymptomatic clinical presentation, with silent progression of the lesion. OMM are associated with poor prognosis due to their invasive and metastasizing tendencies. The condition has poor survival rates, and metastatic melanomas show even worse prognosis. The 5-year survival rate for OMM ranges 4.5–29%, with 18.5 months being the mean survival rate. The tumor is best managed by wide surgical resection; however, consideration should also be made for adjunctive therapies such as chemotherapy, immunotherapy, and radiotherapy. Recurrences may be seen even 10–15 years after the primary therapy. This paper aims to present an interesting report of aggressive OMM in a 50-year-old male patient and emphasizes the role of dental professionals in maintaining a high degree of vigilance for the pigmented lesions of the oral cavity. Pigmented lesions of uncertain origin should be routinely biopsied to rule out malignancy. Early diagnosis of this dreadful entity entails thorough history taking, physical examination, and radiographic features coupled with histopathology. PMID:27114959

  14. Oral malignant melanoma: An aggressive clinical entity - Report of a rare case with review of literature.

    PubMed

    Hasan, Shamimul; Jamdar, Sami Faisal; Jangra, Jogender; Al Beaiji, Sadun Mohammad Al Ageel

    2016-01-01

    Melanomais one of the most dreaded and aggressive neoplasms, being derived from epidermal melanocytes. The majority of melanomas are seen to involve the skin, and primary mucosal melanomas account for less than 1% of all melanomas. Oral malignant melanomas (OMM) are asymptomatic at the initial presentation, but later they become painful with growth and expansion. In the late stages, the patient may present with ulceration, bleeding, tooth mobility, paresthesia, ill-fitting prosthesis, and delayed healing of the extraction sockets. Diagnosis is often delayed due to asymptomatic clinical presentation, with silent progression of the lesion. OMM are associated with poor prognosis due to their invasive and metastasizing tendencies. The condition has poor survival rates, and metastatic melanomas show even worse prognosis. The 5-year survival rate for OMM ranges 4.5-29%, with 18.5 months being the mean survival rate. The tumor is best managed by wide surgical resection; however, consideration should also be made for adjunctive therapies such as chemotherapy, immunotherapy, and radiotherapy. Recurrences may be seen even 10-15 years after the primary therapy. This paper aims to present an interesting report of aggressive OMM in a 50-year-old male patient and emphasizes the role of dental professionals in maintaining a high degree of vigilance for the pigmented lesions of the oral cavity. Pigmented lesions of uncertain origin should be routinely biopsied to rule out malignancy. Early diagnosis of this dreadful entity entails thorough history taking, physical examination, and radiographic features coupled with histopathology. PMID:27114959

  15. Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas

    PubMed Central

    Zhang, Yan; Young, Eric D.; Bill, Katelynn; Belousov, Roman; Peng, Tingsheng; Lazar, Alexander J; Pollock, Raphael E; Simmons, Paul J.; Lev, Dina; Kolonin, Mikhail G.

    2013-01-01

    Liposarcomas are tumors arising in white adipose tissue (WAT) with avidity for local recurrence. Aggressive dedifferentiated liposarcomas (DDLS) may arise from well-differentiated subtypes (WDLS) upon disease progression, however, this key issue is unresolved due in large part to knowledge gaps about liposarcoma cellular composition. Here, we wished to improve insights into liposarcoma cellular hierarchy. Tumor section analysis indicated that the populations, distinguishable based on expression of CD34 (a marker of adipocyte progenitors) and CD36 (a marker of adipocyte differentiation), occupy distinct intra-tumoral locations in both WDLS and DDLS. Taking advantage of these markers, we separated cells from a panel of fresh human surgical specimens by fluorescence-activated cell sorting (FACS). Based on chromosome analysis and the culture phenotypes of the composing populations, we demonstrate that malignant cells comprise four mesenchymal populations distinguished by expression of CD34 and CD36, while vascular (CD31+) and hematopoietic (CD45+) components are non-neoplastic. Finally, we show that mouse xenografts are derivable from both CD36-negative and CD36-positive DDLS cells, and that each population recreates the heterogeneity of CD36 expression in vivo. Combined, our results show that malignant cells in WDLS and DDLS can be classified according to distinct stages of adipogenesis and indicate immonophenotypic plasticity of malignant liposarcoma cells. PMID:23770802

  16. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread.

    PubMed

    Dwivedi, Amit Nandan Dhar; Jain, Shivi; Dixit, Ruhi

    2015-03-16

    The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly. PMID:25789296

  17. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread

    PubMed Central

    Dwivedi, Amit Nandan Dhar; Jain, Shivi; Dixit, Ruhi

    2015-01-01

    The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly. PMID:25789296

  18. Primary vertebral tumors: a review of epidemiologic, histological and imaging findings, part II: locally aggressive and malignant tumors.

    PubMed

    Ropper, Alexander E; Cahill, Kevin S; Hanna, John W; McCarthy, Edward F; Gokaslan, Ziya L; Chi, John H

    2012-01-01

    This second part of a comprehensive review of primary vertebral tumors focuses on locally aggressive and malignant tumors. As discussed in the earlier part of the review, both benign and malignant types of these tumors affect the adult and the pediatric population, and an understanding of their subtleties may increase their effective resection. In this review, we discuss the epidemiologic, histological, and imaging features of the most common locally aggressive primary vertebral tumors (chordoma and giant-cell tumor) and malignant tumors (chondrosarcoma, Ewing sarcoma, multiple myeloma or plasmacytoma, and osteosarcoma). The figures used for illustration are from operative patients of the senior authors (Z.L.G. and J.H.C.). Taken together, parts 1 and 2 of this article provide a thorough and illustrative review of primary vertebral tumors. PMID:21768918

  19. Human-wildlife conflict: proximate predictors of aggression between humans and rhesus macaques in India.

    PubMed

    Beisner, Brianne A; Heagerty, Allison; Seil, Shannon K; Balasubramaniam, Krishna N; Atwill, Edward R; Gupta, Brij K; Tyagi, Praveen C; Chauhan, Netrapal P S; Bonal, B S; Sinha, P R; McCowan, Brenda

    2015-02-01

    Macaques live in close contact with humans across South and Southeast Asia, and direct interaction is frequent. Aggressive contact is a concern in many locations, particularly among populations of rhesus and longtail macaques that co-inhabit urbanized cities and towns with humans. We investigated the proximate factors influencing the occurrence of macaque aggression toward humans as well as human aggression toward macaques to determine the extent to which human behavior elicits macaque aggression and vice versa. We conducted a 3-month study of four free-ranging populations of rhesus macaques in Dehradun, India from October-December 2012, using event sampling to record all instances of human-macaque interaction (N = 3120). Our results show that while human aggression was predicted by the potential for economic losses or damage, macaque aggression was influenced by aggressive or intimidating behavior by humans as well as recent rates of conspecific aggression. Further, adult female macaques participated in aggression more frequently than expected, whereas adult and subadult males participated as frequently as expected. Our analyses demonstrate that neither human nor macaque aggression is unprovoked. Rather, both humans and macaques are responding to one another's behavior. Mitigation of human-primate conflict, and indeed other types of human-wildlife conflict in such coupled systems, will require a holistic investigation of the ways in which each participant is responding to, and consequently altering, the behavior of the other. PMID:25348896

  20. Maintenance Therapy with Interferon Alfa 2b Improves Outcome in Aggressive Malignant Lymphoma.

    PubMed

    Avilés, A; Díaz-Maqueo, J C; Talavera, A; García, E L; Nambo, M J

    1998-01-01

    To assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with malignant lymphoma on complete response after conventional chemotherapy we start a randomized clinical trial. One hundred and seventy patients were randomized to received either IFN 5.0 MU three time at week by one year or no further treatment, as control group. At a median follow-up of 9.0 years (range 4.3 to 11 years) median freedom from relapse (FFR) has not been reached in patients who received IFN, it is statistically significant to patients in control group with a median FFR of 60 months (p <.001). Actuarial curves show that at 10-years, 58 patients (66%, 95% confidence interval (CI) 53% to 79%) remain in first remission, statistical different to control group 33 patients (40%, 95% Cl: 33% to 57%) (p <.001). Event free survival (EFS) shown that a 10-years 63 patients (71%, 95% CI: 59% to 81%) are alive free of disease in the IFN arm compared to only 38 patients (45%, 95% CI: 37% to 57%) in the control group (p <.001). Toxicity was mild, 81 patients received the planned doses of IFN on time and 6 patients had transitory delay secondary to hematological toxicity (grade 1 or 2) and completed the treatment on 13 months. No late side effects has been observed. After a long term follow-up we confirm that IFN used as maintenance therapy improves outcome in patients with aggressive malignant lymphoma who were in complete remission after conventional chemotherapy without excessive toxicity. We feld that IFN will be consider in controlled clinical trials to define the role of this therapeutic option. PMID:27414082

  1. Human Breast Cancer Invasion and Aggression Correlates with ECM Stiffening and Immune Cell Infiltration

    PubMed Central

    Acerbi, I; Cassereau, L; Dean, I; Shi, Q; Au, A; Park, C; Chen, YY; Liphardt, J; Hwang, ES; Weaver, VM

    2015-01-01

    Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive Luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated, macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta. PMID:25959051

  2. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

    PubMed

    Acerbi, I; Cassereau, L; Dean, I; Shi, Q; Au, A; Park, C; Chen, Y Y; Liphardt, J; Hwang, E S; Weaver, V M

    2015-10-01

    Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta. PMID:25959051

  3. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

    PubMed

    Greening, David W; Ji, Hong; Chen, Maoshan; Robinson, Bruce W S; Dick, Ian M; Creaney, Jenette; Simpson, Richard J

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  4. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    PubMed Central

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  5. Human Aggression Across the Lifespan: Genetic Propensities and Environmental Moderators

    PubMed Central

    Tuvblad, Catherine; Baker, Laura A.

    2013-01-01

    This chapter reviews the recent evidence of genetic and environmental influences on human aggression. Findings from a large selection of the twin and adoption studies that have investigated the genetic and environmental architecture of aggressive behavior are summarized. These studies together show that about half (50%) of the variance in aggressive behavior is explained by genetic influences in both males and females, with the remaining 50% of the variance being explained by environmental factors not shared by family members. Form of aggression (reactive, proactive, direct/physical, indirect/relational), method of assessment (laboratory observation, self-report, ratings by parents and teachers), and age of the subjects—all seem to be significant moderators of the magnitude of genetic and environmental influences on aggressive behavior. Neither study design (twin vs. sibling adoption design) nor sex (male vs. female) seems to impact the magnitude of the genetic and environmental influences on aggression. There is also some evidence of gene-environment interaction (G × E) from both twin/adoption studies and molecular genetic studies. Various measures of family adversity and social disadvantage have been found to moderate genetic influences on aggressive behavior. Findings from these G × E studies suggest that not all individuals will be affected to the same degree by experiences and exposures, and that genetic predispositions may have different effects depending on the environment. PMID:22078481

  6. ACR Appropriateness Criteria Follow-Up of Malignant or Aggressive Musculoskeletal Tumors.

    PubMed

    Roberts, Catherine C; Kransdorf, Mark J; Beaman, Francesca D; Adler, Ronald S; Amini, Behrang; Appel, Marc; Bernard, Stephanie A; Fries, Ian Blair; Germano, Isabelle M; Greenspan, Bennett S; Holly, Langston T; Kubicky, Charlotte D; Shek-Man Lo, Simon; Mosher, Timothy J; Sloan, Andrew E; Tuite, Michael J; Walker, Eric A; Ward, Robert J; Wessell, Daniel E; Weissman, Barbara N

    2016-04-01

    Appropriate imaging modalities for the follow-up of malignant or aggressive musculoskeletal tumors include radiography, MRI, CT, (18)F-2-fluoro-2-deoxy-D-glucose PET/CT, (99m)Tc bone scan, and ultrasound. Clinical scenarios reviewed include evaluation for metastatic disease to the lung in low- and high-risk patients, for osseous metastatic disease in asymptomatic and symptomatic patients, for local recurrence of osseous tumors with and without significant hardware present, and for local recurrence of soft tissue tumors. The timing for follow-up of pulmonary metastasis surveillance is also reviewed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID:26922595

  7. Intranasal administration of oxytocin increases human aggressive behavior.

    PubMed

    Ne'eman, R; Perach-Barzilay, N; Fischer-Shofty, M; Atias, A; Shamay-Tsoory, S G

    2016-04-01

    Considering its role in prosocial behaviors, oxytocin (OT) has been suggested to diminish levels of aggression. Nevertheless, recent findings indicate that oxytocin may have a broader influence on increasing the salience of social stimuli and may therefore, under certain circumstances, increase antisocial behaviors such as aggression. This controversy led to the following speculations: If indeed oxytocin promotes primarily prosocial behavior, administration of OT is expected to diminish levels of aggression. However, if oxytocin mainly acts to increase the salience of social stimuli, it is expected to elevate levels of aggression following provocation. In order to test this assumption we used the Social Orientation Paradigm (SOP), a monetary game played against a fictitious partner that allows measuring three types of responses in the context of provocation: an aggressive response - reducing a point from the fictitious partner, an individualistic response - adding a point to oneself, and a collaborative response - adding half a point to the partner and half a point to oneself. In the current double-blind, placebo-controlled, within-subject study design, 45 participants completed the SOP task following the administration of oxytocin or placebo. The results indicated that among subjects naïve to the procedure oxytocin increased aggressive responses in comparison with placebo. These results support the saliency hypothesis of oxytocin and suggest that oxytocin plays a complex role in the modulation of human behavior. PMID:26862988

  8. Human malignant melanoma heterotransplanted to nude mice.

    PubMed

    Tropé, C; Johnsson, J E; Alm, P; Landberg, T; Olsson, H; Wennerberg, J

    1981-01-01

    Five different human malignant melanoma were heterotransplanted subcutaneously to nude mice. When small tissue pieces were used 3 out of 5 tumors grew. Subcutaneous injections of suspended tumor cells were also made, but all failed to take. Metastatic or infiltrative growth was never seen in the mice observed for up to 2.5 months. The successful grafts largely retained the original morphologicaL features. The three successfully transplanted tumors could all be serially transferred with 100% tumor take. In one case passage time was reduced from 40 days to 15 days. As measured with 3H-thymidine incorporation the proliferation rate increased during the passages. These changes might be due to a selection of more rapidly growing tumor cells in the nudes. PMID:7312076

  9. Immunoprevention of human papillomavirus-associated malignancies

    PubMed Central

    Wang1, Joshua W.; Hung, Chein-fu; Huh, Warner K.; Trimble, Cornelia L.; Roden, Richard B.S.

    2014-01-01

    Persistent infection by one of fifteen high risk human papillomavirus (hrHPV) types is a necessary but not sufficient cause of 5% of all human cancers. This provides a remarkable opportunity for cancer prevention via immunization. Since Harald zur Hausen’s pioneering identification of hrHPV types 16 and 18, found in ~50% and ~20% of cervical cancers respectively, two prophylactic HPV vaccines containing virus-like particles (VLP) of each genotype have been widely licensed. These vaccines are beginning to impact infection and HPV-associated neoplasia rates after immunization campaigns in adolescents. Here we review recent progress and opportunities to better prevent HPV-associated cancers, including: broadening immune-protection to cover all hrHPV types, reducing the cost of HPV vaccines especially for developing countries that have the highest rates of cervical cancer, and immune-based treatment of established HPV infections. Screening based upon George Papanicolaou’s cervical cytology testing, and more recently detection of hrHPV DNA/RNA, followed by ablative treatment of high grade cervical intraepithelial neoplasia (CIN2/3) have substantially reduced cervical cancer rates, and we examine their interplay with immune-based modalities for the prevention and eventual elimination of cervical cancer and other HPV-related malignancies. PMID:25488410

  10. Immunoprevention of human papillomavirus-associated malignancies.

    PubMed

    Wang, Joshua W; Hung, Chein-Fu; Huh, Warner K; Trimble, Cornelia L; Roden, Richard B S

    2015-02-01

    Persistent infection by one of 15 high-risk human papillomavirus (hrHPV) types is a necessary but not sufficient cause of 5% of all human cancers. This provides a remarkable opportunity for cancer prevention via immunization. Since Harald zur Hausen's pioneering identification of hrHPV types 16 and 18, found in approximately 50% and 20% of cervical cancers, respectively, two prophylactic HPV vaccines containing virus-like particles (VLP) of each genotype have been widely licensed. These vaccines are beginning to affect infection and HPV-associated neoplasia rates after immunization campaigns in adolescents. Here, we review recent progress and opportunities to better prevent HPV-associated cancers, including broadening immune protection to cover all hrHPV types, reducing the cost of HPV vaccines especially for developing countries that have the highest rates of cervical cancer, and immune-based treatment of established HPV infections. Screening based upon George Papanicolaou's cervical cytology testing, and more recently detection of hrHPV DNA/RNA, followed by ablative treatment of high-grade cervical intraepithelial neoplasia (CIN2/3) have substantially reduced cervical cancer rates, and we examine their interplay with immune-based modalities for the prevention and eventual elimination of cervical cancer and other HPV-related malignancies. PMID:25488410

  11. PTEN: Multiple Functions in Human Malignant Tumors

    PubMed Central

    Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Cesta Incani, Ursula; Del Curatolo, Anais; Inzerilli, Nicola; Nuzzo, Carmen M. A.; Vaccaro, Vanja; Vari, Sabrina; Cognetti, Francesco; Ciuffreda, Ludovica

    2015-01-01

    PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10 years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal, and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers, and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors. PMID:25763354

  12. Fluorescence Spectroscopy of Human Nonmalignant and Malignant Cells and Tissues.

    NASA Astrophysics Data System (ADS)

    Glassman, Wenling Sha

    This thesis explores steady state and time resolved fluorescence spectroscopy from human malignant and non -malignant cells and tissues. The focus of these studies are the analysis of the excitation spectra, emission spectra, and decay time based on the contribution from several key intrinsic fluorophors: NAD(P)H, flavins, tryptophan, elastin and collagen that exist in different amounts in the human tissues and cells. The comparison between the spectra from malignant and non-malignant cells and tissues gives information on the changes that occur from non-malignancy to malignancy in the cells and tissues. The spectra of tissues and cells are also compared to help in understanding what fluorophors are responsible for fluorescence spectral differences between the malignant and non-malignant tissues and cells. The results in this thesis show that the spectral differences between the normal and cancerous tissues and cells exist in various wavelength ranges. The experimental data from GYN tissues have shown with over 95% of the sensitivity and specificity to separate malignant from non-malignant tissues using 300nm excitation. The 340nm band, which is mostly in response to intrinsic fluorophor (amino acid tryptophan), from malignant tissues were relatively higher then that from the non-malignant tissues. This might have been caused by the higher concentration of free tryptophan in the malignant tumor when compared to that of the normal tissue. This has been found in medical clinical study. The experimental data in this thesis also show that the fluorescence intensities around 450nm-460nm, which are mostly due to the intrinsic fluorophor coenzyme NADH, from both malignant cells in vitro and tissues in vitro are relatively higher than from non-malignant cells in vitro and tissues in vitro. These findings are reinforced by the faster decay time of the NADH fluorescence from normal cells in vitro than from neoplasm cells in vitro. Thus, the NADH in the mitochondria might be

  13. Aggressive solitary intracranial metastatic malignant melanoma from a primary mediastinal tumour.

    PubMed

    Sivaraju, Laxminadh; Aryan, Saritha; Hegde, Vinay S; Ghosal, Nandita; Hegde, Alangar S

    2016-08-01

    Malignant melanoma is the third most common tumour to cause cerebral metastases, following breast and lung cancer. Central nervous system metastases occur in 10-40% of patients with melanoma. Intracranial metastasis from a primary malignant melanoma of the anterior mediastinum is uncommon. We report a case of solitary intracranial metastatic melanoma arising from a primary mediastinal tumour. We then discuss the clinico-radiological features and treatment options. PMID:27145991

  14. Hypomethylation of DNA from Benign and Malignant Human Colon Neoplasms

    NASA Astrophysics Data System (ADS)

    Goelz, Susan E.; Vogelstein, Bert; Hamilton, Stanley R.; Feinberg, Andrew P.

    1985-04-01

    The methylation state of DNA from human colon tissue displaying neoplastic growth was determined by means of restriction endonuclease analysis. When compared to DNA from adjacent normal tissue, DNA from both benign colon polyps and malignant carcinomas was substantially hypomethylated. With the use of probes for growth hormone, γ -globin, α -chorionic gonadotropin, and γ -crystallin, methylation changes were detected in all 23 neoplastic growths examined. Benign polyps were hypomethylated to a degree similar to that in malignant tissue. These results indicate that hypomethylation is a consistent biochemical characteristic of human colonic tumors and is an alteration in the DNA that precedes malignancy.

  15. [Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications].

    PubMed

    Blecic, Serge; Rynkowski, Michal; De Witte, Olivier; Lefranc, Florence

    2013-09-01

    In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors. PMID:23883552

  16. Infrared absorption spectra of human malignant tumor tissues

    NASA Astrophysics Data System (ADS)

    Skornyakov, I. V.; Tolstorozhev, G. B.; Butra, V. A.

    2008-05-01

    We used infrared spectroscopy methods to study the molecular structure of tissues from human organs removed during surgery. The IR spectra of the surgical material from breast, thyroid, and lung are compared with data from histological examination. We show that in malignant neoplasms, a change occurs in the hydrogen bonds of protein macromolecules found in the tissue of the studied organs. We identify the spectral signs of malignant pathology.

  17. Aggression in non-human vertebrates: Genetic mechanisms and molecular pathways.

    PubMed

    Freudenberg, Florian; Carreño Gutierrez, Hector; Post, Antonia M; Reif, Andreas; Norton, William H J

    2016-07-01

    Aggression is an adaptive behavioral trait that is important for the establishment of social hierarchies and competition for mating partners, food, and territories. While a certain level of aggression can be beneficial for the survival of an individual or species, abnormal aggression levels can be detrimental. Abnormal aggression is commonly found in human patients with psychiatric disorders. The predisposition to aggression is influenced by a combination of environmental and genetic factors and a large number of genes have been associated with aggression in both human and animal studies. In this review, we compare and contrast aggression studies in zebrafish and mouse. We present gene ontology and pathway analyses of genes linked to aggression and discuss the molecular pathways that underpin agonistic behavior in these species. © 2015 Wiley Periodicals, Inc. PMID:26284957

  18. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    PubMed

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc. PMID:26288127

  19. Epstein-Barr Virus MicroRNA Expression Increases Aggressiveness of Solid Malignancies

    PubMed Central

    Pandya, Deep; Mariani, Marisa; He, Shiquan; Andreoli, Mirko; Spennato, Manuela; Dowell-Martino, Candice; Fiedler, Paul; Ferlini, Cristiano

    2015-01-01

    The Cancer Genome Atlas (TCGA) microRNA (miRNA) initiative has revealed a pivotal role for miRNAs in cancer. Utilizing the TCGA raw data, we performed the first mapping of viral miRNA sequences within cancer and adjacent normal tissues. Results were integrated with TCGA RNA-seq to link the expression of viral miRNAs to the phenotype. Using clinical data and viral miRNA mapping results we also performed outcome analysis. Three lines of evidence lend credence to an active role of viral miRNAs in solid malignancies. First, expression of viral miRNA is consistently higher in cancerous compared to adjacent noncancerous tissues. Second, viral miRNA expression is associated with significantly worse clinical outcome among patients with early stage malignancy. These patients are also featured by increased expression of PD1/PD-L1, a pathway implicated in tumors escaping immune destruction. Finally, a particular cluster of EBV-miRNA (miR-BART2, miR-BART4, miR-BART5, miR-BART18, and miR-BART22) is associated with expression of cytokines known to inhibit host response to cancer. Quantification of specific viral miRNAs may help identify patients who are at risk of poor outcome. These patients may be candidates for novel therapeutic strategies incorporating antiviral agents and/or inhibitors of the PD-1/PD-L1 pathway. PMID:26375401

  20. Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells

    PubMed Central

    Mezzapelle, Rosanna; Rrapaj, Eltjona; Gatti, Elena; Ceriotti, Chiara; Marchis, Francesco De; Preti, Alessandro; Spinelli, Antonello E.; Perani, Laura; Venturini, Massimo; Valtorta, Silvia; Moresco, Rosa Maria; Pecciarini, Lorenza; Doglioni, Claudio; Frenquelli, Michela; Crippa, Luca; Recordati, Camilla; Scanziani, Eugenio; de Vries, Hilda; Berns, Anton; Frapolli, Roberta; Boldorini, Renzo; D’Incalci, Maurizio; Bianchi, Marco E.; Crippa, Massimo P.

    2016-01-01

    Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. PMID:26961782

  1. Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells.

    PubMed

    Mezzapelle, Rosanna; Rrapaj, Eltjona; Gatti, Elena; Ceriotti, Chiara; Marchis, Francesco De; Preti, Alessandro; Spinelli, Antonello E; Perani, Laura; Venturini, Massimo; Valtorta, Silvia; Moresco, Rosa Maria; Pecciarini, Lorenza; Doglioni, Claudio; Frenquelli, Michela; Crippa, Luca; Recordati, Camilla; Scanziani, Eugenio; de Vries, Hilda; Berns, Anton; Frapolli, Roberta; Boldorini, Renzo; D'Incalci, Maurizio; Bianchi, Marco E; Crippa, Massimo P

    2016-01-01

    Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. PMID:26961782

  2. Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.

    PubMed

    Panosyan, Eduard H; Lasky, Joseph L; Lin, Henry J; Lai, Albert; Hai, Yang; Guo, Xiuqing; Quinn, Michael; Nelson, Stanley F; Cloughesy, Timothy F; Nghiemphu, P Leia

    2016-05-01

    Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development. PMID:26922345

  3. Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines

    PubMed Central

    Kim, H-A; Kim, M-C; Kim, N-Y; Kim, Y

    2015-01-01

    Deregulation of crucial embryonic pathways, including hedgehog signaling, has been frequently implicated in a variety of human cancers and is emerging as an important target for anticancer therapy. This study evaluated the potential anticancer effects of cyclopamine, a chemical inhibitor of hedgehog signaling, in human malignant mesothelioma (HMM) cell lines. Cyclopamine treatment significantly decreased the proliferation of HMM cells by promoting apoptosis and shifting the cell cycle toward dormant phase. The clonogenicity and mobility of HMM cells were significantly decreased by cyclopamine treatment. Treatment of HMM cells with cyclopamine significantly reduced the abundance of side population cells, which were measured using an assay composed of Hoechst 33342 dye staining and subsequent flow cytometry. Furthermore, the expression levels of stemness-related genes were significantly affected by cyclopamine treatment. Taken together, the present study showed that targeting hedgehog signaling could reduce a more aggressive subpopulation of the cancer cells, suggesting an alternative approach for HMM therapy. PMID:26206198

  4. Denying humanness to others: a newly discovered mechanism by which violent video games increase aggressive behavior.

    PubMed

    Greitemeyer, Tobias; McLatchie, Neil

    2011-05-01

    Past research has provided abundant evidence that playing violent video games increases aggressive behavior. So far, these effects have been explained mainly as the result of priming existing knowledge structures. The research reported here examined the role of denying humanness to other people in accounting for the effect that playing a violent video game has on aggressive behavior. In two experiments, we found that playing violent video games increased dehumanization, which in turn evoked aggressive behavior. Thus, it appears that video-game-induced aggressive behavior is triggered when victimizers perceive the victim to be less human. PMID:21422464

  5. Some Issues Concerning Aggression and Violence in Human Beings.

    ERIC Educational Resources Information Center

    Ponton, Elizabeth

    1986-01-01

    Examines aggression and violence from an interdisciplinary perspective. Humanistic psychologist Rollo May sees violence as the end product of power deprivation. Anthropologists Konrad Lorenz and Robert Ardrey regard aggression as an innate biological drive. Anthropologist Richard Leakey views it as a learned, culturally determined response.…

  6. The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms.

    PubMed

    Waltes, Regina; Chiocchetti, Andreas G; Freitag, Christine M

    2016-07-01

    Aggression is an evolutionary conserved behavior present in most species including humans. Inadequate aggression can lead to long-term detrimental personal and societal effects. Here, we differentiate between proactive and reactive forms of aggression and review the genetic determinants of it. Heritability estimates of aggression in general vary between studies due to differing assessment instruments for aggressive behavior (AB) as well as age and gender of study participants. In addition, especially non-shared environmental factors shape AB. Current hypotheses suggest that environmental effects such as early life stress or chronic psychosocial risk factors (e.g., maltreatment) and variation in genes related to neuroendocrine, dopaminergic as well as serotonergic systems increase the risk to develop AB. In this review, we summarize the current knowledge of the genetics of human aggression based on twin studies, genetic association studies, animal models, and epigenetic analyses with the aim to differentiate between mechanisms associated with proactive or reactive aggression. We hypothesize that from a genetic perspective, the aminergic systems are likely to regulate both reactive and proactive aggression, whereas the endocrine pathways seem to be more involved in regulation of reactive aggression through modulation of impulsivity. Epigenetic studies on aggression have associated non-genetic risk factors with modifications of the stress response and the immune system. Finally, we point to the urgent need for further genome-wide analyses and the integration of genetic and epigenetic information to understand individual differences in reactive and proactive AB. © 2015 Wiley Periodicals, Inc. PMID:26494515

  7. Social neuroendocrinology of human aggression: examining the role of competition-induced testosterone dynamics.

    PubMed

    Carré, J M; Olmstead, N A

    2015-02-12

    A large body of evidence indicates that individual differences in baseline concentrations of testosterone (T) are only weakly correlated with human aggression. Importantly, T concentrations are not static, but rather fluctuate rapidly in the context of competitive interactions, suggesting that acute fluctuations in T may be more relevant for our understanding of the neuroendocrine mechanisms underlying variability in human aggression. In this paper, we provide an overview of the literature on T and human competition, with a primary focus on the role of competition-induced T dynamics in the modulation of human aggression. In addition, we discuss potential neural mechanisms underlying the effect of T dynamics on human aggression. Finally, we highlight several challenges for the field of social neuroendocrinology and discuss areas of research that may enhance our understanding of the complex bi-directional relationship between T and human social behavior. PMID:25463514

  8. Do human females use indirect aggression as an intrasexual competition strategy?

    PubMed Central

    Vaillancourt, Tracy

    2013-01-01

    Indirect aggression includes behaviours such as criticizing a competitor's appearance, spreading rumours about a person's sexual behaviour and social exclusion. Human females have a particular proclivity for using indirect aggression, which is typically directed at other females, especially attractive and sexually available females, in the context of intrasexual competition for mates. Indirect aggression is an effective intrasexual competition strategy. It is associated with a diminished willingness to compete on the part of victims and with greater dating and sexual behaviour among those who perpetrate the aggression. PMID:24167310

  9. Eliminating malignant contamination from therapeutic human spermatogonial stem cells

    PubMed Central

    Dovey, Serena L.; Valli, Hanna; Hermann, Brian P.; Sukhwani, Meena; Donohue, Julia; Castro, Carlos A.; Chu, Tianjiao; Sanfilippo, Joseph S.; Orwig, Kyle E.

    2013-01-01

    Spermatogonial stem cell (SSC) transplantation has been shown to restore fertility in several species and may have application for treating some cases of male infertility (e.g., secondary to gonadotoxic therapy for cancer). To ensure safety of this fertility preservation strategy, methods are needed to isolate and enrich SSCs from human testis cell suspensions and also remove malignant contamination. We used flow cytometry to characterize cell surface antigen expression on human testicular cells and leukemic cells (MOLT-4 and TF-1a). We demonstrated via FACS that EpCAM is expressed by human spermatogonia but not MOLT-4 cells. In contrast, HLA-ABC and CD49e marked >95% of MOLT-4 cells but were not expressed on human spermatogonia. A multiparameter sort of MOLT-4–contaminated human testicular cell suspensions was performed to isolate EpCAM+/HLA-ABC–/CD49e– (putative spermatogonia) and EpCAM–/HLA-ABC+/CD49e+ (putative MOLT-4) cell fractions. The EpCAM+/HLA-ABC–/CD49e– fraction was enriched for spermatogonial colonizing activity and did not form tumors following human-to–nude mouse xenotransplantation. The EpCAM–/HLA-ABC+/CD49e+ fraction produced tumors following xenotransplantation. This approach could be generalized with slight modification to also remove contaminating TF-1a leukemia cells. Thus, FACS provides a method to isolate and enrich human spermatogonia and remove malignant contamination by exploiting differences in cell surface antigen expression. PMID:23549087

  10. When Violence Pays: A Cost-Benefit Analysis of Aggressive Behavior in Animals and Humans

    PubMed Central

    Georgiev, Alexander V.; Klimczuk, Amanda C. E.; Traficonte, Daniel M.

    2013-01-01

    An optimization analysis of human behavior from a comparative perspective can improve our understanding of the adaptiveness of human nature. Intra-specific competition for resources provides the main selective pressure for the evolution of violent aggression toward conspecifics, and variation in the fitness benefits and costs of aggression can account for inter-specific and inter-individual differences in aggressiveness. When aggression reflects competition for resources, its benefits vary in relation to the characteristics of the resources (their intrinsic value, abundance, spatial distribution, and controllability) while its costs vary in relation to the characteristics of organisms and how they fight (which, in turn, affects the extent to which aggression entails risk of physical injury or death, energetic depletion, exposure to predation, psychological and physiological stress, or damage to social relationships). Humans are a highly aggressive species in comparison to other animals, probably as a result of an unusually high benefit-to-cost ratio for intra-specific aggression. This conclusion is supported by frequent and widespread occurrence of male-male coalitionary killing and by male-female sexual coercion. Sex differences in violent aggression in humans and other species probably evolved by sexual selection and reflect different optimal competitive strategies for males and females. PMID:23864299

  11. Malignant transformation in human chondrosarcoma cells supported by telomerase activation and tumor suppressor inactivation.

    PubMed

    Martin, James A; Forest, Erin; Block, Joel A; Klingelhutz, Aloysius J; Whited, Brent; Gitelis, Steven; Wilkey, Andrew; Buckwalter, Joseph A

    2002-09-01

    Human chondrosarcomas do not respond to current chemotherapies or radiation therapy, and their size and histological appearance do not reliably predict the risk of local recurrence and metastases, making selection of surgical treatment difficult. Identifying mechanisms responsible for the proliferation and invasive behavior of these tumors would be of immense clinical value. We hypothesized that telomerase expression is one of these mechanisms. We detected telomerase expression in 7 of 16 chondrosarcomas, but cells cultured from telomerase-negative chondrosarcomas acquired strong telomerase activity and lost tumor suppressor activity after their establishment in culture. These changes were associated with accelerated indefinite cell proliferation, morphological transition, and increased invasive activity, indicating that telomerase activation and loss of cell cycle control leads to the emergence of aggressive cells from chondrosarcoma cell populations. These observations may lead to better understanding of the factors responsible for malignant transformation, local recurrence, and metastases of cartilage neoplasms. PMID:12354749

  12. Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

    PubMed Central

    Gangoda, Lahiru; Keerthikumar, Shivakumar; Fonseka, Pamali; Edgington, Laura E.; Ang, Ching-Seng; Ozcitti, Cemil; Bogyo, Matthew; Parker, Belinda S.; Mathivanan, Suresh

    2015-01-01

    Neuroblastoma arises from the sympathetic nervous system and accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc is reported to occur in more than 20% of patients. While N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressive progression of the disease is poorly understood. N-Myc being a transcription factor can modulate the secretion of key proteins that may play a pivotal role in tumorigenesis. Characterising the soluble secreted proteins or secretome will aid in understanding their role in the tumour microenvironment, such as promoting cancer cell invasion and resistance to treatment. The aim of this study is to characterise the secretome of human malignant neuroblastoma SK-N-BE2 (N-Myc amplified, more aggressive) and SH-SY5Y (N-Myc non-amplified, less aggressive) cells. Conditioned media from SK-N-BE2 and SH-SY5Y cell lines were subjected to proteomics analysis. We report a catalogue of 894 proteins identified in the secretome isolated from the two neuroblastoma cell lines, SK-N-BE2 and SH-SY5Y. Functional enrichment analysis using FunRich software identified enhanced secretion of proteins implicated in cysteine peptidase activity in the aggressive N-Myc amplified SK-N-BE2 secretome compared to the less tumorigenic SH-SY5Y cells. Protein-protein interaction-based network analysis highlighted the enrichment of cathepsin and epithelial-to-mesenchymal transition sub-networks. For the first time, inhibition of cathepsins by inhibitors sensitized the resistant SK-N-BE2 cells to doxorubicin as well as decreased its migratory potential. The dataset of secretome proteins of N-Myc amplified (more aggressive) and non-amplified (less aggressive) neuroblastoma cells represent the first inventory of neuroblastoma secretome. The study also highlights the prominent role of cathepsins in the N-Myc amplified neuroblastoma pathogenesis. As N-Myc amplification

  13. Clinical significance of the integrin α6β4 in human malignancies

    PubMed Central

    Stewart, Rachel L.; O’Connor, Kathleen L.

    2015-01-01

    Integrin α6β4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6β4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor promoting transcription factors such as the NFATs and NFkB. Expression of integrin α6β4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6β4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6β4 that contribute to tumor progression. PMID:26121317

  14. Behavioural, hormonal and neurobiological mechanisms of aggressive behaviour in human and nonhuman primates.

    PubMed

    de Almeida, Rosa Maria Martins; Cabral, João Carlos Centurion; Narvaes, Rodrigo

    2015-05-01

    Aggression is a key component for social behaviour and can have an adaptive value or deleterious consequences. Here, we review the role of sex-related differences in aggressive behaviour in both human and nonhuman primates. First, we address aggression in primates, which varies deeply between species, both in intensity and in display, ranging from animals that are very aggressive, such as chimpanzees, to the nonaggressive bonobos. Aggression also influences the hierarchical structure of gorillas and chimpanzees, and is used as the main tool for dealing with other groups. With regard to human aggression, it can be considered a relevant adaptation for survival or can have negative impacts on social interaction for both sexes. Gender plays a critical role in aggressive and competitive behaviours, which are determined by a cascade of physiological changes, including GABAergic and serotonergic systems, and sex neurosteroids. The understanding of the neurobiological bases and behavioural determinants of different types of aggression is fundamental for minimising these negative impacts. PMID:25749197

  15. Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters

    PubMed Central

    Azzopardi, Maree; Thomas, Rajesh; Muruganandan, Sanjeevan; Lam, David C L; Garske, Luke A; Kwan, Benjamin C H; Rashid Ali, Muhammad Redzwan S; Nguyen, Phan T; Yap, Elaine; Horwood, Fiona C; Ritchie, Alexander J; Bint, Michael; Tobin, Claire L; Shrestha, Ranjan; Piccolo, Francesco; De Chaneet, Christian C; Creaney, Jenette; Newton, Robert U; Hendrie, Delia; Murray, Kevin; Read, Catherine A; Feller-Kopman, David; Maskell, Nick A; Lee, Y C Gary

    2016-01-01

    Introduction Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. Methods and analysis A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0–1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. Ethics and dissemination The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. Trial registration

  16. You Smell Dangerous: Communicating Fight Responses Through Human Chemosignals of Aggression.

    PubMed

    Mutic, Smiljana; Parma, Valentina; Brünner, Yvonne F; Freiherr, Jessica

    2016-01-01

    The ability to detect conspecifics that represent a potential harm for an individual represents a high survival benefit. Humans communicate socially relevant information using all sensory modalities, including the chemosensory systems. In study 1, we investigated whether the body odor of a stranger with the intention to harm serves as a chemosignal of aggression. Sixteen healthy male participants donated their body odor while engaging in a boxing session characterized by aggression-induction methods (chemosignal of aggression) and while performing an ergometer session (exercise chemosignal). Self-reports on aggression-related physical activity, motivation to harm and angry emotions selectively increased after aggression induction. In study 2, we examined whether receivers smelling such chemosignals experience emotional contagion (e.g., anger) or emotional reciprocity (e.g., anxiety). The aggression and exercise chemosignals were therefore presented to 22 healthy normosmic participants in a double-blind, randomized exposure during which affective/cognitive processing was examined (i.e., emotion recognition task, emotional stroop task). Behavioral results indicate that chemosignals of aggression induce an affective/cognitive modulation compatible with an anxiety reaction in the recipients. These findings are discussed in light of mechanisms of emotional reciprocity as a way to convey not only affective but also motivational information via chemosensory signals in humans. PMID:26453051

  17. Anticancer activity of glucomoringin isothiocyanate in human malignant astrocytoma cells.

    PubMed

    Rajan, Thangavelu Soundara; De Nicola, Gina Rosalinda; Iori, Renato; Rollin, Patrick; Bramanti, Placido; Mazzon, Emanuela

    2016-04-01

    Isothiocyanates (ITCs) released from their glucosinolate precursors have been shown to inhibit tumorigenesis and they have received significant attention as potential chemotherapeutic agents against cancer. Astrocytoma grade IV is the most frequent and most malignant primary brain tumor in adults without any curative treatment. New therapeutic drugs are therefore urgently required. In the present study, we investigated the in vitro antitumor activity of the glycosylated isothiocyanate moringin [4-(α-l-rhamnopyranosyloxy)benzyl isothiocyanate] produced from quantitative myrosinase-induced hydrolysis of glucomoringin (GMG) under neutral pH value. We have evaluated the potency of moringin on apoptosis induction and cell death in human astrocytoma grade IV CCF-STTG1 cells. Moringin showed to be effective in inducing apoptosis through p53 and Bax activation and Bcl-2 inhibition. In addition, oxidative stress related Nrf2 transcription factor and its upstream regulator CK2 alpha expressions were modulated at higher doses, which indicated the involvement of oxidative stress-mediated apoptosis induced by moringin. Moreover, significant reduction in 5S rRNA was noticed with moringin treatment. Our in vitro results demonstrated the antitumor efficacy of moringin derived from myrosinase-hydrolysis of GMG in human malignant astrocytoma cells. PMID:26882972

  18. A quick assessment tool for human-directed aggression in pet dogs.

    PubMed

    Klausz, Barbara; Kis, Anna; Persa, Eszter; Miklósi, Adám; Gácsi, Márta

    2014-01-01

    Many test series have been developed to assess dog temperament and aggressive behavior, but most of them have been criticized for their relatively low predictive validity or being too long, stressful, and/or problematic to carry out. We aimed to develop a short and effective series of tests that corresponds with (a) the dog's bite history, and (b) owner evaluation of the dog's aggressive tendencies. Seventy-three pet dogs were divided into three groups by their biting history; non-biter, bit once, and multiple biter. All dogs were exposed to a short test series modeling five real-life situations: friendly greeting, take away bone, threatening approach, tug-of-war, and roll over. We found strong correlations between the in-test behavior and owner reports of dogs' aggressive tendencies towards strangers; however, the test results did not mirror the reported owner-directed aggressive tendencies. Three test situations (friendly greeting, take-away bone, threatening approach) proved to be effective in evoking specific behavioral differences according to dog biting history. Non-biters differed from biters, and there were also specific differences related to aggression and fear between the two biter groups. When a subsample of dogs was retested, the test revealed consistent results over time. We suggest that our test is adequate for a quick, general assessment of human-directed aggression in dogs, particularly to evaluate their tendency for aggressive behaviors towards strangers. Identifying important behavioral indicators of aggressive tendencies, this test can serve as a useful tool to study the genetic or neural correlates of human-directed aggression in dogs. PMID:23945929

  19. Bcl-B Expression in Human Epithelial and Nonepithelial Malignancies

    PubMed Central

    Krajewska, Maryla; Kitada, Shinichi; Winter, Jane N.; Variakojis, Daina; Lichtenstein, Alan; Zhai, Dayong; Cuddy, Michael; Huang, Xianshu; Luciano, Frederic; Baker, Cheryl H.; Kim, Hoguen; Shin, Eunah; Kennedy, Susan; Olson, Allen H.; Badzio, Andrzej; Jassem, Jacek; Meinhold-Heerlein, Ivo; Duffy, Michael J.; Schimmer, Aaron D.; Tsao, Ming; Brown, Ewan; Sawyers, Anne; Andreeff, Michael; Mercola, Dan; Krajewski, Stan; Reed, John C.

    2014-01-01

    Purpose Apoptosis plays an important role in neoplastic processes. Bcl-B is an antiapoptotic Bcl-2 family member, which is known to change its phenotype upon binding to Nur77/TR3. The expression pattern of this protein in human malignancies has not been reported. Experimental Design We investigated Bcl-B expression in normal human tissues and several types of human epithelial and nonepithelial malignancy by immunohistochemistry, correlating results with tumor stage, histologic grade, and patient survival. Results Bcl-B protein was strongly expressed in all normal plasma cells but found in only18%of multiple myelomas (n = 133). Bcl-B immunostaining was also present in normal germinal center centroblasts and centrocytes and in approximately half of diffuse large B-cell lymphoma (n =48) specimens, whereas follicular lymphomas (n = 57) did not contain Bcl-B. In breast (n = 119), prostate (n = 66), gastric (n = 180), and colorectal (n = 106) adenocarcinomas, as well as in non – small cell lung cancers (n = 82), tumor-specific overexpression of Bcl-B was observed. Bcl-B expression was associated with variables of poor prognosis, such as high tumor grade in breast cancer (P = 0.009), microsatellite stability (P = 0.0002), and left-sided anatomic location (P = 0.02) of colorectal cancers, as well as with greater incidence of death from prostate cancer (P = 0.005) and shorter survival of patients with small cell lung cancer (P = 0.009). Conversely, although overexpressed in many gastric cancers, Bcl-B tended to correlate with better outcome (P = 0.01) and more differentiated tumor histology (P < 0.0001). Conclusions Tumor-specific alterations in Bcl-B expressionmay define subsets of nonepithelial and epithelial neoplasms with distinct clinical behaviors. PMID:18483366

  20. High expression of microRNA-155 is associated with the aggressive malignant behavior of gallbladder carcinoma.

    PubMed

    Kono, Hiroshi; Nakamura, Masafumi; Ohtsuka, Takao; Nagayoshi, Yosuke; Mori, Yasuhisa; Takahata, Shunichi; Aishima, Shinichi; Tanaka, Masao

    2013-07-01

    The prognosis of gallbladder cancer (GBC) remains poor despite recent advances in diagnostics and therapeutic strategies. Although the role of microRNAs (miRs) in GBC have not been well documented, miR-155 is known to be associated with inflammation-associated carcinogenesis in various types of cancers. The aim of this study was to investigate the clinical significance of miR-155 expression and the biological functions of miR-155 in GBC. The expression levels of miR-155 in surgically resected GBCs and gallbladders with pancreaticobiliary maljunction (PBM) were assessed by quantitative reverse transcription-polymerase chain reaction. The relationship between the expression levels of miR-155 and clinicopathological features of GBCs was analyzed. Human GBC cell lines were transfected with miR-155 inhibitors or mimics, and the effects on proliferation and invasion were assessed. miR-155 was significantly overexpressed in GBCs when compared with that in gallbladders with PBM (p=0.007) and normal gallbladders (p=0.04). The high expression level of miR-155 in GBCs was significantly associated with the presence of lymph node metastasis (p=0.01) and a poor prognosis (p=0.02). In vitro assays showed that aberrant expression of miR-155 significantly enhanced GBC cell proliferation and invasion. In conclusion, high miR-155 expression correlates with the aggressive behavior of GBCs, and miR-155 may become a prognostic marker and therapeutic target for GBC. PMID:23660842

  1. Immune reactivity in rats selected for the enhancement or elimination of aggressiveness towards humans.

    PubMed

    Idova, Galina; Alperina, Elizaveta; Plyusnina, Irina; Gevorgyan, Margarita; Zhukova, Elena; Konoshenko, Maria; Kozhemyakina, Rimma; Shui-Wu, Wang

    2015-11-16

    This study analyzes immune reactivity in two lines of rats selected for the enhancement or elimination of aggressiveness toward humans. Compared to nonaggressive line, aggressive rats showed increased blood ratio of CD4(+) and CD8(+)T lymphocytes, monocyte chemoattractant protein (MCP)-1 level both before and after immunization with sheep red blood cells (SRBC), enhanced IgM-immune response, as well as decreased level of interleukin (IL)-1α before immunization. However, antigen administration produced IL-1α increase in aggressive rats and its decrease in nonaggressive rats compared to non-immunized rats of the same lines. In addition, line-dependent alterations of T lymphocyte distribution in response to immune activation have been found only in the spleen. It is suggested that genetic differences in aggressive behavior may contribute to differences in immune function. PMID:26475956

  2. Violence among peoples in the light of human frustration and aggression.

    PubMed

    de Gaay Fortman, Bas

    2005-12-01

    This article sets out to provide a general background to the study of aggression in the social sciences, with a particular focus on its link to collective violence. While the study of what happens in the human brain appears to be already highly complex, analysis of violent behavior appears to be even more intricate. A deductive system in the sense of a general and clear system of propositions logically connected to one another is not feasible, principally because contrary to the natural sciences there are no verities but merely "stylized facts." One of these concerns the setting of human aggression in the light of frustration, as argued in the frustration-aggression hypothesis developed by Dollard et al. in 1939. Apart from conceiving of aggression as a pure human instinct, it may also be seen as externally driven, while a third possibility concerns culturally "learned" aggression. Proof of the latter is that the strongest correlation appears to be that between current violence and previous manifestations thereof. Attention is paid to the way in which Gurr has rooted his relative deprivation theory on causes of collective violence among peoples in mechanisms of frustration and aggression. That theory is taken a bit further in terms of "perceived acquirement failure," which appears to be highly connected to the role of the state. Based on certain observations by Hannah Arendt, the argument then proceeds to violence as a manifestation of powerlessness. Finally, this leads to a discussion of justice as a crucial factor in what Durkheim used to call a "right to conflict." In this way, human aggression is placed in a broad socio-economic context. PMID:16310766

  3. The role of human papilloma virus in urological malignancies.

    PubMed

    Heidegger, Isabel; Borena, Wegene; Pichler, Renate

    2015-05-01

    Human papillomavirus (HPV) is associated with cancer of the cervix uteri, penis, vulva, vagina, anus and oropharynx. However, the role of HPV infection in urological tumors is not yet clarified. HPV appears not to play a major causative role in renal and testicular carcinogenesis. However, HPV infection should be kept in mind regarding cases of prostate cancer, as well as in a sub-group of patients with bladder cancer with squamous differentiation. Concerning the role of HPV in penile cancer incidence, it is a recognized risk factor proven in a large number of studies. This short review provides an update regarding recent literature on HPV in urological malignancies, thereby, also discussing possible limitations on HPV detection in urological cancer. PMID:25964524

  4. Butyrate modulates antioxidant enzyme expression in malignant and non-malignant human colon tissues.

    PubMed

    Jahns, Franziska; Wilhelm, Anne; Jablonowski, Nadja; Mothes, Henning; Greulich, Karl Otto; Glei, Michael

    2015-04-01

    The induction of antioxidant enzymes is an important mechanism in colon cancer chemoprevention, but the response of human colon tissue to butyrate, a gut fermentation product derived from dietary fiber, remains largely unknown. Therefore, our study investigated the effect of a butyrate treatment on catalase (CAT) and superoxide dismutase (SOD2) in matched human colon tissues of different transformation stages (n = 3-15 in each group) ex vivo. By performing quantitative real-time PCR, Western blot, and spectrophotometric measurements, we found an increase in SOD2 at expression and activity level in colonic adenocarcinomas (mRNA: 1.96-fold; protein: 1.41-fold, activity: 1.8-fold; P < 0.05). No difference was detectable for CAT between normal, adenoma, and carcinoma colon tissues. Treatment of normal colon epithelium (12 h) with a physiologically relevant concentration of butyrate (10 mM) resulted in a significant increase (P < 0.05) in CAT mRNA (1.24-fold) and protein (1.39-fold), without affecting the enzymatic activity. Consequently, preliminary experiments failed to show any protective effect of butyrate against H2 O2 -mediated DNA damage. Despite a significantly lowered SOD2 transcript (0.51-fold, P < 0.01) and, to a lesser extent, protein level (0.86-fold) after butyrate exposure of normal colon cells, the catalytic activity was significantly enhanced (1.19-fold, P < 0.05), suggesting an increased protection against tissue superoxide radicals. In malignant tissues, greater variations in response to butyrate were observed. Furthermore, both enzymes showed an age-dependent decrease in activity in normal colon epithelium (CAT: r = -0.49, P = 0.09; SOD2: r = -0.58, P = 0.049). In conclusion, butyrate exhibited potential antioxidant features ex vivo but cellular consequences need to be investigated more in depth. PMID:24677319

  5. Greatwall promotes cell transformation by hyperactivating AKT in human malignancies

    PubMed Central

    Vera, Jorge; Lartigue, Lydia; Vigneron, Suzanne; Gadea, Gilles; Gire, Veronique; Del Rio, Maguy; Soubeyran, Isabelle; Chibon, Frederic; Lorca, Thierry; Castro, Anna

    2015-01-01

    The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL overexpression could participate in cancer development. We show that GWL overexpression promotes cell transformation and increases invasive capacities of cells through hyperphosphorylation of the oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and subsequent SCF-dependent degradation of the PHLPP phosphatase responsible for AKT dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in human colorectal tumoral tissues. Thus, GWL is a human oncoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies. DOI: http://dx.doi.org/10.7554/eLife.10115.001 PMID:26613407

  6. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    PubMed

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs. PMID:26526988

  7. Radiosensitization effect of zidovudine on human malignant glioma cells

    SciTech Connect

    Zhou Fuxiang; Liao Zhengkai; Dai Jing; Xiong Jie; Xie CongHua; Luo Zhiguo; Liu Shiquan; Zhou Yunfeng . E-mail: yfzhouwhu@163.com

    2007-03-09

    Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

  8. The motivation for biological aggression is an inherent and common aspect of the human behavioural repertoire.

    PubMed

    Rózsa, Lajos

    2009-02-01

    According to a widespread opinion shared by the vast majority of historians, instances of aggression using pathogen weapons constitute extremely rare events in human history. Similarly, students of human behaviour tend to believe that their science plays no role in explaining this phenomenon, which is held to be exceptional and abnormal. Contrary to this dominant view, I argue that Hamiltonian spite - like Hamiltonian altruism - is an inherent part of the human behavioural repertoire and it includes the use of pathogens for spiteful purposes. This paradigm is supported by the following observations. The use of pathogens as weapons emerged far before the scientific understanding of the nature of infections and epidemics, though it has been underrepresented in written history ever since. It is also present in our expectations concerning the likely behaviour of an enemy and it is also a frequent component of threats. Several languages appear to bear linguistic references to our motivation for biological aggression in profanity. Finally, given that wartime epidemics kill people at a rate comparable to (or exceeding) that of mechanical weapons, all wars fought in recorded history incorporated an element of aggression through biological means. On the basis of these arguments, I claim that the motivation for biological aggression is an inherent and common aspect of past and present human behaviour. PMID:19006651

  9. Malignant transformation of diploid human fibroblasts by transfection of oncogenes

    SciTech Connect

    McCormick, J.J.

    1992-01-01

    This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

  10. Engraftment of human blood malignancies to the turkey embryo: a robust new in vivo model.

    PubMed

    Grinberg, Igor; Reis, Arbel; Ohana, Avivit; Taizi, Moran; Cipok, Michal; Tavor, Sigal; Rund, Deborah; Deutsch, Varda R; Goldstein, Ronald S

    2009-10-01

    Xenografting of human blood malignancies to immunodeficient SCID mice is a powerful research tool. We evaluate here whether the immunodeficient turkey embryo can also serve as a xenograft host for human blood malignancies. Human leukemia, lymphoma and myeloma lines engrafted robustly into medullary and extramedullary tissues of turkey embryos as detected by PCR, FACS and histology in 8-10 days. Four of eleven patient AML samples also engrafted the bone marrow. Grafts of two lines responded to chemotherapy with doxorubicin. The turkey embryo therefore has the potential to be a complementary xenograft model for the study of human blood malignancies. PMID:19297019

  11. Inside the wire: aggression and functional interhemispheric connectivity in the human brain.

    PubMed

    Hofman, Dennis; Schutter, Dennis J L G

    2009-09-01

    An aggressive personality style has been proposed to arise from a cortical asymmetry between the left and right frontal hemispheres. In the present transcranial magnetic stimulation (TMS) study, evidence was sought for a link between an aggressive personality style and functional interhemispheric connectivity between the left and right frontal cortices. Functional interhemispheric connectivity was measured by determining transcallosal inhibition (TCI) using TMS in 20 healthy right-handed volunteers, who were given the Buss-Perry Aggression Questionnaire (AQ) and a selective attention task. Analyses showed higher levels of left-to-right TCI significantly correlated with higher AQ scores. Furthermore, increased left-to-right together with reduced right-to-left TCI was associated with a stronger attentional bias for angry faces. This is the first study to provide a biological mechanism underlying the asymmetry between left and right frontal cortex activity in human aggression. We conclude that an aggressive personality style and selective attention to angry faces are positively correlated with functional interhemispheric connectivity. PMID:19515104

  12. Revisiting the Serotonin-Aggression Relation in Humans: A Meta-analysis

    PubMed Central

    Duke, Aaron A.; Bègue, Laurent; Bell, Rob; Eisenlohr-Moul, Tory

    2013-01-01

    The inverse relation between serotonin and human aggression is often portrayed as “reliable,” “strong,” and “well-established” despite decades of conflicting reports and widely recognized methodological limitations. In this systematic review and meta-analysis we evaluate the evidence for and against the serotonin deficiency hypothesis of human aggression across four methods of assessing serotonin: (a) cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (CSF 5-HIAA), (b) acute tryptophan depletion, (c) pharmacological challenge, and (d) endocrine challenge. Results across 175 independent samples and over 6,500 total participants were heterogeneous, but, in aggregate, revealed a small, inverse correlation between central serotonin functioning and aggression, anger, and hostility, r = −.12. Pharmacological challenge studies had the largest mean weighted effect size, r = −.21, and CSF 5-HIAA studies had the smallest, r = −.06, p = .21. Potential methodological and demographic moderators largely failed to account for variability in study outcomes. Notable exceptions included year of publication (effect sizes tended to diminish with time) and self-versus other-reported aggression (other-reported aggression was positively correlated to serotonin functioning). We discuss four possible explanations for the pattern of findings: unreliable measures, ambient correlational noise, an unidentified higher-order interaction, and a selective serotonergic effect. Finally, we provide four recommendations for bringing much needed clarity to this important area of research: acknowledge contradictory findings and avoid selective reporting practices; focus on improving the reliability and validity of serotonin and aggression measures; test for interactions involving personality and/or environmental moderators; and revise the serotonin deficiency hypothesis to account for serotonin’s functional complexity. PMID:23379963

  13. Orthotopic Human Choroidal Melanoma Xenografts in Nude Rats with Aggressive and Nonaggressive PAS Staining Patterns

    PubMed Central

    Braun, Rod D.; Abbas, Asad

    2007-01-01

    PURPOSE Choroidal melanoma is the most common primary ocular cancer among the adult population. Patient survival has been linked to the periodic acid-Schiff base (PAS)–positive vascular patterns in the tumors. The presence of PAS-positive loops or cross-linking parallel channels is a marker of an aggressive tumor. The purpose of this study was to develop new xenograft models of human choroidal melanoma that predictably demonstrate the PAS staining patterns associated with nonaggressive and aggressive tumors in humans. METHODS Three human choroidal melanoma cell lines (C918, M619, and OCM-1) were used. C918 and M619 are considered aggressive, based on their ability to form PAS-positive channels in vitro. The nonaggressive OCM-1 cells do not form these channels. C918, M619, and OCM-1 spheroids were grown and implanted in the suprachoroidal space of 20, 17, and 16 WAG/RijHs-rnu nude rats, respectively. Tumors were grown for 1 to >4 weeks, and histology was performed to evaluate tumor growth and determine PAS labeling patterns. RESULTS Growth of C918, M619, and OCM-1 xenografts were histologically verified in 20/20, 15/17, and 16/16 rats, respectively. PAS staining revealed loops and cross-linking parallel channels, typical of aggressive tumors in patients, in 90% of C918 and 100% of M619 xenografts. Only 4 of 16 OCM-1 xenografts showed PAS-positive loops. The rest showed no PAS staining or only perivascular staining, indicative of nonaggressive tumors. CONCLUSIONS It is possible to grow human choroidal melanoma orthotopic xenografts in nude rats that reproduce the PAS staining patterns associated with aggressive and nonaggressive choroidal melanomas in patients. PMID:16384938

  14. Aggressive behavior in humans: Genes and pathways identified through association studies.

    PubMed

    Fernàndez-Castillo, Noèlia; Cormand, Bru

    2016-07-01

    Aggressive behavior has both genetic and environmental components. Many association studies have been performed to identify genetic factors underlying aggressive behaviors in humans. In this review we summarize the previous work performed in this field, considering both candidate gene (CGAS) and genome-wide association studies (GWAS), excluding those performed in samples where the primary diagnosis is a psychiatric or neurological disorder other than an aggression-related phenotype. Subsequently, we have studied the enrichment of pathways and functions in GWAS data. The results of our searches show that most CGAS have identified associations with genes involved in dopaminergic and serotonergic neurotransmission and in hormone regulation. On the other hand, GWAS have not yet identified genome-wide significant associations, but top nominal findings are related to several signaling pathways, such as axon guidance or estrogen receptor signaling, and also to neurodevelopmental processes and synaptic plasticity. Future studies should use larger samples, homogeneous phenotypes and standardized measurements to identify genes that underlie aggressive behaviors in humans. © 2016 Wiley Periodicals, Inc. PMID:26773414

  15. A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

    PubMed Central

    Richter, Sylvia; Gorny, Xenia; Marco-Pallares, Josep; Krämer, Ulrike M.; Machts, Judith; Barman, Adriana; Bernstein, Hans-Gert; Schüle, Rebecca; Schöls, Ludger; Rodriguez-Fornells, Antoni; Reissner, Carsten; Wüstenberg, Torsten; Heinze, Hans-Jochen; Gundelfinger, Eckart D.; Düzel, Emrah; Münte, Thomas F.; Seidenbecher, Constanze I.; Schott, Björn H.

    2011-01-01

    The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing. PMID:22232585

  16. The neurobiology of abnormal manifestations of aggression--a review of hypothalamic mechanisms in cats, rodents, and humans.

    PubMed

    Haller, Jozsef

    2013-04-01

    Aggression research was for long dominated by the assumption that aggression-related psychopathologies result from the excessive activation of aggression-promoting brain mechanisms. This assumption was recently challenged by findings with models of aggression that mimic etiological factors of aggression-related psychopathologies. Subjects submitted to such procedures show abnormal attack features (mismatch between provocation and response, disregard of species-specific rules, and insensitivity toward the social signals of opponents). We review here 12 such laboratory models and the available human findings on the neural background of abnormal aggression. We focus on the hypothalamus, a region tightly involved in the execution of attacks. Data show that the hypothalamic mechanisms controlling attacks (general activation levels, local serotonin, vasopressin, substance P, glutamate, GABA, and dopamine neurotransmission) undergo etiological factor-dependent changes. Findings suggest that the emotional component of attacks differentiates two basic types of hypothalamic mechanisms. Aggression associated with increased arousal (emotional/reactive aggression) is paralleled by increased mediobasal hypothalamic activation, increased hypothalamic vasopressinergic, but diminished hypothalamic serotonergic neurotransmission. In aggression models associated with low arousal (unemotional/proactive aggression), the lateral but not the mediobasal hypothalamus is over-activated. In addition, the anti-aggressive effect of serotonergic neurotransmission is lost and paradoxical changes were noticed in vasopressinergic neurotransmission. We conclude that there is no single 'neurobiological road' to abnormal aggression: the neural background shows qualitative, etiological factor-dependent differences. Findings obtained with different models should be viewed as alternative mechanisms rather than conflicting data. The relevance of these findings for understanding and treating of aggression

  17. Decreased expression of SLC 39A14 is associated with tumor aggressiveness and biochemical recurrence of human prostate cancer

    PubMed Central

    Xu, Xiao-Ming; Wang, Cheng-Gong; Zhu, Yu-Di; Chen, Wei-Hua; Shao, Si-Liang; Jiang, Fu-Neng; Liao, Qian-De

    2016-01-01

    Objective Solute carrier family 39, member 14 (SLC39A14), has been identified as a potential biomarker for various cancers. However, its roles in prostate cancer (PCa) are still unclear. The aim of this study was to investigate the clinical significance of SLC39A14 in patients with PCa and its functions in malignant phenotypes of PCa cells. Patients and methods Subcellular localization and expression pattern of SLC39A14 protein were examined by immunohistochemistry. Then, the associations of SLC39A14 expression with various clinicopathological features and clinical outcome of patients with PCa were statistically evaluated. Subsequently, the effects of SLC39A14 overexpression and knockdown on PCa cell proliferation and motility were, respectively, examined by Cell Counting Kit-8, transwell, and wound-healing assays. Results The immunoreactive scores of SLC39A14 protein in human PCa tissues were significantly lower than those in normal prostate tissues. Based on the Taylor dataset, SLC39A14 downregulation occurred more frequently in patients with PCa with a higher Gleason score (P<0.001), advanced clinical stage (P=0.008), presence of metastasis (P=0.009), and prostate-specific antigen failure (P=0.006). More interestingly, the survival analysis identified SLC39A14 as an independent factor for predicting the biochemical recurrence-free survival of patients with PCa (P=0.017). Functionally, the enforced expression of SLC39A14 could suppress cell proliferation, invasion, and migration of PCa cell lines in vitro, which could be reversed by the knockdown of SLC39A14. Conclusion Decreased expression of SLC39A14 may lead to malignant phenotypes of PCa cells and aggressive tumor progression in patients with PCa. Importantly, SLC39A14 may function as a tumor suppressor and a biomarker for screening patients with biochemical recurrence following radical prostatectomy. PMID:27471394

  18. Horizontal Transmission of Malignancy: In-Vivo Fusion of Human Lymphomas with Hamster Stroma Produces Tumors Retaining Human Genes and Lymphoid Pathology

    PubMed Central

    Goldenberg, David M.; Gold, David V.; Loo, Meiyu; Liu, Donglin; Chang, Chien-Hsing; Jaffe, Elaine S.

    2013-01-01

    We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially-transplanted (over 5–6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy. PMID:23405135

  19. In vivo imaging of human malignant mesothelioma grown orthotopically in the peritoneal cavity of nude mice.

    PubMed

    Feng, Mingqian; Zhang, Jingli; Anver, Miriam; Hassan, Raffit; Ho, Mitchell

    2011-01-01

    Malignant mesothelioma (MM) causes significant morbidity and mortality in patients. With increasing efforts devoted to developing therapeutics targeting mesothelioma, a xenograft mouse model with in vivo tumor imaging is especially desired for evaluating anti-tumor therapies. In the present study, we fluorescently labeled the NCI-H226 human mesothelioma cell line by a lentiviral vector harboring a luciferase-GFP (Luc/GFP) fusion gene driven by the RNA polymerase II promoter. After single-cell cloning by flow cytometry, a clone (named LMB-H226-GL) that stably expresses high levels of Luc/GFP was obtained. The in vivo tumorigenicity of Luc/GFP-labeled LMB-H226-GL was determined by using intraperitoneal injections of the cells in nude mice. LMB-H226-GL was found to be able to consistently form solid tumors in the peritoneum of mice. Tumor growth and aggressive progression could be quantitated via in vivo bioluminescence imaging. The model exhibited the pathological hallmarks consistent with the clinical progression of MM in terms of tumor growth and spread inside the peritoneal cavity. To evaluate the in vivo efficacy of drugs targeting mesothelioma, we treated mice with SS1P, a recombinant immunotoxin currently evaluated in Phase II clinical trials for treatment of mesothelioma. All the tumor-bearing mice had a significant response to SS1P treatment. Our results showed that this is a well-suited model for mesothelioma, and may be useful for evaluating other novel agents for mesothelioma treatment in vivo. PMID:21479131

  20. In Vivo Imaging of Human Malignant Mesothelioma Grown Orthotopically in the Peritoneal Cavity of Nude Mice

    PubMed Central

    Feng, Mingqian; Zhang, Jingli; Anver, Miriam; Hassan, Raffit; Ho, Mitchell

    2011-01-01

    Malignant mesothelioma (MM) causes significant morbidity and mortality in patients. With increasing efforts devoted to developing therapeutics targeting mesothelioma, a xenograft mouse model with in vivo tumor imaging is especially desired for evaluating anti-tumor therapies. In the present study, we fluorescently labeled the NCI-H226 human mesothelioma cell line by a lentiviral vector harboring a luciferase-GFP (Luc/GFP) fusion gene driven by the RNA polymerase II promoter. After single-cell cloning by flow cytometry, a clone (named LMB-H226-GL) that stably expresses high levels of Luc/GFP was obtained. The in vivo tumorigenicity of Luc/GFP-labeled LMB-H226-GL was determined by using intraperitoneal injections of the cells in nude mice. LMB-H226-GL was found to be able to consistently form solid tumors in the peritoneum of mice. Tumor growth and aggressive progression could be quantitated via in vivo bioluminescence imaging. The model exhibited the pathological hallmarks consistent with the clinical progression of MM in terms of tumor growth and spread inside the peritoneal cavity. To evaluate the in vivo efficacy of drugs targeting mesothelioma, we treated mice with SS1P, a recombinant immunotoxin currently evaluated in Phase II clinical trials for treatment of mesothelioma. All the tumor-bearing mice had a significant response to SS1P treatment. Our results showed that this is a well-suited model for mesothelioma, and may be useful for evaluating other novel agents for mesothelioma treatment in vivo. PMID:21479131

  1. Analysis and significance of the malignant 'eclipse' during the progression of primary cutaneous human melanomas.

    PubMed

    Kerbel, R S; Kobayashi, H; Graham, C H; Lu, C

    1996-04-01

    Why is it that primary melanomas which are less than 0.76 mm in thickness are almost always curable by surgery whereas thicker lesions are associated with a worse prognosis? Put in another way, why is it that such small increases in tumor thickness beyond 0.76 mm are often associated with the eventual formation of distant metastases and death? Part of the answer lies in the dramatic qualitative changes which can accompany small increases in the size of primary human melanomas. Thus, primary melanomas less than 0.76 mm in thickness usually contain very low proportions of metastatically competent tumor cells, whereas slightly thicker lesions can contain very high proportions of such cells, resulting from a selective growth advantage of the latter in the dermal mesenchyme. This overgrowth process is akin to a 'malignant eclipse' phenomenon (by analogy with a solar eclipse). We have been studying the causes of the malignant eclipse in melanoma, for which there are at least four possibilities: 1) an increase in autocrine, mitogenic growth factors by melanoma cells; 2) a decreased rate of apoptosis in the same population; 3) an acquired resistance to paracrine growth inhibitory factors; and 4) an increased ability to induce an angiogenic response. Evidence exists for all four possibilities. Our experimental approach to studying this problem has relied heavily on the use of cell lines obtained from early stage radial growth phase or vertical growth phase lesions which have a clinical-like inability to grow progressively in nude mice, and variants obtained from such lines which are aggressively tumorigenic. Using such paired lines, and other experimental systems, we have obtained evidence that shows early stage melanoma cell lines may be deficient in inducing angiogenesis, are highly sensitive to the growth inhibitory effects of a plethora of cytokines, including transforming growth factor beta, interleukin-6, and oncostatin M, and are more sensitive to undergoing

  2. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    SciTech Connect

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S. . E-mail: jrhim@cpdr.org

    2006-04-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

  3. Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

    PubMed Central

    Kushwah, Rahul; Guezguez, Borhane; Lee, Jung Bok; Hopkins, Claudia I; Bhatia, Mickie

    2014-01-01

    The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow. Based on recent insights, we summarize potential strategies for treatment of human hematological malignancies toward the concept of targeting Notch signaling for fate regulation. PMID:25252682

  4. Oncolytic virotherapy for human malignant mesothelioma: recent advances

    PubMed Central

    Boisgerault, Nicolas; Achard, Carole; Delaunay, Tiphaine; Cellerin, Laurent; Tangy, Frédéric; Grégoire, Marc; Fonteneau, Jean-François

    2015-01-01

    Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM. PMID:27512676

  5. Alterations in replication timing of cancer-related genes in malignant human breast cancer cells.

    PubMed

    Fritz, Andrew; Sinha, Seema; Marella, Narasimharao; Berezney, Ronald

    2013-05-01

    The replication timing of nine genes commonly involved in cancer was investigated in the MCF10 cell lines for human breast cancer progression. Six of these nine genes are part of a constellation of tumor suppressor genes that play a major role in familial human breast cancer (TP53, ATM, PTEN, CHK2, BRCA1, and BRCA2). Three other genes are involved in a large number of human cancers including breast as either tumor suppressors (RB1 and RAD51) or as an oncogene (cMYC). Five of these nine genes (TP53, RAD51, ATM, PTEN, and cMYC) show significant differences (P < 0.05) in replication timing between MCF10A normal human breast cells and the corresponding malignant MCF10CA1a cells. These differences are specific to the malignant state of the MCF10CA1a cells since there were no significant differences in the replication timing of these genes between normal MCF10A cells and the non-malignant cancer MCF10AT1 cells. Microarray analysis further demonstrated that three of these five genes (TP53, RAD51, and cMYC) showed significant changes in gene expression (≥2-fold) between normal and malignant cells. Our findings demonstrate an alteration in the replication timing of a small subset of cancer-related genes in malignant breast cancer cells. These alterations partially correlate with the major transcriptional changes characteristic of the malignant state in these cells. PMID:23161755

  6. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling

    SciTech Connect

    Yamada, Tamaki; Tsuda, Masumi; Ohba, Yusuke Kawaguchi, Hideaki; Totsuka, Yasunori; Shindoh, Masanobu

    2008-04-11

    Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.

  7. Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects.

    PubMed

    Coccaro, Emil F; Lee, Royce; Fanning, Jennifer R; Fuchs, Dietmar; Goiny, Michel; Erhardt, Sophie; Christensen, Kyle; Brundin, Lena; Coussons-Read, Mary

    2016-09-01

    Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects. PMID:27318828

  8. Malignancies in human immunodeficiency virus infected patients in India: Initial experience in the HAART era

    PubMed Central

    Sharma, Surendra K.; Soneja, Manish; Ranjan, Sanjay

    2015-01-01

    Background & objectives: Limited data are available on malignancies in human immunodeficiency virus (HIV)-infected patients from India. We undertook this study to assess the frequency and spectrum of malignancies in HIV-infected adult patients during the first eight years of highly active antiretroviral therapy (HAART) rollout under the National ART Programme at a tertiary care centre in New Delhi, India. Methods: Retrospective analysis of records of patients registered at the ART clinic between May 2005 and December 2013 was done. Results: The study included 2598 HIV-infected adult patients with 8315 person-years of follow up. Malignancies were diagnosed in 26 patients with a rate of 3.1 (IQR 2.1-4.5) cases per 1000 person-years. The median age for those diagnosed with malignancy was 45 (IQR 36-54) yr, which was significantly (P<0.01) higher compared with those not developing malignancies 35 (IQR 30-40) yr. The median baseline CD4+ T-cell count in patients with malignancy was 135 (IQR 68-269) cells/µl compared to 164 (IQR 86-243) cells/µl in those without malignancies. AIDS-defining cancers (ADCs) were seen in 19 (73%) patients, while non-AIDS-defining cancers (NADCs) were observed in seven (27%) patients. Malignancies diagnosed included non-Hodgkin's lymphoma (16), carcinoma cervix (3), Hodgkin's lymphoma (2), carcinoma lung (2), hepatocellular carcinoma (1), and urinary bladder carcinoma (1). One patient had primary central nervous system lymphoma. There was no case of Kaposi's sarcoma. Interpretation & conclusions: Malignancies in HIV-infected adult patients were infrequent in patients attending the clinic. Majority of the patients presented with advanced immunosuppression and the ADCs, NHL in particular, were the commonest malignancies. PMID:26658591

  9. Targeting eradication of malignant cells derived from human bone marrow mesenchymal stromal cells

    SciTech Connect

    Yang, Yingbin; Cai, Shaoxi; Yang, Li; Yu, Shuhui; Jiang, Jiahuan; Yan, Xiaoqing; Zhang, Haoxing; Liu, Lan; Liu, Qun; Du, Jun; Cai, Shaohui; Sung, K.L. Paul

    2010-12-10

    Human bone marrow mesenchymal stromal cells (hBMSC) have been shown to participate in malignant transformation. However, hampered by the low frequency of malignant transformation of hBMSC, we do not yet know how to prevent malignant transformation of implanted hBMSC. In this study, in order to establish a model for the eradication of hBMSC-derived malignant cells, a gene fusion consisting of a human telomerase (hTERT) promoter modified with both c-Myc and myeloid zinc finger protein2 (MZF-2) binding elements and followed by the E. coli cytosine deaminase (CD) and luciferase genes was stably transferred into hBMSC via lentiviral transduction; n-phosphonacelyl-L-aspartic acid (PALA) selection was used to generate malignant cell colonies derived from transduced hBMSC after treatment with the carcinogenic reagent BPDE. Cells that were amplified after PALA selection were used for transplantation and 5-FC pro-drug cytotoxicity tests. The results showed that PALA-resistant malignant cells could be generated from hBMSC co-induced with lentiviral transduction and treatment with Benzo(a)pyrene Diol Epoxide (BPDE); the modification of c-Myc and MZF-2 binding elements could remarkably enhance the transcriptional activities of the hTERT promoter in malignant cells, whereas transcriptional activity was depressed in normal hBMSC; malignant cells stably expressing CD under the control of the modified hTERT promoter could be eliminated by 5-FC administration. This study has provided a method for targeted eradication of malignant cells derived from hBMSC.

  10. Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers.

    PubMed

    Elgui de Oliveira, Deilson; Müller-Coan, Bárbara G; Pagano, Joseph S

    2016-08-01

    Cancer progression begins when malignant cells colonize adjacent sites, and it is characterized by increasing tumor heterogeneity, invasion and dissemination of cancer cells. Clinically, progression is the most relevant stage in the natural history of cancers. A given virus is usually regarded as oncogenic because of its ability to induce malignant transformation of cells. Nonetheless, oncogenic viruses may also be important for the progression of infection-associated cancers. Recently this hypothesis has been addressed because of studies on the contribution of the Epstein-Barr virus (EBV) to the aggressiveness of nasopharyngeal carcinoma (NPC). Several EBV products modulate cancer progression phenomena, such as the epithelial-mesenchymal transition, cell motility, invasiveness, angiogenesis, and metastasis. In this regard, there are compelling data about the effects of EBV latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs), as well as nontranslated viral RNAs, such as the EBV-encoded small nonpolyadenylated RNAs (EBERs) and viral microRNAs, notably EBV miR-BARTs. The available data on the mechanisms and players involved in the contribution of EBV infection to the aggressiveness of NPC are discussed in this review. Overall, this conceptual framework may be valuable for the understanding of the contribution of some infectious agents in the progression of cancers. PMID:27068530

  11. The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas.

    PubMed

    Ding, Mao-Hua; Wang, Zhen; Jiang, Lei; Fu, Hua-Lin; Gao, Jie; Lin, Xian-Bin; Zhang, Chun-Lei; Liu, Zhen-Yang; Shi, Yi-Fei; Qiu, Guan-Zhong; Ma, Yue; Cui, Da-Xiang; Hu, Guo-Han; Jin, Wei-Lin

    2015-07-01

    Malignant meningiomas are a rare meningioma subtype and tend to have post-surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N-terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1-PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas. PMID:25934289

  12. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

    PubMed Central

    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  13. Deleted in liver cancer protein family in human malignancies (Review)

    PubMed Central

    Lukasik, D.; Wilczek, E.; Wasiutynski, A.; Gornicka, B.

    2011-01-01

    The Deleted in Liver Cancer (DLC) protein family comprises proteins that exert their function mainly by the Rho GTPase-activating protein (GAP) domain and by regulation of the small GTPases. Since Rho GTPases are key factors in cell proliferation, polarity, cytoskeletal remodeling and migration, the aberrant function of their regulators may lead to cell transformation. One subgroup of these proteins is the DLC family. It was found that the first identified gene from this family, DLC1, is often lost in hepatocellular carcinoma and may be involved as a tumor suppressor in the liver. Subsequent studies evaluated the hypothesis that the DLC1 gene acts as a tumor suppressor, not only in liver cancer, but also in other types of cancer. Following DLC1, two other members of the DLC protein family, DLC2 and DLC3, were identified. However, limited published data are available concerning the role of these proteins in malignant transformation. This review focuses on the structure and the role of DLC1 and its relatives in physiological conditions and summarizes data published thus far regarding DLC function in the neoplastic process. PMID:22866123

  14. Intraoral malignant melanoma

    PubMed Central

    Babburi, Suresh; Subramanyam, R. V.; Aparna, V.; Sowjanya, P.

    2013-01-01

    Primary oral mucosal melanoma is a rare aggressive neoplasm and accounts for only 0.2-8% of all reported melanomas. It is a malignant neoplasm of melanocytes that may arise from a benign melanocytic lesion or de novo from melanocytes within normal skin or mucosa. It is considered to be the most deadly and biologically unpredictable of all human neoplasms, having the worst prognosis. In this article, we report a case of oral melanoma in a 52-year-old female patient with a chief complaint of black discolouration of the maxillary gingiva and palate. PMID:24249959

  15. Native cellular fluorescence characteristics of normal and malignant epithelial cells from human larynx

    NASA Astrophysics Data System (ADS)

    Parmeswearan, Diagaradjane; Ganesan, Singaravelu; Nalini, R.; Aruna, Prakasa R.; Veeraganesh, V.; Alfano, Robert R.

    1997-08-01

    Many applications of native fluorescence spectroscopy of intrinsic biomolecules such as Try, Tyr, Phe, NADH and FAD are reported on both the characterization and the discrimination of malignant tissues from the normal. In the field of diagnostic oncology, extensive studies have been made to distinguish the normal from malignant condition in breast, cervix, colon and bronchus. From the studies made by Alfano and co-workers, it was found that the emission at 340 and 440 nm under UV excitation have shown statistically significant difference between normal and malignant tissues. As tissues are highly complex in nature, it is worth to known whether the changes arise from cells or from other extracellular tissue components, so as to enable us to have better understanding on the transformation mechanism of normal into malignant and to go for an improved approach in the effective optical diagnosis. In this context, the present study addresses the question of whether there are differences in the native cellular fluorescence characteristics between normal and malignant epithelial cells from human larynx. With this aim, the UV fluorescence emission spectra in the wavelength region of excitation between 270 - 310 nm and the excitation spectra for 340 nm emission were measured and analyzed. In order to quantify the altered fluorescence signal between the normal and malignant cells, different ratio parameters were introduced.

  16. Targeting Androgen Receptor/Src Complex Impairs the Aggressive Phenotype of Human Fibrosarcoma Cells

    PubMed Central

    Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Background Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). Experimental Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. Conclusion This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the

  17. Big bad wolf or man's best friend? Unmasking a false wolf aggression on humans.

    PubMed

    Caniglia, R; Galaverni, M; Delogu, M; Fabbri, E; Musto, C; Randi, E

    2016-09-01

    The return of the wolf in its historical range is raising social conflicts with local communities for the perceived potential threat to people safety. In this study we applied molecular methods to solve an unusual case of wolf attack towards a man in the Northern Italian Apennines. We analysed seven biological samples, collected from the clothes of the injured man, using mtDNA sequences, the Amelogenin gene, 39 unlinked autosomal and four Y-linked microsatellites. Results indicated that the aggression was conducted by a male dog and not by a wolf nor a wolf x dog hybrid. Our findings were later confirmed by the victim, who confessed he had been attacked by the guard dog of a neighbour. The genetic profile of the owned dog perfectly matched with that identified from the samples previously collected. Our results prove once again that the wolf does not currently represent a risk for human safety in developed countries, whereas most animal aggressions are carried out by its domestic relative, the dog. PMID:27353864

  18. Swooping in the Suburbs; Parental Defence of an Abundant Aggressive Urban Bird against Humans.

    PubMed

    Lees, Daniel; Sherman, Craig D H; Maguire, Grainne S; Dann, Peter; Cardilini, Adam P A; Weston, Michael A

    2013-01-01

    Masked Lapwings, Vanellus miles, often come into 'conflict' with humans, because they often breed in close proximity to humans and actively defend their ground nests through aggressive behaviour, which typically involves swooping. This study examined whether defensive responses differed when nesting birds were confronted with different human stimuli ('pedestrian alone' vs. 'person pushing a lawn mower' approaches to nests) and tested the effectiveness of a commonly used deterrent (mock eyes positioned on the top or back of a person's head) on the defensive response. Masked Lapwings did not swoop closer to a person with a lawn mower compared with a pedestrian, but flushed closer and remained closer to the nest in the presence of a lawn mower. The presence of eye stickers decreased (pedestrians) and increased (lawn mowers) swooping behaviour. Masked Lapwings can discriminate between different human activities and adjust their defensive behaviour accordingly. We also conclude that the use of eye stickers is an effective method to mitigate the human-lapwing 'conflict' in some, but not all, circumstances. PMID:26479532

  19. Myosin VI contributes to malignant proliferation of human glioma cells

    PubMed Central

    Xu, Rong; Fang, Xu-hao

    2016-01-01

    Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma. PMID:26937209

  20. Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function

    SciTech Connect

    Hu, Yamei; Wang, Lingxian; Wang, Lu; Wu, Xuefeng; Wu, Xudong; Gu, Yanhong; Shu, Yongqian; Sun, Yang; Shen, Yan; Xu, Qiang

    2015-02-15

    Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SW872-S cells compared with its parental SW872 cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo. Treatment of cells with Jun-N-terminal kinase (JNK) inhibitor SP60015 or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. Bortezomib inhibited MDR1 expression and function more effectively in SW872-S cells than in SW872 cells, indicating that the increased cytotoxicity relies on the degree of proteasome inhibition. Furthermore, the pharmacological or genetic inhibition of sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2, which is highly expressed in SW872-S cells, resulted in partial reversal of cell growth inhibition and increase of MDR1 expression in bortezomib-treated SW872-S cells. These results show that bortezomib exhibits preferential cytotoxicity toward SW872-S cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma. - Highlights: • We compare the cytotoxicity of different drugs between SW872-S and SW872 cells. • Highly malignant liposarcoma cells SW872-S show hypersensitivity to bortezomib. • Apoptotic signaling is robustly enhanced in bortezomib-treated SW872-S cells. • Bortezomib has strong suppression on MDR1 expression and function in SW872-S cells. • Inhibition of SERCA2 protects SW872-S cells from bortezomib.

  1. Malignant Transformation of Hymenolepis nana in a Human Host.

    PubMed

    Muehlenbachs, Atis; Bhatnagar, Julu; Agudelo, Carlos A; Hidron, Alicia; Eberhard, Mark L; Mathison, Blaine A; Frace, Michael A; Ito, Akira; Metcalfe, Maureen G; Rollin, Dominique C; Visvesvara, Govinda S; Pham, Cau D; Jones, Tara L; Greer, Patricia W; Vélez Hoyos, Alejandro; Olson, Peter D; Diazgranados, Lucy R; Zaki, Sherif R

    2015-11-01

    Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer. PMID:26535513

  2. Zebrafish as a Model for the Study of Human Myeloid Malignancies.

    PubMed

    Lu, Jeng-Wei; Hsieh, Meng-Shan; Liao, Heng-An; Yang, Yi-Ju; Ho, Yi-Jung; Lin, Liang-In

    2015-01-01

    Myeloid malignancies are heterogeneous disorders characterized by uncontrolled proliferation or/and blockage of differentiation of myeloid progenitor cells. Although a substantial number of gene alterations have been identified, the mechanism by which these abnormalities interact has yet to be elucidated. Over the past decades, zebrafish have become an important model organism, especially in biomedical research. Several zebrafish models have been developed to recapitulate the characteristics of specific myeloid malignancies that provide novel insight into the pathogenesis of these diseases and allow the evaluation of novel small molecule drugs. This report will focus on illustrative examples of applications of zebrafish models, including transgenesis, zebrafish xenograft models, and cell transplantation approaches, to the study of human myeloid malignancies. PMID:26064935

  3. Transcriptional signatures of Ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer

    PubMed Central

    Smith, Steven C.; Baras, Alexander S.; Owens, Charles R.; Dancik, Garrett; Theodorescu, Dan

    2013-01-01

    RalA and RalB are small GTPases which support malignant development and progression in experimental models of bladder, prostate and squamous cancer. However, demonstration of their clinical relevance in human tumors remains lacking. Here, we developed tools to evaluate Ral protein expression, activation and transcriptional output and evaluated their association with clinicopathologic parameters in common human tumor types. In order to evaluate the relevance of Ral activation and transcriptional output, we correlated RalA and RalB activation with the mutational status of key human bladder cancer genes. We also identified and evaluated a “transcriptional signature” of genes that correlates with depletion of RalA and RalB in vivo. The Ral transcriptional signature score, but not protein expression as evaluated by immunohistochemistry, predicted disease stage, progression to muscle invasion, and survival in human bladder cancers, and metastatic and stem cell phenotypes in bladder cancer models. In prostate cancer, the Ral transcriptional signature score was associated with seminal vesicle invasion, androgen-independent progression, and reduced survival. In squamous cell carcinoma, this score was decreased in cancer tissues compared with normal mucosa, validating the experimental findings that Ral acts as a tumor-suppressor in this tumor type. Together, our findings demonstrate the clinical relevance of Ral in human cancer and provide a rationale for the development of Ral-directed therapies. PMID:22586063

  4. Assessment of cell surface glycoconjugates in normal, benign and malignant human nasal mucosa.

    PubMed

    Fang, S Y; Ohyama, M

    1997-12-01

    Aberrant glycosylation of proteins is a common characteristic of neoplastic changes. No reports exist relating cell surface glycoconjugates to normal, benign and malignant human nasal mucosa. Using lectin affinity histochemistry, glycoconjugate reactivities for peanut agglutinin (PNA), concanavalin A (Con A), Griffonia simplicifolia agglutinin II (GSA-II), soy bean agglutinin (SBA) and Ulex europaeus agglutinin l (UEA-I) were analysed in the following groups: normal, benign (polyp, papilloma, and inverted papilloma) and malignant (squamous cell carcinoma (SCC) alone, SCC arising in inverted papilloma, and adenocarcinoma). The positive rate of lectin staining was evaluated using a quantitative AutoCAD programme. We correlated glycoconjugate expression to clinical features, diagnosis, and malignant transformation. The positive rate of PNA after neuraminidase pre-treatment (NA-PNA) staining was higher in inverted papilloma, while all-negative in polyp and papilloma. NA-PNA staining may be used as a differential diagnostic tool. Both inverted papilloma portions and SCC portions of the SCC synchronized with inverted papilloma subjects showed similar Con A and NA-PNA staining patterns. The biological characteristics define inverted papilloma as a pre-malignant neoplasm. The positive rate of PNA staining was significantly higher in inverted papilloma (inverted papilloma transformed to SCC) compared to inverted papilloma alone. Hence, PNA staining may predict malignant transformation of inverted papilloma. However, further investigations are required to prove this possibly worthwhile prognostic marker. PMID:9532636

  5. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers

    PubMed Central

    Mendillo, Marc L.; Santagata, Sandro; Koeva, Martina; Bell, George W.; Hu, Rong; Tamimi, Rulla M.; Fraenkel, Ernest; Ince, Tan A.; Whitesell, Luke; Lindquist, Susan

    2012-01-01

    SUMMARY Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their non-transformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications. PMID:22863008

  6. From Melanocyte to Metastatic Malignant Melanoma

    PubMed Central

    Bandarchi, Bizhan; Ma, Linglei; Navab, Roya; Seth, Arun; Rasty, Golnar

    2010-01-01

    Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented. PMID:20936153

  7. Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells.

    PubMed

    Silva, Patrícia Benites Gonçalves da; Rodini, Carolina Oliveira; Kaid, Carolini; Nakahata, Adriana Miti; Pereira, Márcia Cristina Leite; Matushita, Hamilton; Costa, Silvia Souza da; Okamoto, Oswaldo Keith

    2016-08-01

    Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment. PMID:26358937

  8. Confocal reflectance imaging of excised malignant human bladder biopsies

    NASA Astrophysics Data System (ADS)

    Daniltchenko, Dmitri I.; Kastein, Albrecht; Koenig, Frank; Sachs, Markus; Schnorr, Dietmar; Al-Shukri, Salman; Loening, Stefan A.

    2004-08-01

    To evaluate the potential of reflectance confocal scanning laser microscopy (CM) for rapid imaging of non-processed freshly excised human bladder biopsies and cystectomy specimens. Freshly excised bladder tumors from three cystectomy specimens and random biopsies from twenty patients with a history of superficial bladder tumors were imaged with CM. Additional acetic acid washing prior to CM imaging was performed in some of the samples. Confocal images were compared to corresponding routine histologic sections. CM allows imaging of unprocessed bladder tissue at a subcellular resolution. Urothelial cell layers, collagen, vessels and muscle fibers can be rapidly visualized, in native state. In this regard, umbrella cells, basement membrane elucidated. Besides obvious limitations partly due to non-use of exogenous dyes, CM imaging offers several advantages: rapid imaging of the tissue in its native state like the basement membrane, normally seen only by using immunohistopathology. Reflectance CM opens a new avenue for imaging bladder cancer.

  9. Iron induces cancer stem cells and aggressive phenotypes in human lung cancer cells.

    PubMed

    Chanvorachote, Pithi; Luanpitpong, Sudjit

    2016-05-01

    Evidence has accumulated in support of the critical impact of cancer stem cells (CSCs) behind the chemotherapeutic failure, cancer metastasis, and subsequent disease recurrence and relapse, but knowledge of how CSCs are regulated is still limited. Redox status of the cells has been shown to dramatically influence cell signaling and CSC-like aggressive behaviors. Here, we investigated how subtoxic concentrations of iron, which have been found to specifically induce cellular hydroxyl radical, affected CSC-like subpopulations of human non-small cell lung carcinoma (NSCLC). We reveal for the first time that subchronic iron exposure and higher levels of hydroxyl radical correlated well with increased CSC-like phenotypes. The iron-exposed NSCLC H460 and H292 cells exhibited a remarkable increase in propensities to form CSC spheroids and to proliferate, migrate, and invade in parallel with an increase in level of a well-known CSC marker, ABCG2. We further observed that such phenotypic changes induced by iron were not related to an epithelial-to-mesenchymal transition (EMT). Instead, the sex-determining region Y (SRY)-box 9 protein (SOX9) was substantially linked to iron treatment and hydroxyl radical level. Using gene manipulations, including ectopic SOX9 overexpression and SOX9 short hairpin RNA knockdown, we have verified that SOX9 is responsible for CSC enrichment mediated by iron. These findings indicate a novel role of iron via hydroxyl radical in CSC regulation and its importance in aggressive cancer behaviors and likely metastasis through SOX9 upregulation. PMID:26911281

  10. Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells.

    PubMed

    Li, Yin; Mao, Yuehua; Rosal, Ramon V; Dinnen, Richard D; Williams, Ann C; Brandt-Rauf, Paul W; Fine, Robert L

    2005-05-20

    A p53 C-terminal peptide (aa 361-382, p53p), fused at its C-terminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The mechanism of cell death by p53p-Ant was through the FADD/caspase-8-dependent pathway without the involvement of the TRAIL pathway, Bcl-2 family and cell cycle changes. Blocking Fas with antibody did not alter the peptide's effect, suggesting that Fas itself did not interact with the peptide. Transfection with a dominant-negative FADD with a deleted N-terminus inhibited p53p-Ant-induced apoptosis. Its mechanism of action is related to the FADD-induced pathway without restoration of other p53 functions. p53p-Ant is a novel anticancer agent with unique selectivity for human cancer cells and could be useful as a prototype for the development of new anti-cancer agents. PMID:15645452

  11. From The Cover: Reconstruction of functionally normal and malignant human breast tissues in mice

    NASA Astrophysics Data System (ADS)

    Kuperwasser, Charlotte; Chavarria, Tony; Wu, Min; Magrane, Greg; Gray, Joe W.; Carey, Loucinda; Richardson, Andrea; Weinberg, Robert A.

    2004-04-01

    The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

  12. [Malignant peritoneal mesothelioma].

    PubMed

    Scripcariu, V; Dajbog, Elena; Lefter, L; Ferariu, D; Pricop, Adriana; Grigoraş, M; Dragomir, Cr

    2006-01-01

    Mesothelioma is a neoplasm originating from the mesothelial surface lining cells of the serous human cavities. It may involve the pleura, less frequently the peritoneum rarely, the pericardium, the tunica vaginalis testis and ovarian epithelium. Asbestos has been widely used in industry. A causal relationship between asbestos exposure and pleural, peritoneal and pericardial malign mesothelioma was suggested, the risk of cancer being correlated to cumulate exposure. Studies from National Cancer Institute, USA, show that the malignant mesothelioma is a rare and aggressive asbestos related malignancy. The symptomatology is insidious and poses difficult problems in diagnosis and treatment. This paper presents the case of a 59 year old patient with malignant peritoneal mesothelioma who worked almost 40 years as an electrician, exposed to asbestos fibers. He was hospitalized for important weight loss, abdominal pain and tiredness being diagnosed after imaging tests with a giant tumor, localized at the abdominal upper level, which seems to originate from the spleen's superior pole. During surgery we discovered a tumor with cystic parts, intense vascularized, which turn to be adherent in the upper side to the lower face of the left midriff cupola, to the spleen superior pole and 1/3 middle level of the great gastric curve. It was performed surgical ablation of the tumor, splenectomy with favorable postoperative evolution, the patient being now under chemotherapy treatment. PMID:17283842

  13. Claudin-20 promotes an aggressive phenotype in human breast cancer cells

    PubMed Central

    Martin, Tracey A; Lane, Jane; Ozupek, Hulya; Jiang, Wen G

    2013-01-01

    Claudin-20 is a member of the Claudin family of transmembrane proteins located in the tight junction (TJ) of cells of epithelial origin. Due to the increasing evidence supporting the role of TJ proteins in preventing tumor cell metastatic behavior, this study sought to evaluate the distribution of Claudin-20 in human breast cancer and the effect of Claudin-20 overexpression in human breast cancer cells. Q-PCR data from breast cancer primary tumors (n = 114) and matched background tissue (n = 30) showed that high claudin-20 expression was correlated with poor survival of patients with breast cancer (p = 0.022). Following transformation of the breast cancer cell lines MDA-MB-231 and MCF7 with a Claudin-20 expression construct functional assays were performed to ascertain changes in cell behavior. Claudin-20 transformed cells showed significantly increased invasion (p < 0.005) and were significantly less adhesive than wild type cells (p < 0.05). There was no effect on growth (either in vitro or in vivo) for either cell line. Overexpression of Claudin-20 resulted in reduced transepithelial resistance (induced by the motogen HGF at 25 ng/ml, p = 0.0007). Interestingly, this was not mirrored by paracellular permeability, as overexpression of Claudin-20 caused a decrease in permeability. The introduction of Claudin-20 into human breast cancer cells resulted in breast cancer cells with an aggressive phenotype and reduced trans-epithelial resistance. There was no corresponding decrease in paracellular permeability, indicating that this Claudin has a differential function in epithelial TJ. This provides further insight into the importance of correctly functioning TJ in preventing the progression of human breast cancer. PMID:24665404

  14. Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells

    PubMed Central

    Huang, Tzuu-Yuan; Hsu, Che-Wen; Chang, Weng-Cheng; Wang, Miin-Yau; Wu, June-Fu; Hsu, Yi-Chiang

    2012-01-01

    Demethoxycurcumin (DMC; a curcumin-related demethoxy compound) has been recently shown to display antioxidant and antitumor activities. It has also produced a potent chemopreventive action against cancer. In the present study, the antiproliferation (using the MTT assay, DMC was found to have cytotoxic activities against GBM 8401 cell with IC50 values at 22.71 μM) and induced apoptosis effects of DMC have been investigated in human brain malignant glioma GBM 8401 cells. We have studied the mitochondrial membrane potential (MMP), DNA fragmentation, caspase activation, and NF-κB transcriptional factor activity. By these approaches, our results indicated that DMC has produced an inhibition of cell proliferation as well as the activation of apoptosis in GBM 8401 cells. Both effects were observed to increase in proportion with the dosage of DMC treatment, and the apoptosis was induced by DMC in human brain malignant glioma GBM 8401 cells via mitochondria- and caspase-dependent pathways. PMID:22454662

  15. The softening of human bladder cancer cells happens at an early stage of the malignancy process

    PubMed Central

    Ramos, Jorge R; Pabijan, Joanna

    2014-01-01

    Summary Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young’s modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non-malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force. PMID:24778971

  16. MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer.

    PubMed

    Eyking, Annette; Reis, Henning; Frank, Magdalena; Gerken, Guido; Schmid, Kurt W; Cario, Elke

    2016-01-01

    . Reversely, inhibition of miR-373 allowed mesenchymal IEC to regain epithelial properties, which correlated with absence of neoplastic progression. Using xenografts in mice demonstrated miR-373-mediated acceleration of malignant intestinal tumor growth. In conclusion, our results provide first evidence that miR-205 and miR-373 may differentially contribute to the aggressive phenotype of MAC in CRC. PMID:27271572

  17. MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer

    PubMed Central

    Eyking, Annette; Reis, Henning; Frank, Magdalena; Gerken, Guido; Schmid, Kurt W.; Cario, Elke

    2016-01-01

    . Reversely, inhibition of miR-373 allowed mesenchymal IEC to regain epithelial properties, which correlated with absence of neoplastic progression. Using xenografts in mice demonstrated miR-373-mediated acceleration of malignant intestinal tumor growth. In conclusion, our results provide first evidence that miR-205 and miR-373 may differentially contribute to the aggressive phenotype of MAC in CRC. PMID:27271572

  18. Neo-epitopes on methylglyoxal modified human serum albumin lead to aggressive autoimmune response in diabetes.

    PubMed

    Jyoti; Mir, Abdul Rouf; Habib, Safia; Siddiqui, Sheelu Shafiq; Ali, Asif; Moinuddin

    2016-05-01

    Glyco-oxidation of proteins has implications in the progression of diabetes type 2. Human serum albumin is prone to glyco-oxidative attack by sugars and methylglyoxal being a strong glycating agent may have severe impact on its structure and consequent role in diabetes. This study has probed the methylglyoxal mediated modifications of HSA, the alterations in its immunological characteristics and possible role in autoantibody induction. We observed an exposure of chromophoric groups, loss in the fluorescence intensity, generation of AGEs, formation of cross-linked products, decrease in α-helical content, increase in hydrophobic clusters, FTIR band shift, attachment of methylglyoxal to HSA and the formation of N(ε)-(carboxyethyl) lysine in the modified HSA, when compared to the native albumin. MG-HSA was found to be highly immunogenic with additional immunogenicity invoking a highly specific immune response than its native counterpart. The binding characteristics of circulating autoantibodies in type 2 diabetes mellitus (DM) patients showed the generation of anti-MG-HSA auto-antibodies in the these patients, that are preferentially recognized by the modified albumin. We propose that MG induced structural perturbations in HSA, result in the generation of neo-epitopes leading to an aggressive auto-immune response and may contribute to the immunopathogenesis of diabetes type 2 associated complications. PMID:26861824

  19. Classification of normal and malignant human gastric mucosa tissue with confocal Raman microspectroscopy and wavelet analysis

    NASA Astrophysics Data System (ADS)

    Hu, Yaogai; Shen, Aiguo; Jiang, Tao; Ai, Yong; Hu, Jiming

    2008-02-01

    Thirty-two samples from the human gastric mucosa tissue, including 13 normal and 19 malignant tissue samples were measured by confocal Raman microspectroscopy. The low signal-to-background ratio spectra from human gastric mucosa tissues were obtained by this technique without any sample preparation. Raman spectral interferences include a broad featureless sloping background due to fluorescence and noise. They mask most Raman spectral feature and lead to problems with precision and quantitation of the original spectral information. A preprocessed algorithm based on wavelet analysis was used to reduce noise and eliminate background/baseline of Raman spectra. Comparing preprocessed spectra of malignant gastric mucosa tissues with those of counterpart normal ones, there were obvious spectral changes, including intensity increase at ˜1156 cm -1 and intensity decrease at ˜1587 cm -1. The quantitative criterion based upon the intensity ratio of the ˜1156 and ˜1587 cm -1 was extracted for classification of the normal and malignant gastric mucosa tissue samples. This could result in a new diagnostic method, which would assist the early diagnosis of gastric cancer.

  20. Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer

    PubMed Central

    Mimeault, M; Batra, S K

    2010-01-01

    Recent progress on pancreatic stem/progenitor cell research has revealed that the putative multipotent pancreatic stem/progenitor cells and/or more committed beta cell precursors may persist in the pancreatic gland in adult life. The presence of immature pancreatic cells with stem cell-like properties offers the possibility of stimulating their in vivo expansion and differentiation or to use their ex vivo expanded progenies for beta cell replacement-based therapies for type 1 or 2 diabetes mellitus in humans. In addition, the transplantation of either insulin-producing beta cells derived from embryonic, fetal and other tissue-resident adult stem/progenitor cells or genetically modified adult stem/progenitor cells may also constitute alternative promising therapies for treating diabetic patients. The genetic and/or epigenetic alterations in putative pancreatic adult stem/progenitor cells and/or their early progenies may, however, contribute to their acquisition of a dysfunctional behaviour as well as their malignant transformation into pancreatic cancer stem/progenitor cells. More particularly, the activation of distinct tumorigenic signalling cascades, including the hedgehog, epidermal growth factor–epidermal growth factor receptor (EGF–EGFR) system, wingless ligand (Wnt)/β-catenin and/or stromal cell-derived factor-1 (SDF-1)–CXC chemokine receptor 4 (CXCR4) pathways may play a major role in the sustained growth, survival, metastasis and/or drug resistance of pancreatic cancer stem/progenitor cells and their further differentiated progenies. The combination of drugs that target the oncogenic elements in pancreatic cancer stem/progenitor cells and their microenvironment, with the conventional chemotherapeutic regimens, could represent promising therapeutic strategies. These novel targeted therapies should lead to the development of more effective treatments of locally advanced and metastatic pancreatic cancers, which remain incurable with current therapies

  1. Alpha-CaMKII plays a critical role in determining the aggressive behavior of human osteosarcoma.

    PubMed

    Daft, Paul G; Yuan, Kaiyu; Warram, Jason M; Klein, Michael J; Siegal, Gene P; Zayzafoon, Majd

    2013-04-01

    Osteosarcoma is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. Despite improvements in osteosarcoma treatment, more specific molecular targets are needed as potential therapeutic options. One target of interest is α-Ca(2+)/calmodulin-dependent protein kinase II (α-CaMKII), a ubiquitous mediator of Ca(2+)-linked signaling, which has been shown to regulate tumor cell proliferation and differentiation. Here, we investigate the role of α-CaMKII in the growth and tumorigenicity of human osteosarcoma. We show that α-CaMKII is highly expressed in primary osteosarcoma tissue derived from 114 patients, and is expressed in varying levels in different human osteosarcoma (OS) cell lines [MG-63, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/HOS, and 143B). To examine whether α-CaMKII regulates osteosarcoma tumorigenic properties, we genetically inhibited α-CaMKII in two osteosarcoma cell lines using two different α-CaMKII shRNAs delivered by lentiviral vectors and overexpressed α-CaMKII by retrovirus. The genetic deletion of α-CaMKII by short hairpin RNA (shRNA) in MG-63 and 143B cells resulted in decreased proliferation (50% and 41%), migration (22% and 25%), and invasion (95% and 90%), respectively. The overexpression of α-CaMKII in HOS cells resulted in increased proliferation (240%), migration (640%), and invasion (10,000%). Furthermore, α-CaMKII deletion in MG-63 cells significantly reduced tumor burden in vivo (65%), whereas α-CaMKII overexpression resulted in tumor formation in a previously nontumor forming osteosarcoma cell line (HOS). Our results suggest that α-CaMKII plays a critical role in determining the aggressive phenotype of osteosarcoma, and its inhibition could be an attractive therapeutic target to combat this devastating adolescent disease. PMID:23364534

  2. Identification of cancer stem cell markers in human malignant mesothelioma cells

    SciTech Connect

    Ghani, Farhana Ishrat; Yamazaki, Hiroto; Iwata, Satoshi; Okamoto, Toshihiro; Aoe, Keisuke; Okabe, Kazunori; Mimura, Yusuke; Fujimoto, Nobukazu; Kishimoto, Takumi; Yamada, Taketo; Xu, C. Wilson; Morimoto, Chikao

    2011-01-14

    Research highlights: {yields} We performed serial transplantation of surgical samples and established new cell lines of malignant mesothelioma. {yields} SP cell and expressions of CD9/CD24/CD26 were often observed in mesothelioma cell lines. {yields} SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony. {yields} The marker-positive cells have clear tendency to generate larger tumors in mice. -- Abstract: Malignant mesothelioma (MM) is an aggressive and therapy-resistant neoplasm arising from the pleural mesothelial cells and usually associated with long-term asbestos exposure. Recent studies suggest that tumors contain cancer stem cells (CSCs) and their stem cell characteristics are thought to confer therapy-resistance. However, whether MM cell has any stem cell characteristics is not known. To understand the molecular basis of MM, we first performed serial transplantation of surgical samples into NOD/SCID mice and established new cell lines. Next, we performed marker analysis of the MM cell lines and found that many of them contain SP cells and expressed several putative CSC markers such as CD9, CD24, and CD26. Interestingly, expression of CD26 closely correlated with that of CD24 in some cases. Sorting and culture assay revealed that SP and CD24{sup +} cells proliferated by asymmetric cell division-like manner. In addition, CD9{sup +} and CD24{sup +} cells have higher potential to generate spheroid colony than negative cells in the stem cell medium. Moreover, these marker-positive cells have clear tendency to generate larger tumors in mouse transplantation assay. Taken together, our data suggest that SP, CD9, CD24, and CD26 are CSC markers of MM and could be used as novel therapeutic targets.

  3. Role of Phosphodiesterase 2 in Growth and Invasion of Human Malignant Melanoma Cells

    PubMed Central

    Hiramoto, Kenichi; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Manganiello, Vincent C.; Tagawa, Toshiro; Arai, Naoya

    2014-01-01

    Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3’,5’-cyclic monophosphate (cAMP) and guanosine 3’,5’-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-Hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N6-benzoyl-c AMP, a PKA specific cAMP analogue, whereas 8-(4-chlorophenylthio)-2’-O-methyl-cAMP, an Epac specific cAMP analogue, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines. PMID:24705027

  4. Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells.

    PubMed

    Hiramoto, Kenichi; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Manganiello, Vincent C; Tagawa, Toshiro; Arai, Naoya

    2014-09-01

    Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N(6)-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines. PMID:24705027

  5. Malignant melanoma maxilla

    PubMed Central

    Devi, Seema; Sinha, Richi; Singh, Rakesh Kumar

    2015-01-01

    A malignant melanoma is a highly lethal melanocytic neoplasm. A neoplasm usually affects the skin. Malignant melanomas in the head and neck region are rare, accounting for less than 1% of all melanomas. Malignant melanoma of the nose and paranasal sinuses is an aggressive disease typically presenting at an advanced stage, with a 5-year survival rate ranging 20-30%. Melanomas are tumors arising from melanocytes, which are neuroectodermally derived cells located in the basal layers of the skin. This is a case report of a 35-year-old male, who presented with very aggressive disease and developed liver metastasis. PMID:26668467

  6. Acute topiramate differentially affects human aggressive responding at low vs. moderate doses in subjects with histories of substance abuse and antisocial behavior.

    PubMed

    Lane, Scott D; Gowin, Joshua L; Green, Charles E; Steinberg, Joel L; Moeller, F Gerard; Cherek, Don R

    2009-04-01

    Anticonvulsant drugs have demonstrated efficacy in the management of irritability and aggression in a variety of psychiatric populations. We examined the acute effects of topiramate on aggression using a laboratory model of human aggression (PSAP) in individuals at high risk for aggressive and violent behavior.Twelve subjects, on parole/probation and with an Axis-II personality disorder and/or a substance use disorder, received 100, 200, 300, and 400 mg in an ascending sequence, with intervening placebo doses.Subjects participated 2-3 days per week over 4-6 weeks. Due to cognitive side effects at 300 mg, two subjects only completed through the 200 mg dose. Topiramate produced an inverted U-shaped dose response curve, with increases in aggression peaking at 200 mg and a modest decrease at 400 mg. Statistical analysis revealed a polynomial trend for dose (p=0.001). The observed inverted U-shaped function in aggressive responding is consistent with non-human aggression studies of GABA-A modulators. Acute topiramate doses >400 mg may have anti-aggressive effects, but dose levels in the 200-300 mg range may produce increases in aggression and side effects. PMID:19353809

  7. Dynamic holographic endoscopy--ex vivo investigations of malignant tumors in the human stomach.

    PubMed

    Avenhaus, Wolfgang; Kemper, Björn; Knoche, Sabine; Domagk, Dirk; Poremba, Christopher; von Bally, Gert; Domschke, Wolfram

    2005-01-01

    Laser holographic interferometry is based on the superimposition of the holograms of different motional states of an object on a single holographic storing medium. Using a combination of holographic interferometry and endoscopic imaging, we tried to detect areas of focally disturbed tissue elasticity in gastric cancer preparations. By connecting a mobile electronic speckle pattern interferometry (ESPI) camera system (light source: double frequency Nd:YAG laser, lambda = 532 nm) to different types of endoscopes, ex vivo experiments were performed on ten formalin fixed human stomachs, nine containing adenocarcinomas and one with a gastric lymphoma. Linking the endoscopic ESPI camera complex to a fast image processing system, the method of double pulse exposure image subtraction was applied at a video frame rate of 12.5 Hz. Speckle correlation patterns and corresponding phase difference distributions resulting from gastric wall deformation by gentle touch with a guide wire were analyzed. Tumor-free gastric areas showed high-contrast concentric fringes around the point of stimulation. In contrast, fringe patterns and filtered phase difference distributions corresponding to the areas of malignancy in all the cases were characterized by largely parallel lines, indicating that stimulation of rigid tumor tissue primarily led to tilting. Our ex vivo investigations of malignant gastric tumors show that the application of dynamic holographic endoscopy makes it possible to distinguish areas of malignancy from surrounding healthy tissue based on the differences in tissue elasticity. PMID:15726298

  8. Expression of cyclin D1 correlates with malignancy in human ovarian tumours.

    PubMed Central

    Barbieri, F.; Cagnoli, M.; Ragni, N.; Pedullà, F.; Foglia, G.; Alama, A.

    1997-01-01

    Cyclin D1 is a cell cycle regulator of G1 progression that has been suggested to play a relevant role in the pathogenesis of several human cancer types. In the current study, the expression of cyclin D1 has been investigated in a series of 33 patients, with benign (10 patients), borderline (five patients) and malignant (18 patients) ovarian disease. Cyclin D1 protein and mRNA content were analysed by Western blotting and reverse transcriptase polymerase chain reaction respectively. The levels of cyclin D1 protein were undetectable in patients with benign disease, detectable in the majority of patients with borderline disease and elevated in those with ovarian carcinomas, being significantly related to the degree of malignancy (carcinoma vs benign, P = 0.0001; benign vs borderline, P = 0.0238). A significant relationship between cyclin D1 expression and tumour proliferative activity was also found (P = 0.000001). Moreover, eight benign lesions, two borderline tumours and 11 carcinomas proved to be suitable for the analysis of cyclin D1 transcript, and emerging data demonstrated significant agreement between protein abundance and mRNA expression. Results from the current study suggest that cyclin D1 expression is associated with the degree of transformation and most probably plays a role in the early development of ovarian malignancy. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:9155044

  9. Association of Childhood Chronic Physical Aggression with a DNA Methylation Signature in Adult Human T Cells

    PubMed Central

    Guillemin, Claire; Vitaro, Frank; Côté, Sylvana M.; Hallett, Michael; Tremblay, Richard E.; Szyf, Moshe

    2014-01-01

    Background Chronic physical aggression (CPA) is characterized by frequent use of physical aggression from early childhood to adolescence. Observed in approximately 5% of males, CPA is associated with early childhood adverse environments and long-term negative consequences. Alterations in DNA methylation, a covalent modification of DNA that regulates genome function, have been associated with early childhood adversity. Aims To test the hypothesis that a trajectory of chronic physical aggression during childhood is associated with a distinct DNA methylation profile during adulthood. Methods We analyzed genome-wide promoter DNA methylation profiles of T cells from two groups of adult males assessed annually for frequency of physical aggression between 6 and 15 years of age: a group with CPA and a control group. Methylation profiles covering the promoter regions of 20 000 genes and 400 microRNAs were generated using MeDIP followed by hybridization to microarrays. Results In total, 448 distinct gene promoters were differentially methylated in CPA. Functionally, many of these genes have previously been shown to play a role in aggression and were enriched in biological pathways affected by behavior. Their locations in the genome tended to form clusters spanning millions of bases in the genome. Conclusions This study provides evidence of clustered and genome-wide variation in promoter DNA methylation in young adults that associates with a history of chronic physical aggression from 6 to 15 years of age. However, longitudinal studies of methylation during early childhood will be necessary to determine if and how this methylation variation in T cells DNA plays a role in early development of chronic physical aggression. PMID:24691403

  10. Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations

    PubMed Central

    Sato, Mitsuo; Larsen, Jill E.; Lee, Woochang; Sun, Han; Shames, David S.; Dalvi, Maithili P.; Ramirez, Ruben D.; Tang, Hao; DiMaio, J. Michael; Gao, Boning; Xie, Yang; Wistuba, Ignacio I.; Gazdar, Adi F.; Shay, Jerry W.; Minna, John D.

    2013-01-01

    We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes. PMID:23449933

  11. p27 modulates cell cycle progression and chemosensitivity in human malignant glioma.

    PubMed

    Naumann, U; Weit, S; Rieger, L; Meyermann, R; Weller, M

    1999-08-11

    The cell cycle regulatory protein p27, an inhibitor of cyclin-dependent kinases (CDK), has been attributed a role in (i) prognosis in breast and colon cancer, (ii) induction of apoptosis in cancer cells, and (iii) resistance to cancer chemotherapy. Here we report that p27 is widely expressed in human malignant gliomas in vivo and in glioma cell lines in vitro. Serum deprivation or confluency promotes p27 protein accumulation in vitro. Neither baseline p27 levels nor p27 levels induced by confluency or serum deprivation correlate with p53 status or drug sensitivity of human glioma cell lines. Expression of antisense p27 mRNA increased the doubling times in T98G glioma cells, whereas sense p27 mRNA had no such effect. There was a density-dependent and drug-specific modulation of chemosensitivity by sense or antisense mRNA expression in T98G cells. Taken together, these data define a strong p27 response to altered growth conditions and suggest a role for p27 in modulating response to chemotherapy in human malignant glioma cells. PMID:10441521

  12. Short Chain Fatty Acids (SCFA) Reprogram Gene Expression in Human Malignant Epithelial and Lymphoid Cells.

    PubMed

    Astakhova, Lidiia; Ngara, Mtakai; Babich, Olga; Prosekov, Aleksandr; Asyakina, Lyudmila; Dyshlyuk, Lyubov; Midtvedt, Tore; Zhou, Xiaoying; Ernberg, Ingemar; Matskova, Liudmila

    2016-01-01

    The effect of short chain fatty acids (SCFAs) on gene expression in human, malignant cell lines was investigated, with a focus on signaling pathways. The commensal microbial flora produce high levels of SCFAs with established physiologic effects in humans. The most abundant SCFA metabolite in the human microflora is n-butyric acid. It is well known to activate endogenous latent Epstein-Barr virus (EBV), that was used as a reference read out system and extended to EBV+ epithelial cancer cell lines. N-butyric acid and its salt induced inflammatory and apoptotic responses in tumor cells of epithelial and lymphoid origin. Epithelial cell migration was inhibited. The n-butyric gene activation was reduced by knock-down of the cell membrane transporters MCT-1 and -4 by siRNA. N-butyric acid show biologically significant effects on several important cellular functions, also with relevance for tumor cell phenotype. PMID:27441625

  13. Short Chain Fatty Acids (SCFA) Reprogram Gene Expression in Human Malignant Epithelial and Lymphoid Cells

    PubMed Central

    Astakhova, Lidiia; Ngara, Mtakai; Babich, Olga; Prosekov, Aleksandr; Asyakina, Lyudmila; Dyshlyuk, Lyubov; Midtvedt, Tore; Zhou, Xiaoying; Ernberg, Ingemar; Matskova, Liudmila

    2016-01-01

    The effect of short chain fatty acids (SCFAs) on gene expression in human, malignant cell lines was investigated, with a focus on signaling pathways. The commensal microbial flora produce high levels of SCFAs with established physiologic effects in humans. The most abundant SCFA metabolite in the human microflora is n-butyric acid. It is well known to activate endogenous latent Epstein-Barr virus (EBV), that was used as a reference read out system and extended to EBV+ epithelial cancer cell lines. N-butyric acid and its salt induced inflammatory and apoptotic responses in tumor cells of epithelial and lymphoid origin. Epithelial cell migration was inhibited. The n-butyric gene activation was reduced by knock-down of the cell membrane transporters MCT-1 and -4 by siRNA. N-butyric acid show biologically significant effects on several important cellular functions, also with relevance for tumor cell phenotype. PMID:27441625

  14. ETM study of electroporation influence on cell morphology in human malignant melanoma and human primary gingival fibroblast cells

    PubMed Central

    Skolucka, Nina; Daczewska, Malgorzata; Saczko, Jolanta; Chwilkowska, Agnieszka; Choromanska, Anna; Kotulska, Malgorzata; Kaminska, Iwona; Kulbacka, Julita

    2011-01-01

    Objective To estimate electroporation (EP) influence on malignant and normal cells. Methods Two cell lines including human malignant melanoma (Me-45) and normal human gingival fibroblast (HGFs) were used. EP parameters were the following: 250, 1 000, 1 750, 2 500 V/cm; 50 µs by 5 impulses for every case. The viability of cells after EP was estimated by MTT assay. The ultrastructural analysis was observed by transmission electron microscope (Zeiss EM 900). Results In the current study we observed the intracellular effect following EP on Me-45 and HGF cells. At the conditions applied, we did not observe any significant damage of mitochondrial activity in both cell lines treated by EP. Conversely, we showed that EP in some conditions can stimulate cells to proliferation. Some changes induced by EP were only visible in electron microscopy. In fibroblast cells we observed significant changes in lower parameters of EP (250 and 1 000 V/cm). After applying higher electric field intensities (2 500 V/cm) we detected many vacuoles, myelin-like bodies and swallowed endoplasmic reticulum. In melanoma cells such strong pathological modifications after EP were not observed, in comparison with control cells. The ultrastructure of both treated cell lines was changed according to the applied parameters of EP. Conclusions We can claim that EP conditions are cell line dependent. In terms of the intracellular morphology, human fibroblasts are more sensitive to electric field as compared with melanoma cells. Optimal conditions should be determined for each cell line. Summarizing our study, we can conclude that EP is not an invasive method for human normal and malignant cells. This technique can be safely applied in chemotherapy for delivering drugs into tumor cells. PMID:23569735

  15. Expression of protein kinase A regulatory subunits in benign and malignant human thyroid tissues: A systematic review.

    PubMed

    Del Gobbo, Alessandro; Peverelli, Erika; Treppiedi, Donatella; Lania, Andrea; Mantovani, Giovanna; Ferrero, Stefano

    2016-08-01

    In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on the malignant thyroid. The PKA signaling pathway is differentially activated by the expression of regulatory subunits 1 (R1) and 2 (R2), whose levels change during development, differentiation, and neoplastic transformation. Following the identification of gene mutations within the PKA regulatory subunit R1A (PRKAR1A) that cause Carney complex-associated neoplasms, several investigators have studied PRKAR1A expression in sporadic thyroid tumors. The PKA regulatory subunit R2B (PRKAR2B) is highly expressed in benign, as well as in malignant differentiated and undifferentiated lesions. PRKAR1A is highly expressed in follicular adenomas and malignant lesions with a statistically significant gradient between benign and malignant tumors; however, it is not expressed in hyperplastic nodules. Although the importance of PKA in human malignancy outcomes is not completely understood, PRKAR1A expression correlates with tumor dimension in malignant lesions. Additional studies are needed to determine whether a relationship exists between PKA subunit expression and clinical outcomes, particularly in undifferentiated tumors. In conclusion, the R1A subunit might be a good molecular candidate for the targeted treatment of malignant thyroid tumors. PMID:27321957

  16. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

    PubMed

    Ogawa, Hisataka; Wu, Xin; Kawamoto, Koichi; Nishida, Naohiro; Konno, Masamitsu; Koseki, Jun; Matsui, Hidetoshi; Noguchi, Kozou; Gotoh, Noriko; Yamamoto, Tsuyoshi; Miyata, Kanjiro; Nishiyama, Nobuhiro; Nagano, Hiroaki; Yamamoto, Hirofumi; Obika, Satoshi; Kataoka, Kazunori; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

    2015-01-01

    Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors. PMID:25970424

  17. Epigenetic regulation of inflammatory cytokines and associated genes in human malignancies.

    PubMed

    Yasmin, Rehana; Siraj, Sami; Hassan, Amjad; Khan, Abdul Rehman; Abbasi, Rashda; Ahmad, Nafees

    2015-01-01

    Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies. PMID:25814785

  18. Epigenetic Regulation of Inflammatory Cytokines and Associated Genes in Human Malignancies

    PubMed Central

    Yasmin, Rehana; Hassan, Amjad; Khan, Abdul Rehman; Abbasi, Rashda; Ahmad, Nafees

    2015-01-01

    Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies. PMID:25814785

  19. [Human recombinant leukocyte interferon alpha-2-A in 22 cases of metastatic malignant melanoma].

    PubMed

    Maral, J; Steinberg, M; Weil, M; Chleq, C; Khayat, D; Banzet, P; Jacquillat, C

    1987-06-01

    Twenty-two patients with metastatic malignant melanoma received either 36 X 10(6) U (15 patients) or 18 X 10(6) U (7 patients) of human recombinant interferon alpha-2-A daily for 3 months by the intramuscular route, with progressive increase of dosage. This was followed in responders by a maintenance treatment consisting of 3 intramuscular injections per week in the same doses as those received at the end of the induction treatment. Out of 18 patients assessable for effectiveness, 1 had complete remission (7 months +) and 3 had partial response (52,61 and 82 days respectively), an overall improvement rate of 22%. The main side-effects observed were: pseudoinfluenza syndrome (100%), fatigue (100%), somnolence (95%), anorexia (90%) and haematological disorders. Dosage reduction was necessary in 13 of the 15 patients receiving 36 MU. This study shows that human recombinant interferon alpha-2-A has antitumoral activity in metastatic malignant melanoma. Other studies, notably with therapeutic combinations, are needed to determine the optimal dosage regimen of the drug and to increase its effectiveness. PMID:2955323

  20. Functional reconstruction after subtotal glossectomy in the surgical treatment of an uncommon and aggressive neoplasm in this location: Primary malignant melanoma in the base of the tongue

    PubMed Central

    Manzano-Solo-de-Zaldívar, Damián; Moreno-Sánchez, Manuel; Hernández-Vila, Cristina; Ramírez-Pérez, Francisco-Alejandro; González-Ballester, David; Ruíz-Laza, Luis; González-García, Raúl; Monje-Gil, Florencio

    2014-01-01

    Primary malignant melanoma of the oral cavity is a rare neoplasm, especially on the tongue. We report a case of mucosal melanoma at the base of the tongue, an extremely rare location (only about 30 cases have been reported in literature). The extension study doesn´t revealed distant metastatic lesions. The patient was treated by subtotal glossectomy and bilateral functional neck dissection. Tongue is one of the most difficult structures to reconstruct, because of their central role in phonation, swallowing and airway protection. The defect was reconstructed with anterolateral thigh free flap. Surgical treatment was supplemented with adjuvant immunotherapy. The post-operative period was uneventful. At present, 24 months after surgery, patient is asymptomatic, there isn´t evidence of recurrence of melanoma and he hasn´t any difficulty in swallowing or phonation. Key words:Malignant mucosal melanoma, anterolateral thigh free flap, phonation, swallowing. PMID:25593674

  1. Molecular biology of malignant gliomas.

    PubMed

    Belda-Iniesta, Cristóbal; de Castro Carpeño, Javier; Casado Sáenz, Enrique; Cejas Guerrero, Paloma; Perona, Rosario; González Barón, Manuel

    2006-09-01

    Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies. PMID:17005465

  2. Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors.

    PubMed

    Mondal, Sujan Kumar; Jinka, Sudhakar; Pal, Krishnendu; Nelli, Swetha; Dutta, Shamit Kumar; Wang, Enfeng; Ahmad, Ajaz; AlKharfy, Khalid M; Mukhopadhyay, Debabrata; Banerjee, Rajkumar

    2016-07-01

    Many cancers including the late stage ones become drug-resistant and undergo epithelial-to-mesenchymal transition (EMT). These lead to enhanced invasion, migration, and metastasis toward manifesting its aggressiveness and malignancy. One of the key hallmarks of cancer is its overdependence on glycolysis as its preferred energy metabolism pathway. The strict avoidance of alternate energy pathway gluconeogenesis by cancer cells points to a yet-to-be hoisted role of glucocorticoid receptor (GR) especially in tumor microenvironment, where cells are known to become drug-sensitive through induction of gluconeogenesis. However, since GR is involved in metabolism, anti-inflammatory reactions, immunity besides inducing gluconeogenesis, a greater role of GR in tumor microenvironment is envisaged. We have shown previously that GR, although ubiquitously expressed in all cells; afford to be an effective cytoplasmic target for killing cancer cells selectively. Herein, we report the therapeutic use of a newly developed GR-targeted liposomal concoction (DXE) coformulating a lipophilic drug (ESC8) and an anti-Hsp90 anticancer gene against aggressive tumor models. This induced drug-sensitivity and apoptosis while reversing EMT in tumor cells toward effective retardation of aggressive growth in pancreas and skin tumor models. Additionally, the ESC8-free lipid formulation upon cotreatment with hydrophilic drugs, gemcitabine and doxorubicin, could effectively sensitize and kill pancreatic cancer and melanoma cells, respectively. The formulation-triggered EMT-reversal was GR-dependent. Overall, we found a new strategy for drug sensitization that led to the advent of new GR-targeted anticancer therapeutics. PMID:27184196

  3. Characterization of phosphodiesterase 2A in human malignant melanoma PMP cells

    PubMed Central

    MORITA, HIROSHI; MURATA, TAKU; SHIMIZU, KASUMI; OKUMURA, KENYA; INUI, MADOKA; TAGAWA, TOSHIRO

    2013-01-01

    The prognosis for malignant melanoma is poor; therefore, new diagnostic methods and treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of 21 phosphodiesterases, which are divided into 11 families (PDE1-PDE11). PDE2 hydrolyzes cyclic AMP (cAMP) and cyclic GMP (cGMP), and its binding to cGMP enhances the hydrolysis of cAMP. We previously reported the expression of PDE1, PDE3 and PDE5 in human malignant melanoma cells. However, the expression of PDE2 in these cells has not been investigated. Herein, we examined the expression of PDE2A and its role in human oral malignant melanoma PMP cells. Sequencing of RT-PCR products revealed that PDE2A2 was the only variant expressed in PMP cells. Four point mutations were detected; one missense mutation at nucleotide position 734 (from C to T) resulted in the substitution of threonine with isoleucine at amino acid position 214. The other three were silent mutations. An in vitro migration assay and a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay revealed that suppressing PDE2 activity with its specific inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no impact on cell motility or apoptosis. Furthermore, the cytotoxicity of EHNA, assessed using a trypan blue exclusion assay, was negligible. On the other hand, assessment of cell proliferation by BrdU incorporation and cell cycle analysis by flow cytometry revealed that EHNA treatment inhibited DNA synthesis and increased the percentage of G2/M-arrested cells. Furthermore, cyclin A mRNA expression was downregulated, while cyclin E mRNA expression was upregulated in EHNA-treated cells. Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. Thus, PDE2A2 is a possible new molecular target for the treatment of malignant melanoma. PMID:23381931

  4. Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma

    PubMed Central

    HIRATA, TOMOMI; ZHENG, QINGFENG; CHEN, ZHAO; KINOSHITA, HIROYASU; OKAMOTO, JUNICHI; KRATZ, JOHANNES; LI, HUI; LUI, NATALIE; DO, HANH; CHENG, TIFFANY; TSENG, HSIN-HUI KATTY; KOIZUMI, KIYOSHI; SHIMIZU, KAZUO; ZHOU, HAI-MENG; JABLONS, DAVID; HE, BIAO

    2015-01-01

    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a poor prognosis, limited treatment options, and a worldwide incidence that is expected to increase in the next decade. We evaluated Wnt7A expression in 50 surgically resected tumor specimens using quantitative PCR. The expression values, were assessed by clinicopathological factors and K-M and Cox’s regression with OS. The mean level of Wnt7A expression had a significant correlation with International Mesothelioma Interest Group (IMIG) stage (P<0.034), gender, smoking history and ethnicity, respectively (P=0.020, P=0.014, P=0.039). In the univariate analysis, low Wnt7A expression was a significant negative factor for overall survival (P=0.043, HR=2.30). However, multivariate Cox’s regression revealed no significant factors for overall survival (low Wnt7A: P=0.051, HR=2.283; non-epithelioid subtype: P=0.050, HR=2.898). In patients with epithelioid tumors, those with low Wnt7A expression had significantly worse prognosis (P=0.019, HR=2.98). In patients with epithelioid tumors, females had significantly better prognosis than males (P=0.035). In patients who did not have neoadjuvant chemotherapy, prognosis was significantly more favorable for patients with high Wnt7A expression than for those with low Wnt7A expression (P=0.031). Among the patients with low Wnt7A-expressing tumors, those who received neoadjuvant chemotherapy had better prognosis than those who did not (P=0.024). The results of our study suggest that Wnt7A expression is a putative prognostic factor and a predictor of chemosensitivity. PMID:25632963

  5. Warburg effect's manifestation in aggressive pheochromocytomas and paragangliomas: insights from a mouse cell model applied to human tumor tissue.

    PubMed

    Fliedner, Stephanie M J; Kaludercic, Nina; Jiang, Xiao-Sheng; Hansikova, Hana; Hajkova, Zuzana; Sladkova, Jana; Limpuangthip, Andrea; Backlund, Peter S; Wesley, Robert; Martiniova, Lucia; Jochmanova, Ivana; Lendvai, Nikoletta K; Breza, Jan; Yergey, Alfred L; Paolocci, Nazareno; Tischler, Arthur S; Zeman, Jiri; Porter, Forbes D; Lehnert, Hendrik; Pacak, Karel

    2012-01-01

    A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human

  6. Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells.

    PubMed

    Seol, Ho Jun; Chang, Jong Hee; Yamamoto, Junkoh; Romagnuolo, Rocco; Suh, Youngchul; Weeks, Adrienne; Agnihotri, Sameer; Smith, Christian A; Rutka, James T

    2012-09-01

    The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas. PMID:23486730

  7. Hexokinase and phosphofructokinase activity and intracellular distribution correlate with aggressiveness and invasiveness of human breast carcinoma

    PubMed Central

    Coelho, Raquel G.; Calaça, Isadora C.; Celestrini, Deborah M.; Correia-Carneiro, Ana Helena P.; Costa, Mauricio M.; Zancan, Patricia; Sola-Penna, Mauro

    2015-01-01

    Glycolytic enzymes, such as hexokinase and phosphofructokinase, have been reported to be upregulated in many cancer types. Here, we evaluated these two enzymes in 54 breast cancer samples collected from volunteers subjected to mastectomy, and the results were correlated with the prognosis markers commonly used. We found that both enzymes positively correlate with the major markers for invasiveness and aggressiveness. For invasiveness, the enzymes activities increase in parallel to the tumor size. Moreover, we found augmented activities for both enzymes when the samples were extirpated from patients presenting lymph node involvement or occurrence of metastasis. For aggressiveness, we stained the samples for the estrogen and progesterone receptors, HER-2, p53 and Ki-67. The enzyme activities positively correlated with all markers but Ki-67. Finally, we conclude that these enzymes are good markers for breast cancer prognosis. PMID:26320188

  8. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies

    PubMed Central

    Hoyos, Valentina; Savoldo, Barbara; Dotti, Gianpietro

    2012-01-01

    Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies. PMID:22929977

  9. Intracellular ionized calcium concentration in muscles from humans with malignant hyperthermia.

    PubMed

    López, J R; Alamo, L; Caputo, C; Wikinski, J; Ledezma, D

    1985-06-01

    Ca2+ selective microelectrodes have been used to determine the free myoplasmic [Ca2+] in human skeletal muscle obtained from patients who had developed early signs associated with malignant hyperthermia (MH) during anesthesia. Intercostal muscle biopsies were performed under local anesthesia in four MH patients 15 days to 4 months after developing the MH crisis and in three control subjects. We used only microelectrodes that showed a Nernstian response between pCa3 and pCa7 (30.5 mV per decade at 37 degrees C). Membrane resting potential (V(m)) and calcium potential (V(Ca)) were obtained from superficial fibers. The free cytosolic [Ca2+] was 0.39 +/- 0.1 microM (mean +/- SEM, n = 18) in muscle fibers obtained from malignant hyperthermic patients, whereas in control subjects it was 0.11 +/- 0.02 microM (n = 10). These results suggest that this syndrome might be related to an abnormally high myoplasmic free resting calcium concentration, probably due to a defective function of the plasma membrane or the sarcoplasmic reticulum. PMID:16758579

  10. The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease

    PubMed Central

    Hieken, Tina J.; Chen, Jun; Hoskin, Tanya L.; Walther-Antonio, Marina; Johnson, Stephen; Ramaker, Sheri; Xiao, Jian; Radisky, Derek C.; Knutson, Keith L.; Kalari, Krishna R.; Yao, Janet Z.; Baddour, Larry M.; Chia, Nicholas; Degnim, Amy C.

    2016-01-01

    Globally breast cancer is the leading cause of cancer death among women. The breast consists of epithelium, stroma and a mucosal immune system that make up a complex microenvironment. Growing awareness of the role of microbes in the microenvironment recently has led to a series of findings important for human health. The microbiome has been implicated in cancer development and progression at a variety of body sites including stomach, colon, liver, lung, and skin. In this study, we assessed breast tissue microbial signatures in intraoperatively obtained samples using 16S rDNA hypervariable tag sequencing. Our results indicate a distinct breast tissue microbiome that is different from the microbiota of breast skin tissue, breast skin swabs, and buccal swabs. Furthermore, we identify distinct microbial communities in breast tissues from women with cancer as compared to women with benign breast disease. Malignancy correlated with enrichment in taxa of lower abundance including the genera Fusobacterium, Atopobium, Gluconacetobacter, Hydrogenophaga and Lactobacillus. This work confirms the existence of a distinct breast microbiome and differences between the breast tissue microbiome in benign and malignant disease. These data provide a foundation for future investigation on the role of the breast microbiome in breast carcinogenesis and breast cancer prevention. PMID:27485780

  11. The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease.

    PubMed

    Hieken, Tina J; Chen, Jun; Hoskin, Tanya L; Walther-Antonio, Marina; Johnson, Stephen; Ramaker, Sheri; Xiao, Jian; Radisky, Derek C; Knutson, Keith L; Kalari, Krishna R; Yao, Janet Z; Baddour, Larry M; Chia, Nicholas; Degnim, Amy C

    2016-01-01

    Globally breast cancer is the leading cause of cancer death among women. The breast consists of epithelium, stroma and a mucosal immune system that make up a complex microenvironment. Growing awareness of the role of microbes in the microenvironment recently has led to a series of findings important for human health. The microbiome has been implicated in cancer development and progression at a variety of body sites including stomach, colon, liver, lung, and skin. In this study, we assessed breast tissue microbial signatures in intraoperatively obtained samples using 16S rDNA hypervariable tag sequencing. Our results indicate a distinct breast tissue microbiome that is different from the microbiota of breast skin tissue, breast skin swabs, and buccal swabs. Furthermore, we identify distinct microbial communities in breast tissues from women with cancer as compared to women with benign breast disease. Malignancy correlated with enrichment in taxa of lower abundance including the genera Fusobacterium, Atopobium, Gluconacetobacter, Hydrogenophaga and Lactobacillus. This work confirms the existence of a distinct breast microbiome and differences between the breast tissue microbiome in benign and malignant disease. These data provide a foundation for future investigation on the role of the breast microbiome in breast carcinogenesis and breast cancer prevention. PMID:27485780

  12. Value of human chorionic gonadotropin compared to CEA in discriminating benign from malignant effusions.

    PubMed

    Lamerz, R; Stoetzer, O J; Mezger, J; Brandt, A; Darsow, M; Wilmanns, W

    1999-01-01

    Human chorionic gonadotropin (HCG) is expressed in germ cell tumors and urothelial, breast, lung and colon cancers. The aim of the study was to investigate if the determination of HCG in comparison with CEA is able to discriminate between malignant and benign effusions. Effusion and partially serum samples of 61 patients with benign (g.i., heart/kidney isnuff.) and 116 patients with malignant diseases (g.i., gynec., lung, misc., CUP) were investigated. HCG was specifically determined by an IRMA using 2 monoclonal antibodies, CEA by a conventional double Ab RIA. Cytological staining was preformed using the Pappenheim-method on cytospin preparations. Significant differences (p < 0.001) were found for HCG between benign and malignant ascitic effusions with the best discrimination at 5 IU/l (ROC) and an overall sensitivity of 31.3% (spec. vs benign eff. 93.4%) increasing in subgroups from hematol. (5.8%) < misc. (31.3%) < gynec. (32.1%) < g.i. (36%) < lung (38.1%) to CUP (50%). CEA also showed significant differences between benign and malignant total and ascitic effusions, and weaker for the pleural subgroup (cutoff 9 ng/ml) with a total sensitivity of 44.6% (sp = 100%) increasing from misc. (30.8%) < lung (47.1%) < CUP (50%) < gynec. (60%) < g.i. (60.9%). Comparative cytology and TM determinations increased the positiverate of cytology (45.2%) to 58.3% for either cytology or HCG positive cases, or to 61.6% for either cytology or CEA positive cases. For the combined determination of cytologoy and HCG and CEA, the overall TM positive rate for 33 cytology-pos. cases was 78.8%, but in 40 cytology-negative cases 37.5% for TM positive cases. In conclusion HCG is useful in ascitic > pleural effusions with high specificity (90% at 5 IU/l) but low sensitivity of 31% increasing in g.i., lung and gynecologic cases, CEA a more general TM with higher sensitivity of 45% increasing in g.i., gynecologic and lung cases (sp. 100% at 9 ng/ml) both adding significantly to cytology

  13. Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies

    PubMed Central

    Viswanathan, Srinivas R.; Powers, John T.; Einhorn, William; Hoshida, Yujin; Ng, Tony; Toffanin, Sara; O'Sullivan, Maureen; Lu, Jun; Philips, Letha A.; Lockhart, Victoria L.; Shah, Samar P.; Tanwar, Pradeep S.; Mermel, Craig H.; Beroukhim, Rameen; Azam, Mohammad; Teixeira, Jose; Meyerson, Matthew; Hughes, Timothy P.; Llovet, Josep M; Radich, Jerald; Mullighan, Charles G.; Golub, Todd R.; Sorensen, Poul H.; Daley, George Q.

    2009-01-01

    Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs5–8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis. PMID:19483683

  14. Frequency analysis of multispectral photoacoustic images for differentiating malignant region from normal region in excised human prostate

    NASA Astrophysics Data System (ADS)

    Sinha, Saugata; Rao, Navalgund A.; Valluru, Keerthi S.; Chinni, Bhargava K.; Dogra, Vikram S.; Helguera, Maria

    2014-03-01

    Frequency domain analysis of the photoacoustic (PA) radio frequency signals can potentially be used as a tool for characterizing microstructure of absorbers in tissue. This study investigates the feasibility of analyzing the spectrum of multiwavelength PA signals generated by excised human prostate tissue samples to differentiate between malignant and normal prostate regions. Photoacoustic imaging at five different wavelengths, corresponding to peak absorption coefficients of deoxyhemoglobin, whole blood, oxyhemoglobin, water and lipid in the near infrared (NIR) (700 nm - 1000 nm) region, was performed on freshly excised prostate specimens taken from patients undergoing prostatectomy for biopsy confirmed prostate cancer. The PA images were co-registered with the histopathology images of the prostate specimens to determine the region of interest (ROI) corresponding to malignant and normal tissue. The calibrated power spectrum of each PA signal from a selected ROI was fit to a linear model to extract the corresponding slope, midband fit and intercept parameters. The mean value of each parameter corresponding to malignant and adjacent normal prostate ROI was calculated for each of the five wavelengths. The results obtained for 9 different human prostate specimens, show that the mean values of midband fit and intercept are significantly different between malignant and normal regions. In addition, the average midband fit and intercept values show a decreasing trend with increasing wavelength. These preliminary results suggest that frequency analysis of multispectral PA signals can be used to differentiate malignant region from the adjacent normal region in human prostate tissue.

  15. FTIR microscopic comparative study on normal, premalignant, and malignant tissues of human intenstine

    NASA Astrophysics Data System (ADS)

    Mordechai, Shaul; Argov, Shmuel; Salman, Ahmad O.; Cohen, Beny; Ramesh, Jagannathan; Erukhimovitch, Vitaly; Goldstein, Jed; Sinelnikov, Igor

    2000-07-01

    Fourier-Transform Infrared Spectroscopy (FTIR) employs a unique approach to optical diagnosis of tissue pathology based on the characteristic molecular vibrational spectra of the tissue. The architectural changes in the cellular and sub-cellular levels developing in abnormal tissue, including a majority of cancer forms, manifest themselves in different optical signatures, which can be detected in infrared spectroscopy. The biological systems we have studied include normal, premalignant (polyp) and malignant human colonic tissues from three patients. Our method is based on microscopic infrared study (FTIR-microscopy) of thin tissue specimens and a direct comparison with normal histopathological analysis, which serves as a `gold' reference. The normal intestine tissue has a stronger absorption than polyp and cancerous types over a wide region in all three cases. The detailed analysis showed that there is a significant decrease in total phosphate and creatine contents for polyp and cancerous tissue types in comparison to the controls.

  16. Prognostic significance of neoplastic cell proliferation parameters in human haematological malignancies.

    PubMed

    Kotelnikov, V M

    1990-01-01

    High percentage of neoplastic cells in S, G2 and M phases of cell cycle is unfavourable prognostic sign in human haematological malignancies. In chronic leukaemias (CML and CLL) it is true for peripheral blood leukaemic cells, in non-Hodgkin lymphomas--for lymph node cells, in multiple myeloma--for bone marrow plasma cells. In acute leukaemia results are controversial: some authors found a correlation between proliferation parameters of bone marrow blast cells while others did not. These parameters correlate positively with the rate of complete remission and negatively with its duration. It is concluded that proliferation parameters of neoplastic cells may be used for individual prognosis in patients with haematological tumours especially in combination with other biological and clinical prognostic markers. PMID:1703108

  17. Phase I study of recombinant human tumor necrosis factor-alpha in patients with advanced malignancies.

    PubMed

    Bartsch, H H; Nagel, G A; Mull, R; Flener, R; Pfizenmaier, K

    1988-01-01

    A clinical phase I trial with recombinant human tumor necrosis factor-alpha (rTNF-alpha) was performed in 30 patients with advanced malignancies. The maximal tolerated dose (MTD) by 3 times weekly intramuscular (i.m.) application was 150 micrograms m-2. Main subjective toxicities including chills, fever, hypotension, fatigue, and anorexia were dose-related. In addition, transient changes in hematologic parameters and lipid metabolism were noted. Two out of 25 evaluated patients showed a minor tumor response after eight weeks of therapy. There was evidence for an improvement of in vivo immuneresponsiveness as revealed from positive delayed type hypersensitivity (DTH) skin tests of 3 out of 6 pretherapeutically anergic patients. We conclude from this phase I trial that rTNF-alpha can be safely administered at doses up to 150 micrograms m-2 i.m., 3 times weekly, without evidence of cumulative toxicity in long-term treatment. PMID:3267369

  18. A B-Cell Superantigen Induces the Apoptosis of Murine and Human Malignant B Cells.

    PubMed

    Lorenzo, Daniela; Duarte, Alejandra; Mundiñano, Juliana; Berguer, Paula; Nepomnaschy, Irene; Piazzon, Isabel

    2016-01-01

    B-cell superantigens (Sags) bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. No attempts to investigate whether B-cell Sags are able to induce the apoptosis of cognate malignant B cells were reported. In the present study we show that protein L (PpL), secreted by Finegoldia magna, a B-cell Sag which interacts with κ+ bearing cells, induces the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo. Apoptosis was not altered by caspase-8 inhibitor. No alterations in the levels of Bid, Fas and Fas-L were found suggesting that PpL does not activate the extrinsic pathway of apoptosis. The involvement of the intrinsic pathway was clearly indicated by: i) alterations in mitochondrial membrane potential (ΔΨm) both in murine and human lymphoma cells exposed to PpL; ii) decreased levels of apoptosis in the presence of caspase-9 inhibitor; iii) significant increases of Bim and Bax protein levels and downregulation of Bcl-2; iv) the translocation from the cytoplasm to the mitochondria of Bax and Bim pro-apoptotic proteins and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor and v) the translocation of Bcl-2 protein from the mitochondria to the cytosol and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor. The possibility of a therapeutic use of Sags in lymphoma/leukemia B cell malignancies is discussed. PMID:27603942

  19. Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma

    PubMed Central

    Wang, Jinghan; Zhang, Keqiang; Wang, Jinhui; Wu, Xiwei; Liu, Xiyong; Li, Bin; Zhu, Yan; Yu, Yong; Cheng, Qingbao; Hu, Zhenli; Guo, Chao; Hu, Shuya; Mu, Bing; Tsai, Chun-Hao; Li, Jie; Smith, Lynne; Yang, Lu; Liu, Qi; Chu, Peiguo; Chang, Vincent; Zhang, Baihe; Wu, Mengchao; Jiang, Xiaoqing; Yen, Yun

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression. PMID:26056085

  20. Surface charge characteristics of cells from malignant cell lines and normal cell lines of the human hematopoietic system.

    PubMed

    Marikovsky, Y; Ben-Bassat, H; Leibovich, S J; Cividalli, L; Fischler, H; Danon, D

    1979-02-01

    Cells from malignant and normal lines of human hematopoietic origin were studied for their surface charge characteristics with the use of the following criteria: 1) the electron microscopic appearance of cell membranes after labeling with cationized ferritin (CF) either before or after glutaraldehyde fixation, 2) electrophoretic mobility, 3) total sialic acid content, and 4) agglutinability with poly-L-lysine (PLL). CF induced a time-dependent redistribution of surface receptors in unfixed malignant cells but not in unfixed normal cells. After 10 seconds of labeling with CF, both normal and malignant unfixed cells showed a uniform and even labeling pattern. After 5 minutes of labeling, malignant cells exhibited a highly pronounced pattern of clusters and patches, as distinct from a random and even pattern exhibited by normal cells. Both normal and malignant cells after fixation exhibited an equivalent random and even labeling pattern with CF, independent of the duration of labeling. The malignant cells studied possessed less sialic acid, had a lower electric mobility, and were agglutinated more readily with PLL than were the normal cells. PMID:310907

  1. Two new trifunctional antibodies for the therapy of human malignant melanoma.

    PubMed

    Ruf, Peter; Jäger, Michael; Ellwart, Joachim; Wosch, Susanne; Kusterer, Elisabeth; Lindhofer, Horst

    2004-02-20

    Trifunctional antibodies are able to redirect T cells and Fcgamma receptor(+) accessory immune cells to tumor targets. The simultaneous activation of these different classes of effector cells results in efficient killing of the tumor cells by different mechanisms such as phagocytosis and perforin-mediated cytotoxicity. Here, we introduce 2 new trifunctional antibodies specific for human melanoma. These trifunctional antibodies recognize with one binding arm CD3 on human T cells. The other binding arm is directed against melanoma-associated proteoglycans or melanoma-associated gangliosides (GD2 as well as GD3). They mediate specific lysis of various melanoma cell lines in correlation with the level of antigen expression in short-term cytotoxicity experiments. A combination of the 2 trifunctional antibodies was equally or even more efficient. Moreover, they induced a strong Th1 cytokine pattern with high amounts of IFN-gamma and low or no IL-4. Accordingly, CD4(+) and especially CD8(+) T cells expanded, whereas B cells, NK cells and monocytes decreased. The cytokine response was up to 16-fold higher when tumor cells were present. IFN-gamma reached cytotoxic concentrations for SK-MEL-23 melanoma cells. The induction of a T-cell-activatory and melanoma cell-inhibitory cytokine milieu together with the redirection of T-cell- and accessory cell-mediated cytotoxicity are interesting features of these trifunctional antibodies. They may be a new option for the therapy of human malignant melanoma. PMID:14696099

  2. Influence of zinc deficiency on AKT-MDM2-P53 signaling axes in normal and malignant human prostate cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    With prostate being the highest zinc-accumulating tissue before the onset of cancer, the effects of physiologic levels of zinc on Akt-Mdm2-p53 and Akt-p21 signaling axes in human normal prostate epithelial cells (PrEC) and malignant prostate LNCaP cells were examined. Cells were cultured for 6 d in...

  3. Frequent detection of high human papillomavirus DNA loads in oral potentially malignant disorders.

    PubMed

    Pierangeli, A; Cannella, F; Scagnolari, C; Gentile, M; Sciandra, I; Antonelli, G; Ciolfi, C; Russo, C; Palaia, G; Romeo, U; Polimeni, A

    2016-01-01

    Human papillomavirus (HPV) is estimated to be the cause of 40--80% of the squamous cell carcinoma of the oropharynx but only of a small fraction of the oral cavity cancers. The prevalence of oral HPV infection has significantly increased in the last decade, raising concerns about the role of HPV in progression of oral potentially malignant disorders (OPMD) toward squamous cell carcinomas. We sought to study HPV infection in patients with oral lesions, and in control individuals, using non-invasive and site-specific oral brushing and sensitive molecular methods. HPV DNA positivity and viral loads were evaluated in relation to patient data and clinical diagnosis. We enrolled 116 individuals attending Dental Clinics: 62 patients with benign oral lesions (e.g. fibromas, papillomatosis, ulcers) or OPMD (e.g. lichen, leukoplakia) and 54 controls. Oral cells were collected with Cytobrush and HPV-DNA was detected with quantitative real-time PCR for the more common high-risk (HR) and low-risk (LR) genotypes. HPV detection rate, percentage of HR HPVs and HPV-DNA loads (namely HPV16 and in particular, HPV18) were significantly higher in patients than in controls. Lichen planus cases had the highest HPV-positive rate (75.0%), hairy leukoplakia the lowest (33.3%). This study detected unexpectedly high rates of HPV infection in cells of the oral mucosa. The elevated HR HPV loads found in OPMD suggest the effectiveness of quantitative PCR in testing oral lesions. Prospective studies are needed to establish whether elevated viral loads represent a clinically useful marker of the risk of malignant progression. PMID:26408278

  4. Human papillomavirus infection and the malignant transformation of sinonasal inverted papilloma: A meta-analysis.

    PubMed

    Zhao, Ren-Wu; Guo, Zhi-Qiang; Zhang, Ru-Xin

    2016-06-01

    A growing number of molecular epidemiological studies have been conducted to evaluate the association between human papillomavirus (HPV) infection and the malignancy of sinonasal inverted papilloma (SNIP). However, the results remain inconclusive. Here, a meta-analysis was conducted to quantitatively assess this association. Case-control studies investigating SNIP tissues for presence of HPV DNA were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the Mantel-Haenszel method. An assessment of publication bias and sensitivity analysis were also performed. We calculated a pooled OR of 2.16 (95% CI=1.46-3.21, P<0.001) without statistically significant heterogeneity or publication bias. Stratification by HPV type showed a stronger association for patients with high-risk HPV (hrHPV) types, HPV-16, HPV-18, and HPV-16/18 infection (OR=8.8 [95% CI: 4.73-16.38], 8.04 [95% CI: 3.34-19.39], 18.57 [95% CI: 4.56-75.70], and 26.24 [4.35-158.47], respectively). When only using PCR studies, pooled ORs for patients with hrHPV, HPV-16, and HPV18 infection still reached statistical significance. However, Egger's test reflected significant publication bias in the HPV-16 sub-analysis (P=0.06), and the adjusted OR was no longer statistically significant (OR=1.65, 95%CI: 0.58-4.63). These results suggest that HPV infection, especially hrHPV (HPV-18), is significantly associated with malignant SNIP. PMID:27085508

  5. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    PubMed Central

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  6. Isolation and characterization of human malignant glioma cells from histologically normal brain.

    PubMed

    Silbergeld, D L; Chicoine, M R

    1997-03-01

    Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines

  7. Horizontal Transmission and Retention of Malignancy, as well as Functional Human Genes, After Spontaneous Fusion of Human Glioblastoma and Hamster Host Cells In Vivo

    PubMed Central

    Goldenberg, David M.; Zagzag, David; Heselmeyer-Haddad, Kerstin M.; Berroa Garcia, Lissa Y; Ried, Thomas; Loo, Meiyu; Chang, Chien-Hsing; Gold, David V.

    2011-01-01

    Cell fusion in vitro has been used to study cancer, gene mapping and regulation, and the production of antibodies via hybridomas. However, in-vivo heterosynkaryon formation by cell-cell fusion has received less attention. This investigation describes the spontaneous fusion of a human glioblastoma with normal hamster cells after xenogeneic transplantation, resulting in malignant cells that express both human and hamster genes and gene products, and retention of glioblastoma traits with an enhanced ability to metastasize. Three of 7 human genes found showed translation of their proteins during serial propagation in vivo or in vitro for years; namely, CD74, CXCR4, and PLAGL2, each implicated with malignancy or glioblastoma. This supports the thesis that genetic hybridization of cancer and normal cells can transmit malignancy and also, as first described herein, regulatory genes involved in the tumor’s organotypic morphology. Evidence also is increasing that even cell-free human cancer DNA can induce malignancy and transfer genetic information to normal cells. Hence, we posit that the transfer of genetic information between tumor and stromal cells, whether by cell-cell fusion or other mechanisms, is implicated in the progression of malignancy, and may further define the crosstalk between cancer cells and their stromal neighbors. PMID:21796629

  8. Decrease of miR-146a is associated with the aggressiveness of human oral squamous cell carcinoma

    PubMed Central

    Shi, Zonggao; Johnson, Jeffrey J.; Jiang, Rong; Liu, Yueying; Stack, M. Sharon

    2015-01-01

    With the aim to identify microRNAs that may contribute to oral squamous cell carcinoma (OSCC) progression, we compared the microRNA expression profiles of two related cell lines that form tumors with differential aggressiveness. A panel of 28 microRNAs was found to be more than 1.5-fold altered, among which miR-146a was the most significantly changed (-4.6-fold). Loss of miR-146a expression was validated in human high-grade tumors, while normal oral mucosa retained expression, using fluorescence in situ hybridization on a tissue microarray. Restoration of miR-146a in SCC25 and UMSCC1 cells decreased in vitro invasive activity, suppressed tumor growth in vivo, and decreased the incidence of UMSCC1 lung metastasis. The transcription factor Sox2 was found to be a putative target of miR-146a. In conclusion, the loss or decrease of miR-146a is a new feature that is associated with more aggressive behavior in oral squamous carcinoma. PMID:26159827

  9. CD44 enhances tumor aggressiveness by promoting tumor cell plasticity.

    PubMed

    Paulis, Yvette W J; Huijbers, Elisabeth J M; van der Schaft, Daisy W J; Soetekouw, Patricia M M B; Pauwels, Patrick; Tjan-Heijnen, Vivianne C G; Griffioen, Arjan W

    2015-08-14

    Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry. PMID:26189059

  10. Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies

    PubMed Central

    Johnson, Benny; Mahadevan, Daruka

    2015-01-01

    Background: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the CEA family of cell adhesion proteins that belong to the immunoglobulin superfamily. CEACAM6 is normally expressed on the surface of myeloid (CD66c) and epithelial surfaces. Stiochiomertic expression of members of the CEA family (CEACAM1, 5, 6, 7) on epithelia maintains normal tissue architecture through homo-and hetero-philic interactions. Dysregulated over-expression of CEACAM6 is oncogenic, is associated with anoikis resistance and an invasive phenotype mediated by excessive TGFβ, AKT, FAK and SRC signaling in human malignancies. Methods: Extensive literature review through PubMed was conducted to identify relevant preclinical and clinical research publications regarding CEACAM6 over the last decade and was summarized in this manuscript. Results: CEACAM5 and 6 are over-expressed in nearly 70% of epithelial malignancies including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), hepatobiliary, gastric, breast, non-small cell lung and head/neck cancers. Importantly, CEACAM6 is a poor prognostic marker in CRC, while its expression correlates with tumor stage, metastasis and post-operative survival in PDA. CEACAM6 appears to be an immune checkpoint suppressor in hematologic malignancies including acute lymphoblastic leukemia and multiple myeloma. Several therapeutic monoclonal antibodies or antibody fragments targeting CEACAM6 have been designed and developed as a targeted therapy for human malignancies. A Llama antibody targeting CEACAM6 is being evaluated in early phase clinical trials. Conclusion: This review focuses on the role of CEACAM6 in the pathogenesis and signaling of the malignant phenotype in solid and hematologic malignancies and highlights its potential as a therapeutic target for anti-cancer therapy.

  11. Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy of human malignant neoplasias

    PubMed Central

    Scala, Stefania; Portella, Giuseppe; Fedele, Monica; Chiappetta, Gennaro; Fusco, Alfredo

    2000-01-01

    High mobility group I (HMGI) proteins are overexpressed in several human malignant tumors. We previously demonstrated that inhibition of HMGI synthesis prevents thyroid cell transformation. Here, we report that an adenovirus carrying the HMGI(Y) gene in an antisense orientation (Ad-Yas) induced programmed cell death of two human thyroid anaplastic carcinoma cell lines (ARO and FB-1), but not normal thyroid cells. The Ad-Yas virus led to death of lung, colon, and breast carcinoma cells. A control adenovirus carrying the lacZ gene did not inhibit the growth of either normal or neoplastic cells. Ad-Yas treatment of tumors induced in athymic mice by ARO cells caused a drastic reduction in tumor size. Therefore, suppression of HMGI(Y) protein synthesis by an HMGI(Y) antisense adenoviral vector may be a useful treatment strategy in a variety of human malignant neoplasias, in which HMGI(Y) gene overexpression is a general event. PMID:10759549

  12. Human papillomavirus-58 and -73-associated digital squamous cell carcinoma in a patient with aggressive digital papillary adenocarcinoma.

    PubMed

    DePond, William; Kure, Kiyoe; Lankachandra, Kamani; Gidwani, Raja; Nelson, Brook V; Zimmerman, Hannah; Talboy, Glenn E; Miranda, Roberto N

    2009-06-01

    Aggressive digital papillary adenocarcinoma (ADPA) is a rare tumor that is considered to arise from eccrine sweat glands of the skin. It occurs predominantly in men with a mean age in the sixth decade. It shows a strong tendency for local recurrence and has the potential to metastasize to distant sites. Prompt diagnosis and regular follow-up are important to ensure the best possible outcome. We discuss a case of recurrent ADPA associated with subsequent squamous cell carcinoma (SCC) in different contralateral digits in a 55-year-old man. One SCC lesion tested positive for human papillomavirus (HPV)-58. HPV-associated digital SCCs have been reported; most cases are HPV-16 positive. This report describes a rare case of an HPV-58-positive invasive digital SCC and an HPV-73-positive SCC in situ associated with ADPA. PMID:19461243

  13. Establishment and characterization of OS 99-1, a cell line derived from a highly aggressive primary human osteosarcoma.

    PubMed

    Gillette, Jennifer M; Gibbs, C Parker; Nielsen-Preiss, Sheila M

    2008-01-01

    Osteosarcoma is the most common form of primary bone cancer. In this study, we established a human osteosarcoma cell line (OS 99-1) from a highly aggressive primary tumor. G-banding karyotype analysis demonstrated a large number of clonal abnormalities, as well as extensive intercellular heterogeneity. Through the use of immunologic, molecular, and biochemical analyses, we characterized protein and gene expression profiles confirming the osteogenic nature of the cells. Further evaluation indicated that OS 99-1 cells maintain the capacity to differentiate in an in vitro mineralization assay as well as form tumors in the in vivo chicken embryo model. This cell line provides a useful tool to investigate the molecular mechanisms contributing to osteosarcoma and may have the potential to serve as a culture system for studies involving bone physiology. PMID:18247100

  14. The Growth and Aggressive Behavior of Human Osteosarcoma Is Regulated by a CaMKII-Controlled Autocrine VEGF Signaling Mechanism

    PubMed Central

    Daft, Paul G.; Yang, Yang; Napierala, Dobrawa; Zayzafoon, Majd

    2015-01-01

    Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease. PMID:25860662

  15. Human Cytomegalovirus Antigens in Malignant Gliomas as Targets for Adoptive Cellular Therapy

    PubMed Central

    Landi, Daniel; Hegde, Meenakshi; Ahmed, Nabil

    2014-01-01

    Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM). This discovery is significant because HCMV gene products can be targeted by immune-based therapies. In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients. PMID:25505736

  16. Function and significance of MicroRNAs in benign and malignant human stem cells.

    PubMed

    Utikal, Jochen; Abba, Mohammed; Novak, Daniel; Moniuszko, Marcin; Allgayer, Heike

    2015-12-01

    MicroRNAs now not only represent a significant mechanism for post-transcriptional gene regulation, but have come to be appreciated as molecules with far reaching tentacles affecting diverse processes and pathologies by modulating amongst others, cellular gene expression, epigentic mechanisms, complex signaling cascades, cell-cell communication, the immune system and microenvironmental interactions between several cell types, tissues and organ systems. In this review, we systematically reflect on the impact of miRNAs on all types of benign and malignant human stem cells, looking at the roles they play in maintaining or changing the stem cell state, and review how aberrations of their expression and function within diverse types of stem cells orchestrate carcinogenesis and metastasis. As a conclusion, we consider it striking to see how similar some miR-driven mechanisms are between different types of stem cells and cancer cells, and how this might support hypotheses of miR-driven embryologic pathway reactivation in metastasis or propose putative functions of miRs in important novel cross-topic fields such as obesity and cancer. PMID:26192966

  17. Human metapneumovirus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review.

    PubMed

    Shah, Dimpy P; Shah, Pankil K; Azzi, Jacques M; El Chaer, Firas; Chemaly, Roy F

    2016-08-28

    Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients. PMID:27260872

  18. Analgesic-antitumor peptide inhibits proliferation and migration of SHG-44 human malignant glioma cells.

    PubMed

    Zhao, Youlong; Cai, Xueting; Ye, Tingmei; Huo, Jiege; Liu, Chao; Zhang, Shuangquan; Cao, Peng

    2011-09-01

    Malignant gliomas, the most common subtype of primary brain tumors, are characterized by high proliferation, great invasion, and neurological destruction and considered to be the deadliest of human cancers. Analgesic-antitumor peptide (AGAP), one of scorpion toxic polypeptides, has been shown to have antitumor activity. Here, we show that recombinant AGAP (rAGAP) not only inhibits the proliferation of gliomas cell SHG-44 and rat glioma cell C6, but also suppresses the migration of SHG-44 cells during wound healing. To explain these phenomena, we find that rAGAP leads to cell cycle of SHG-44 arrested in G1 phase accompanied by suppressing G1 cell cycle regulatory proteins CDK2, CDK6, and p-RB by means of the down-regulated protein expression of p-AKT. Meanwhile, rAGAP significantly decreases the production of NF-κB, BCL-2, p-p38, p-c-Jun, and p-Erk1/2 and further suppresses the activation of VEGF and MMP-9 in SHG-44 cells. These findings suggest rAGAP inhibit proliferation and migration of SHG-44 cells by arresting cell cycle and interfering p-AKT, NF-κB, BCL-2, and MAPK signaling pathways. PMID:21538480

  19. β-lapachone suppresses the proliferation of human malignant melanoma cells by targeting specificity protein 1.

    PubMed

    Bang, Woong; Jeon, Young-Joo; Cho, Jin Hyoung; Lee, Ra Ham; Park, Seon-Min; Shin, Jae-Cheon; Choi, Nag-Jin; Choi, Yung Hyun; Cho, Jung-Jae; Seo, Jae-Min; Lee, Seung-Yeop; Shim, Jung-Hyun; Chae, Jung-Il

    2016-02-01

    β-lapachone (β-lap), a novel natural quinone derived from the bark of the Pink trumpet tree (Tabebuia avellanedae) has been demonstrated to have anticancer activity. In this study, we investigated whether β-lap exhibits anti-proliferative effects on two human malignant melanoma (HMM) cell lines, G361 and SK-MEL-28. The effects of β-lap on the HMM cell lines were investigated using 3-(4,5-dimethylthiazol-2-yl)‑5-(3-carboxymethoxyphenyl)‑2-(4-sulfophenyl-2H-tetrazolium (MTS) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, Annexin V and Dead cell assay, mitochondrial membrane potential (MMP) assay and western blot analysis. We demonstrated that β-lap significantly induced apoptosis and suppressed cell viability in the HMM cells. Intriguingly, the transcription factor specificity protein 1 (Sp1) was significantly downregulated by β-lap in a dose- and time-dependent manner. Furthermore, β-lap modulated the protein expression level of the Sp1 regulatory genes including cell cycle regulatory proteins and apoptosis-associated proteins. Taken together, our findings indicated that β-lap modulates Sp1 transactivation and induces apoptotic cell death through the regulation of cell cycle- and apoptosis-associated proteins. Thus, β-lap may be used as a promising anticancer drug for cancer prevention and may improve the clinical outcome of patients with cancer. PMID:26718788

  20. [Phase I study of human lymphoblastoid alpha-interferon on malignant tumor].

    PubMed

    Furue, H

    1986-04-01

    A phase I study with human lymphoblastoid alpha-interferon (IFN-alpha) was conducted in 31 patients with malignant tumors. IFN-alpha was administered by intravenous drip infusion, intramuscular injection or local injection. In each patient, the dose was increased in 6 steps from 3 X 10(6) IU/body up to 54 X 10(6) IU/body for the purpose of investigating the safety, optimal regimen, pharmacokinetics and antitumor effect. The following findings were obtained: 1) Fever as a side effect was most frequently (in about 80%) found. However, the temperature did not exceed 40 degrees C in most cases and, on the next day, spontaneously fell to normal. 2) The dose-limiting factors (DLF) may include the subjective symptoms of anorexia, general fatigue and nausea/vomiting and the objective symptom of pancytopenia. 3) The maximum tolerated dose (MTD) was estimated to be between 36 X 10(6) and 54 X 10(6) IU/body per dose. 4) As for the route of administration, the intramuscular one was considered most suitable on the basis of the plasma concentration profile of INF-alpha. It was therefore concluded that the drug may be further submitted to a phase II study which is to be conducted with due consideration of its safety. PMID:3963861

  1. Molecular Mechanisms of Malignant Transformation by Low Dose Cadmium in Normal Human Bronchial Epithelial Cells

    PubMed Central

    Kluz, Thomas; Cohen, Lisa; Shen, Steven S.; Costa, Max

    2016-01-01

    Cadmium is a carcinogenic metal, the mechanisms of which are not fully understood. In this study, human bronchial epithelial cells were transformed with sub-toxic doses of cadmium (0.01, 0.05, and 0.1 μM) and transformed clones were characterized for gene expression changes using RNA-seq, as well as other molecular measurements. 440 genes were upregulated and 47 genes were downregulated in cadmium clones relative to control clones over 1.25-fold. Upregulated genes were associated mostly with gene ontology terms related to embryonic development, immune response, and cell movement, while downregulated genes were associated with RNA metabolism and regulation of transcription. Several embryonic genes were upregulated, including the transcription regulator SATB2. SATB2 is critical for normal skeletal development and has roles in gene expression regulation and chromatin remodeling. Small hairpin RNA knockdown of SATB2 significantly inhibited growth in soft agar, indicating its potential as a driver of metal-induced carcinogenesis. An increase in oxidative stress and autophagy was observed in cadmium clones. In addition, the DNA repair protein O6-methylguanine-DNA-methyltransferase was depleted by transformation with cadmium. MGMT loss caused significant decrease in cell viability after treatment with the alkylating agent temozolomide, demonstrating diminished capacity to repair such damage. Results reveal various mechanisms of cadmium-induced malignant transformation in BEAS-2B cells including upregulation of SATB2, downregulation of MGMT, and increased oxidative stress. PMID:27186882

  2. Preliminary micro-Raman images of normal and malignant human skin cells

    NASA Astrophysics Data System (ADS)

    Short, Michael A.; Lui, Harvey; McLean, David I.; Zeng, Haishan; Chen, Michael X.

    2006-02-01

    Micro-Raman spectroscopy covering a frequency range from 200 to 4000 cm -1 was used to image human skin melanocytes and keratinocytes with a spatial resolution of 0.5 μm. The cells were either cultivated on glass microscope slides or were located within thin sections of skin biopsies mounted on low fluorescence BaF II. A commercially available system was used to obtain the spectra utilizing a x100 long working distance objective with a numerical aperture of 0.8, and a cooled CCD. Both 633 and 515 nm excitations were tried, although the latter proved to be more effcient at producing Raman emission mostly due to the 1/λ 4 dependence in light scattering. Fluorescence emission from the cells was surprisingly low. The excitation power at the sample was kept below about 2 mW to avoid damaging the cells; this was the limiting factor on how quickly a Raman image could be obtained. Despite this diffculty we were able to obtain Raman images with rich information about the spectroscopic and structural features within the cytoplasm and cell nuclei. Differences were observed between the Raman images of normal and malignant cells. Spectra from purified DNA, RNA, lipids, proteins and melanin were obtained and these spectra were compared with the skin cell spectra with the aim of understanding how they are distributed over a cell and how the distribution changes between different cells.

  3. Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues

    PubMed Central

    Azemikhah, Mitra; Ashtiani, Hamidreza Ahmadi; Aghaei, Mahmoud; Rastegar, Hosein

    2015-01-01

    Discoidin domain receptor (DDR) is a new member of the receptor tyrosine kinase family. There are two isoforms of discoidin domain receptor (DDR), DDR1 and DDR2. These receptors play a major role in the adhesion, motility and cell proliferation. Due to the important role of DDR2 in the development of tumor extension, this receptor is pivotal in the field of carcinogenesis. The aim of this study was to investigate the mRNA and protein expression of DDR2, in the malignant, benign prostatic hyperplasia (BPH) and normal tissues of patients with prostate cancer. In this study the gene and protein expression of DDR2 in adjacent normal (n=40), BPH (n=40), and malignant (n=40) prostate tissue were measured using real-time PCR and Western blotting. Then, the correlation of DDR2 gene and protein expression with prognostic factors such as age, tumor grade, tumor stage, lymph node involvement, and serum prostate-specific antigen (PSA) concentration were evaluated. The relative mRNA and protein expression level of DDR2 in malignant and benign prostate tissue was significantly higher than those of adjacent normal tissues (P<0.01). This expression was found to increase approximately 3.5 and 2.1 fold for mRNA and protein levels, respectively. Spearman test indicated a significant correlation between DDR2 mRNA and protein expression with prognostic factors such as tumor grade, stage, lymph node involvement, and serum PSA concentration. However, significant correlation with age was not observed. These findings suggest that DDR2 is a cancer-related gene associated with the aggressive progression of prostate cancer patients. PMID:26600862

  4. Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues.

    PubMed

    Azemikhah, Mitra; Ashtiani, Hamidreza Ahmadi; Aghaei, Mahmoud; Rastegar, Hosein

    2015-01-01

    Discoidin domain receptor (DDR) is a new member of the receptor tyrosine kinase family. There are two isoforms of discoidin domain receptor (DDR), DDR1 and DDR2. These receptors play a major role in the adhesion, motility and cell proliferation. Due to the important role of DDR2 in the development of tumor extension, this receptor is pivotal in the field of carcinogenesis. The aim of this study was to investigate the mRNA and protein expression of DDR2, in the malignant, benign prostatic hyperplasia (BPH) and normal tissues of patients with prostate cancer. In this study the gene and protein expression of DDR2 in adjacent normal (n=40), BPH (n=40), and malignant (n=40) prostate tissue were measured using real-time PCR and Western blotting. Then, the correlation of DDR2 gene and protein expression with prognostic factors such as age, tumor grade, tumor stage, lymph node involvement, and serum prostate-specific antigen (PSA) concentration were evaluated. The relative mRNA and protein expression level of DDR2 in malignant and benign prostate tissue was significantly higher than those of adjacent normal tissues (P<0.01). This expression was found to increase approximately 3.5 and 2.1 fold for mRNA and protein levels, respectively. Spearman test indicated a significant correlation between DDR2 mRNA and protein expression with prognostic factors such as tumor grade, stage, lymph node involvement, and serum PSA concentration. However, significant correlation with age was not observed. These findings suggest that DDR2 is a cancer-related gene associated with the aggressive progression of prostate cancer patients. PMID:26600862

  5. Expression of Human Herpesvirus-6 Antigens in Benign and Malignant Lymphoproliferative Diseases

    PubMed Central

    Luppi, Mario; Barozzi, Patrizia; Garber, Richard; Maiorana, Antonio; Bonacorsi, Goretta; Artusi, Tullio; Trovato, Raffaella; Marasca, Roberto; Torelli, Giuseppe

    1998-01-01

    Immunohistochemistry was used to look for the expression of human herpesvirus-6 (HHV-6) antigens in a well characterized series of benign, atypical, and malignant lymphoid lesions, which tested positive for the presence of HHV-6 DNA. A panel of specific antibodies against HHV-6 antigens, characteristic either of the early (p41) or late (p101K, gp106, and gp116) phases of the viral cycle, was applied to the lymphoid tissues from 15 non-Hodgkin’s lymphomas, 14 Hodgkin’s disease cases, 5 angioimmunoblastic lymphadenopathies with dysproteinemia, 14 reactive lymphadenopathies, and 2 cases of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). In lymphomatous tissues, the expression of late antigens was documented only in reactive cells, and mainly in plasma cells. Of interest, the expression of the early p41 antigen was detected in the so-called “mummified” Reed-Sternberg cells, in two Hodgkin’s disease cases. In reactive lymphadenopathies, the HHV-6 late antigen-expressing cells were plasma cells, histiocytes, and rare granulocytes distributed in interfollicular areas. In both cases of Rosai-Dorfman disease, the p101K showed an intense staining in follicular dendritic cells of germinal centers, whereas the gp106 exhibited an intense cytoplasmic reaction in the abnormal histiocytes, which represent the histological hallmark of the disease. The expression of HHV-6 antigens is tightly controlled in lymphoid tissues. The lack of HHV-6 antigen expression in neoplastic cells and the limited expression in degenerating Reed-Sternberg cells argue against a major pathogenetic role of the virus in human lymphomagenesis. The detection of a rather unique pattern of viral late antigen expression in Rosai-Dorfman disease suggests a possible pathogenetic involvement of HHV-6 in some cases of this rare lymphoproliferative disorder. PMID:9736030

  6. Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy

    PubMed Central

    Okada, Kazue; Kimura, Taichi; Piao, Jinhua; Tanaka, Shinya; Shinohara, Yasuro

    2015-01-01

    Cancer cells frequently express glycans at different levels and/or with fundamentally different structures from those expressed by normal cells, and therefore elucidation and manipulation of these glycosylations may provide a beneficial approach to cancer therapy. However, the relationship between altered glycosylation and causal genetic alteration(s) is only partially understood. Here, we employed a unique approach that applies comprehensive glycomic analysis to a previously described multistep tumorigenesis model. Normal human astrocytes were transformed via the serial introduction of hTERT, SV40ER, H-RasV12, and myrAKT, thereby mimicking human brain tumor grades I-IV. More than 160 glycans derived from three major classes of cell surface glycoconjugates (N- and O-glycans on glycoproteins, and glycosphingolipids) were quantitatively explored, and specific glycosylation patterns related to malignancy were systematically identified. The sequential introduction of hTERT, SV40ER, H-RasV12, and myrAKT led to (i) temporal expression of pauci-mannose/mono-antennary type N-glycans and GD3 (hTERT); (ii) switching from ganglio- to globo-series glycosphingolipids and the appearance of Neu5Gc (hTERT and SV40ER); (iii) temporal expression of bisecting GlcNAc residues, α2,6-sialylation, and stage-specific embryonic antigen-4, accompanied by suppression of core 2 O-glycan biosynthesis (hTERT, SV40ER and Ras); and (iv) increased expression of (neo)lacto-series glycosphingolipids and fucosylated N-glycans (hTERT, SV40ER, Ras and AKT). These sequential and transient glycomic alterations may be useful for tumor grade diagnosis and tumor prognosis, and also for the prediction of treatment response. PMID:26132161

  7. A Three-dimensional Tissue Culture Model to Study Primary Human Bone Marrow and its Malignancies

    PubMed Central

    Parikh, Mukti R.; Belch, Andrew R.; Pilarski, Linda M; Kirshner, Julia

    2014-01-01

    Tissue culture has been an invaluable tool to study many aspects of cell function, from normal development to disease. Conventional cell culture methods rely on the ability of cells either to attach to a solid substratum of a tissue culture dish or to grow in suspension in liquid medium. Multiple immortal cell lines have been created and grown using such approaches, however, these methods frequently fail when primary cells need to be grown ex vivo. Such failure has been attributed to the absence of the appropriate extracellular matrix components of the tissue microenvironment from the standard systems where tissue culture plastic is used as a surface for cell growth. Extracellular matrix is an integral component of the tissue microenvironment and its presence is crucial for the maintenance of physiological functions such as cell polarization, survival, and proliferation. Here we present a 3-dimensional tissue culture method where primary bone marrow cells are grown in extracellular matrix formulated to recapitulate the microenvironment of the human bone (rBM system). Embedded in the extracellular matrix, cells are supplied with nutrients through the medium supplemented with human plasma, thus providing a comprehensive system where cell survival and proliferation can be sustained for up to 30 days while maintaining the cellular composition of the primary tissue. Using the rBM system we have successfully grown primary bone marrow cells from normal donors and patients with amyloidosis, and various hematological malignancies. The rBM system allows for direct, in-matrix real time visualization of the cell behavior and evaluation of preclinical efficacy of novel therapeutics. Moreover, cells can be isolated from the rBM and subsequently used for in vivo transplantation, cell sorting, flow cytometry, and nucleic acid and protein analysis. Taken together, the rBM method provides a reliable system for the growth of primary bone marrow cells under physiological conditions

  8. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

    PubMed

    Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

    2014-07-01

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID:24789042

  9. Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions

    PubMed Central

    Lakiotaki, Eleftheria; Giaginis, Constantinos; Tolia, Maria; Alexandrou, Paraskevi; Delladetsima, Ioanna; Giannopoulou, Ioanna; Kyrgias, George; Patsouris, Efstratios; Theocharis, Stamatios

    2015-01-01

    The endocannabinoid system is comprised of cannabinoid receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism participate in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to evaluate the clinical significance of CB1 and CB2 expression in human benign and malignant thyroid lesions. CB1 and CB2 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 87 patients with benign (n = 43) and malignant (n = 44) lesions and was statistically analyzed with clinicopathological parameters, follicular cells' proliferative capacity, and risk of recurrence rate estimated according to the American Thyroid Association (ATA) staging system. Enhanced CB1 and CB2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p = 0.0010 and p = 0.0005, resp.). Enhanced CB1 and CB2 expression was also significantly more frequently observed in papillary carcinomas compared to hyperplastic nodules (p = 0.0097 and p = 0.0110, resp.). In malignant thyroid lesions, elevated CB2 expression was significantly associated with the presence of lymph node metastases (p = 0.0301). Enhanced CB2 expression was also more frequently observed in malignant thyroid cases with presence of capsular (p = 0.1165), lymphatic (p = 0.1989), and vascular invasion (p = 0.0555), as well as in those with increased risk of recurrence rate (p = 0.1165), at a nonsignificant level though, whereas CB1 expression was not associated with any of the clinicopathological parameters examined. Our data suggest that CB receptors may be involved in malignant thyroid transformation and especially CB2 receptor could serve as useful biomarker and potential therapeutic target in thyroid neoplasia. PMID:26539529

  10. Malignant mesothelioma

    PubMed Central

    Moore, Alastair J; Parker, Robert J; Wiggins, John

    2008-01-01

    Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis. PMID:19099560

  11. Outbreak of aggressions and transmission of rabies in human beings by vampire bats in northeastern Brazil.

    PubMed

    Gonçalves, Marcio A S; Sá-Neto, Raymundo J; Brazil, Tania K

    2002-01-01

    Outbreaks of attacks upon human beings by vampire bats seems to be a common phenomenon in several regions of Latin America, but the occurrence of rabies infection among humans bled by vampires, is relatively low. In the present study, two outbreaks of human rabies transmitted by common vampire bats (Desmodus rotundus) are described from Bahia State, Northeastern Brazil, in 1991 and 1992. The first was recorded in Aporá where 308 people were bled by vampires bats and three of these die from this zoonosis. The 2nd outbreak occurred in Conde where only five people were bled by vampires, and two deaths by rabies were registered. Our data suggest that rabies transmitted by bats basically depends on the presence of virus in the vampire bat population and not on the number of humans bled by them. PMID:12621664

  12. Malignant cancer and invasive placentation

    PubMed Central

    D'Souza, Alaric W.; Wagner, Günter P.

    2014-01-01

    Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971;47:1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness. PMID:25324490

  13. The Guanine Nucleotide Exchange Factor SWAP-70 Modulates the Migration and Invasiveness of Human Malignant Glioma Cells12

    PubMed Central

    Seol, Ho Jun; Smith, Christian A; Salhia, Bodour; Rutka, James T

    2009-01-01

    The malignant glioma is the most common primary human brain tumor. Its tendency to invade away from the primary tumor mass is considered a leading cause of tumor recurrence and treatment failure. Accordingly, the molecular pathogenesis of glioma invasion is currently under investigation. Previously, we examined a gene expression array database comparing human gliomas to nonneoplastic controls and identified several Rac guanine nucleotide exchange factors with differential expression. Here, we report that the guanine nucleotide exchange factor SWAP-70 has increased expression in malignant gliomas and strongly correlates with lowered patient survival. SWAP-70 is a multifunctional signaling protein involved in membrane ruffling that works cooperatively with activated Rac. Using a glioma tissue microarray, we validated that SWAP-70 demonstrates higher expression in malignant gliomas compared with low-grade gliomas or nonneoplastic brain tissue. Through immunofluorescence, SWAP-70 localizes to membrane ruffles in response to the growth factor, epidermal growth factor. To assess the role of SWAP-70 in glioma migration and invasion, we inhibited its expression withsmall interfering RNAs and observed decreased glioma cell migration and invasion. SWAP-70 overexpression led to increased levels of active Rac even in low-serum conditions. In addition, when SWAP-70 was overexpressed in glioma cells, we observed enhanced membrane ruffle formation followed by increased cellmigration and invasiveness. Taken together, our findings suggest that the guanine nucleotide exchange factor SWAP-70 plays an important role in the migration and invasion of human gliomas into the surrounding tissue. PMID:19956392

  14. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    PubMed Central

    Lai, Wen-Lin; Harn, Horng-jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man

    2013-01-01

    Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer. PMID:24319475

  15. p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia

    SciTech Connect

    Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. ); Neri, A, Centro Malattie del Sangue G. Marcora, Milan ); Newcomb, E.W. ); Magrath, I.T. )

    1991-06-15

    The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

  16. Catalase ameliorates polychlorinated biphenyl-induced cytotoxicity in non-malignant human breast epithelial cells

    PubMed Central

    Venkatesha, Venkatasubbaiah A.; Venkataraman, Sujatha; Sarsour, Ehab H.; Kalen, Amanda L.; Buettner, Garry R.; Robertson, Larry W.; Lehmler, Hans-Joachim; Goswami, Prabhat C.

    2008-01-01

    Polychlorinated biphenyls (PCBs) are environmental chemical contaminants believed to adversely affect cellular processes. We investigated the hypothesis that PCB-induced changes in the levels of cellular reactive oxygen species (ROS) induce DNA damage resulting in cytotoxicity. Exponentially growing cultures of human non-malignant breast epithelial cells (MCF10A) were incubated with PCBs for 3 days and assayed for cell number, ROS levels, DNA damage, and cytotoxicity. Exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) or 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of 4-chlorobiphenyl (PCB3) significantly decreased cell number, MTS reduction, and increased the percentage of cells with sub G1 DNA content. Results from electron paramagnetic resonance (EPR) spectroscopy showed a 4-fold increase in the steady-state levels of ROS, which was suppressed in cells pre-treated with catalase. EPR measurements in cells treated with 4-Cl-BQ detected the presence of a semiquinone radical, suggesting that the increased levels of ROS could be due to the redox-cycling of 4-Cl-BQ. A dose-dependent increase in micronuclei frequency was observed in PCB-treated cells, consistent with an increase in histone 2AX-phosphorylation. Treatment of cells with catalase blunted the PCB-induced increase in micronuclei frequency and H2AX phosphorylation that was consistent with an increase in cell survival. Our results demonstrate a PCB-induced increase in cellular levels of ROS causing DNA damage, resulting in cell killing. PMID:18691649

  17. Virus-like particles for the prevention of human papillomavirus-associated malignancies

    PubMed Central

    Wang, Joshua W.; Roden, Richard B.S.

    2013-01-01

    As compared to peptide/protein-based vaccines, naked DNA vectors and even traditional attenuated or inactived virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform because they offer a combination of safety, ease of production, and both high density B cell epitope display and intracellular presentation of T cell epitopes that induce potent humoral and cellular immune responses respectively. Indeed, human papillomavirus (HPV) vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil®, Merck & Co.) or insect cells (Cervarix®, GlaxoSmithKline) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. These HPV vaccines however have not been demonstrated as effective to treat existing infections, and efforts to develop a therapeutic HPV vaccine continue. Furthermore, current HPV L1-VLP vaccines provide type-restricted protection, requiring highly multivalent formulations to broaden coverage to the dozen or more oncogenic HPV genotypes. This raises the complexity and cost of vaccine production. The lack of access to screening and high disease burden in developing countries has spurred efforts to develop second generation HPV vaccines that are more affordable, induce wider protective coverage and offer therapeutic coverage against HPV-associated malignancies. Given the previous success with L1 VLP-based vaccines against HPV, VLPs have been also adopted as platforms for many second generation HPV and non-HPV vaccine candidates with both prophylactic and therapeutic intent. Here we examine the progress and challenges of these efforts, with a focus on how they inform VLP vaccine design. PMID:23414405

  18. Genetic deletion of osteopontin in TRAMP mice skews prostate carcinogenesis from adenocarcinoma to aggressive human-like neuroendocrine cancers

    PubMed Central

    Mauri, Giorgio; Jachetti, Elena; Comuzzi, Barbara; Dugo, Matteo; Arioli, Ivano; Miotti, Silvia; Sangaletti, Sabina; Di Carlo, Emma; Tripodo, Claudio; Colombo, Mario P.

    2016-01-01

    Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN−/−) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN−/− TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors. PMID:26700622

  19. Genetic deletion of osteopontin in TRAMP mice skews prostate carcinogenesis from adenocarcinoma to aggressive human-like neuroendocrine cancers.

    PubMed

    Mauri, Giorgio; Jachetti, Elena; Comuzzi, Barbara; Dugo, Matteo; Arioli, Ivano; Miotti, Silvia; Sangaletti, Sabina; Di Carlo, Emma; Tripodo, Claudio; Colombo, Mario P

    2016-01-26

    Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN-/-) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN-/- TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors. PMID:26700622

  20. Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes

    PubMed Central

    2014-01-01

    Background Carbon nanotubes (CNT) hold great promise to create new and better products for commercial and biomedical applications, but their long-term adverse health effects are a major concern. The objective of this study was to address human lung cancer risks associated with chronic pulmonary exposure to single-walled (SW) CNT through the fundamental understanding of cellular and molecular processes leading to carcinogenesis. We hypothesized that the acquisition of cancer stem cells (CSC), a subpopulation that drive tumor initiation and progression, may contribute to CNT carcinogenesis. Methods Non-tumorigenic human lung epithelial cells were chronically exposed to well-dispersed SWCNT for a period of 6 months at the physiologically relevant concentration of 0.02 μg/cm2 surface area dose. Chronic SWCNT-exposed cells were evaluated for the presence of CSC-like cells under CSC-selective conditions of tumor spheres and side population (SP). CSC-like cells were isolated using fluorescence-activated cell sorting and were assessed for aggressive behaviors, including acquired apoptosis resistance and increased cell migration and invasion in vitro, and tumor-initiating capability in vivo. Non-small cell lung cancer cells served as a positive control. Results We demonstrated for the first time the existence of CSC-like cells in all clones of chronic SWCNT-exposed lung epithelial cells. These CSC-like cells, in contrary to their non-CSC counterpart, possessed all biological features of lung CSC that are central to irreversible malignant transformation, self-renewal, aggressive cancer behaviors, and in vivo tumorigenesis. These cells also displayed aberrant stem cell markers, notably Nanog, SOX-2, SOX-17 and E-cadherin. Restored expression of tumor suppressor p53 abrogated CSC properties of CSC-like cells. Furthermore, we identified specific stem cell surface markers CD24low and CD133high that are associated with SWCNT-induced CSC formation and tumorigenesis. Conclusions

  1. Nogo-A inhibits the migration and invasion of human malignant glioma U87MG cells.

    PubMed

    Jin, Shu-Guang; Ryu, Hyang-Hwa; Li, Song-Yuan; Li, Chun-Hao; Lim, Sa-Hoe; Jang, Woo-Youl; Jung, Shin

    2016-06-01

    Nogo or reticulon-4 (RTN4), also known as neurite outgrowth inhibitor, is a member of the reticulon family of genes. Nogo-A, one of the three isoforms, is enriched in the central nervous system (CNS). The extracellular domain of Nogo-A, Nogo-66, has neurite growth inhibitory activity that is specific for neurons and is mediated by the Nogo receptor. However, most of its functions are not known yet. We investigated whether Nogo-A modulates the migration and invasion of a glioblastoma cell line, as well as the factors that have an effect on Nogo-A. The expression of Nogo-A was evaluated using western blotting and immunohistochemistry in human brain tumor specimens. U87MG cells were transfected with a sense-Nogo-A cDNA construct (U87-Nogo-A cells expressing Nogo-A) and an empty vector (U87MG-E cells not expressing Nogo-A). The migration and invasion abilities of these cells were investigated using simple scratch and Matrigel invasion assays. Morphologic and cytoskeletal changes were documented by confocal microscopy. The proliferation rate was estimated using doubling time assay. The effects of Nogo-A on Rho activity and phosphorylated cofilin were determined by a Rho activity assay and western blotting. Among primary brain tumors, Nogo-A expression was found in a higher percentage of oligodendrogliomas (90.0%) compared with the percentage in the glioblastomas (68.4%). In addition, the percentage in mixed gliomas was 42.9%, while it was not expressed in pituitary adenomas or schwannomas. The migration and invasion abilities of the U87-Nogo-A cells were decreased compared with the control. In the U87-Nogo-A cell line, Rho activity and phosphorylated cofilin expression were also decreased and morphology became more flat in comparison with the U87MG-E cell line. Nogo-A may inhibit the migration and invasion of human malignant glioma cells via the downregulation of RhoA-cofilin signaling. PMID:27109183

  2. Lethal aggression in Pan is better explained by adaptive strategies than human impacts.

    PubMed

    Wilson, Michael L; Boesch, Christophe; Fruth, Barbara; Furuichi, Takeshi; Gilby, Ian C; Hashimoto, Chie; Hobaiter, Catherine L; Hohmann, Gottfried; Itoh, Noriko; Koops, Kathelijne; Lloyd, Julia N; Matsuzawa, Tetsuro; Mitani, John C; Mjungu, Deus C; Morgan, David; Muller, Martin N; Mundry, Roger; Nakamura, Michio; Pruetz, Jill; Pusey, Anne E; Riedel, Julia; Sanz, Crickette; Schel, Anne M; Simmons, Nicole; Waller, Michel; Watts, David P; White, Frances; Wittig, Roman M; Zuberbühler, Klaus; Wrangham, Richard W

    2014-09-18

    Observations of chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) provide valuable comparative data for understanding the significance of conspecific killing. Two kinds of hypothesis have been proposed. Lethal violence is sometimes concluded to be the result of adaptive strategies, such that killers ultimately gain fitness benefits by increasing their access to resources such as food or mates. Alternatively, it could be a non-adaptive result of human impacts, such as habitat change or food provisioning. To discriminate between these hypotheses we compiled information from 18 chimpanzee communities and 4 bonobo communities studied over five decades. Our data include 152 killings (n = 58 observed, 41 inferred, and 53 suspected killings) by chimpanzees in 15 communities and one suspected killing by bonobos. We found that males were the most frequent attackers (92% of participants) and victims (73%); most killings (66%) involved intercommunity attacks; and attackers greatly outnumbered their victims (median 8:1 ratio). Variation in killing rates was unrelated to measures of human impacts. Our results are compatible with previously proposed adaptive explanations for killing by chimpanzees, whereas the human impact hypothesis is not supported. PMID:25230664

  3. Association of epigenetic alterations in the human C7orf24 gene with the aberrant gene expression in malignant cells.

    PubMed

    Ohno, Yuji; Hattori, Akira; Yoshiki, Tatsuhiro; Kakeya, Hideaki

    2013-10-01

    Human chromosome 7 open reading frame 24 (C7orf24)/γ-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells. In contrast, elevated levels of histone modifications leading to transcriptional repression and accumulation of heterochromatin proteins in the C7orf24 promoter were observed in the ARPE-19 and IMR-90 cells, compared to the levels in HeLa and MCF-7 cancer cells. In parallel, the CpG island of the C7orf24 promoter was methylated to a greater extent in the normal cells than in the cancer cells. These results suggest that the transcriptional silencing of the C7orf24 gene in the non-malignant cells is elicited through heterochromatin formation in its promoter region; aberrant expression of C7orf24 associated with malignant alterations results from changes in chromatin dynamics. PMID:23853312

  4. The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation

    SciTech Connect

    Serafino, A. Balestrieri, E.; Pierimarchi, P.; Matteucci, C.; Moroni, G.; Oricchio, E.; Rasi, G.; Mastino, A.; Spadafora, C.; Garaci, E.; Vallebona, P. Sinibaldi

    2009-03-10

    Melanoma development is a multi-step process arising from a series of genetic and epigenetic events. Although the sequential stages involved in progression from melanocytes to malignant melanoma are clearly defined, our current understanding of the mechanisms leading to melanoma onset is still incomplete. Growing evidence show that the activation of endogenous retroviral sequences might be involved in transformation of melanocytes as well as in the increased ability of melanoma cells to escape immune surveillance. Here we show that human melanoma cells in vitro undergo a transition from adherent to a more malignant, non-adherent phenotype when exposed to stress conditions. Melanoma-derived non-adherent cells are characterized by an increased proliferative potential and a decreased expression of both HLA class I molecules and Melan-A/MART-1 antigen, similarly to highly malignant cells. These phenotypic and functional modifications are accompanied by the activation of human endogenous retrovirus K expression (HERV-K) and massive production of viral-like particles. Down-regulation of HERV-K expression by RNA interference prevents the transition from the adherent to the non-adherent growth phenotype in low serum. These results implicate HERV-K in at least some critical steps of melanoma progression.

  5. Evaluation of T and B lymphocyte membrane markers in human non-Hodgkin malignant lymphomata.

    PubMed Central

    Brouet, J. C.; Labaume, S.; Seligmann, M.

    1975-01-01

    Lymphoma cells from 25 patients were studied for the presence of B lymphocytes (membrane bound Ig and Fc receptor) and T lymphocytes (rosette formation with sheep erythrocytes) membrane markers. All cases of well differentiated lymphocytic lymphoma and of acute lymphosarcoma cell leukaemia and most cases of poorly differentiated lymphocytic lymphoma behaved as B cell monoclonal malignancies. However, the malignant cells of some patients were not definitely classified according to their B or T cell origin or lacked these membrane markers. The latter situation was encountered in 4 reticulum cell sarcomata. Polyclonal Ig were found on the surface of B cells in a case of hyperbasophilic undifferentiated lymphoma. The need for using several membrane markers to study the abnormal lymphoma cells is outlined. Such studies improve our understanding of these malignancies and may lead in the future to a satisfactory classification of non-Hodgkin lymphomata. PMID:1081001

  6. First-in-human uPAR PET: Imaging of Cancer Aggressiveness.

    PubMed

    Persson, Morten; Skovgaard, Dorthe; Brandt-Larsen, Malene; Christensen, Camilla; Madsen, Jacob; Nielsen, Carsten H; Thurison, Tine; Klausen, Thomas Levin; Holm, Søren; Loft, Annika; Berthelsen, Anne Kiil; Ploug, Michael; Pappot, Helle; Brasso, Klaus; Kroman, Niels; Højgaard, Liselotte; Kjaer, Andreas

    2015-01-01

    A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with (64)Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of (64)Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of (64)Cu-DOTA-AE105 for uPAR PET imaging in cancer patients. PMID:26516369

  7. First-in-human uPAR PET: Imaging of Cancer Aggressiveness

    PubMed Central

    Persson, Morten; Skovgaard, Dorthe; Brandt-Larsen, Malene; Christensen, Camilla; Madsen, Jacob; Nielsen, Carsten H.; Thurison, Tine; Klausen, Thomas Levin; Holm, Søren; Loft, Annika; Berthelsen, Anne Kiil; Ploug, Michael; Pappot, Helle; Brasso, Klaus; Kroman, Niels; Højgaard, Liselotte; Kjaer, Andreas

    2015-01-01

    A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with 64Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of 64Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of 64Cu-DOTA-AE105 for uPAR PET imaging in cancer patients. PMID:26516369

  8. Human non-Hodgkin's malignant lymphomas serially transplanted in nude mice conditioned with whole-body irradiation.

    PubMed Central

    Igarashi, T.; Oka, K.; Miyamoto, T.

    1989-01-01

    Direct transplantation of non-Hodgkin's malignant lymphoma into athymic nude mice was successfully achieved after whole-body irradiation (5 Gy). Twenty-seven per cent (6/22) of transplanted lymphomas were established as nude mouse lines. The successful lines were derived solely from the patients with diffuse lymphoma who showed advanced clinical stage, high LDH value, large mass and poor prognosis. The histological, immunophenotypic and chromosomal characteristics of the nude mouse lines were compared with those of the original lymphomas, and the proliferative characteristics of the lines were examined. The transplanted lymphomas substantially retained the characteristics of the original lymphomas, and could be useful in biological, oncological and therapeutic studies of human malignant lymphoma. Images Figure 1 Figure 2 Figure 3 PMID:2649134

  9. High expression of Sox10 correlates with tumor aggressiveness and poor prognosis in human nasopharyngeal carcinoma

    PubMed Central

    Zhao, Yu; Liu, Zhi-gang; Tang, Jiao; Zou, Ren-fang; Chen, Xiao-yan; Jiang, Guan-min; Qiu, Yan-fang; Wang, Hui

    2016-01-01

    Purpose The aim of the study was to detect the expression of Sox10 in human nasopharyngeal carcinoma (NPC) and investigate the relationship between its expression and the clinicopathological characteristics of NPC patients. Patients and methods Tumor specimens (n=105) were retrospectively collected from patients with NPC diagnosed between 2004 and 2005 who presented at Hunan Cancer Hospital. Immunohistochemistry analyses were performed to characterize the expression of Sox10 in NPC. Kaplan–Meier survival and Cox regression analyses were employed to evaluate the prognosis of 105 NPC patients. Results The results showed that Sox10 was markedly overexpressed in human NPC tissues. Analysis of clinicopathological parameters showed that high Sox10 expression was significantly correlated with the clinical stage (P=0.032), T classification (P=0.034), and lymph node metastasis (P=0.03). Cox regression analyses further showed that Sox10 expression was an independent prognostic factor for overall survival (P=0.005). This is the first time Sox10 has shown its importance in predicting NPC progressiveness and survival outcomes. Conclusion Sox10 serves as a potential biomarker for NPC patients. It may hopefully become a novel therapeutic target for NPC patients. PMID:27051302

  10. 5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors*

    PubMed Central

    Laderoute, Keith R.; Calaoagan, Joy M.; Chao, Wan-ru; Dinh, Dominc; Denko, Nicholas; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, Laszlo G.

    2014-01-01

    Rapid tumor growth can establish metabolically stressed microenvironments that activate 5′-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [13C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. PMID:24993821

  11. Fas-mediated apoptosis of melanoma cells and infiltrating lymphocytes in human malignant melanomas.

    PubMed

    Shukuwa, Tetsuo; Katayama, Ichiro; Koji, Takehiko

    2002-04-01

    In a rodent system, melanoma cells expressing Fas ligand (FasL) could kill Fas-positive lymphocytes, suggesting that FasL expression was an essential factor for melanoma cell survival in vivo. These findings led us to investigate apoptosis, and to histochemically analyze involvement of Fas and FasL in the induction of apoptosis, in human malignant melanoma tissues. The percentages of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL)-positive melanoma cells and of proliferating cell nuclear antigen (PCNA)-positive melanoma cells in melanoma tissues (n = 22) were greater than those in melanocytes in uninvolved skin (n = 6) and nevus cells in nevi tissues (n = 9). The infiltrating lymphocytes around melanomas were also TUNEL positive. Immunohistochemistry revealed expression of Fas and FasL in melanoma cells and lymphocytes, whereas no Fas or FasL expression was detected in normal skin melanocytes and nevus cells. There was significant correlation between Fas-positive indices and TUNEL indices in melanoma tissues. Moreover, TUNEL-, Fas-, and FasL-positive indices of melanoma cells from patients with Stage 3 melanomas were significantly lower than those with Stage 2 melanomas. The PCNA index of Stage 1 melanoma was significantly lower than that of the other stages, although the difference of PCNA index was insignificant among Stages 2 to 4. Among Stages 1 to 4, there was no difference in the PCNA, TUNEL-, and Fas-positive indices of lymphocytes, although the FasL-positive index of lymphocytes from Stage 3 melanomas was significantly lower than in that from Stage 2. These data reveal that melanoma cells and infiltrating lymphocytes have the potential to induce their own apoptosis regulated by Fas and FasL in an autocrine and/or paracrine fashion and that the decline of Fas-mediated apoptosis of melanoma cells, rather than the apoptosis of infiltrating lymphocytes, may affect the prognosis of melanoma patients, possibly through the

  12. Increased aggression during human group contests when competitive ability is more similar

    PubMed Central

    Stulp, Gert; Kordsmeyer, Tobias; Buunk, Abraham P.; Verhulst, Simon

    2012-01-01

    Theoretical analyses and empirical studies have revealed that conflict escalation is more likely when individuals are more similar in resource-holding potential (RHP). Conflicts can also occur between groups, but it is unknown whether conflicts also escalate more when groups are more similar in RHP. We tested this hypothesis in humans, using data from two professional sports competitions: football (the Bundesliga, the German first division of football) and basketball (the NBA, the North American National Basketball Association). We defined RHP based on the league ranks of the teams involved in the competition (i.e. their competitive ability) and measured conflict escalation by the number of fouls committed. We found that in both sports the number of fouls committed increased when the difference in RHP was smaller. Thus, we provide what is to our best knowledge the first evidence that, as in conflicts between individuals, conflicts escalate more when groups are more similar in RHP. PMID:22896272

  13. TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo.

    PubMed

    Zhang, Qifang; Hossain, Dewan Md Sakib; Nechaev, Sergey; Kozlowska, Anna; Zhang, Wang; Liu, Yong; Kowolik, Claudia M; Swiderski, Piotr; Rossi, John J; Forman, Stephen; Pal, Sumanta; Bhatia, Ravi; Raubitschek, Andrew; Yu, Hua; Kortylewski, Marcin

    2013-02-21

    STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9(+) hematopoietic cells in vivo. We have developed new human cell-specific CpG(A)-STAT3 siRNA conjugates capable of inducing TLR9-dependent gene silencing and activation of primary immune cells such as myeloid dendritic cells, plasmacytoid dendritic cells, and B cells in vitro. TLR9 is also expressed by several human hematologic malignancies, including B-cell lymphoma, multiple myeloma, and acute myeloid leukemia. We further demonstrate that oncogenic proteins such as STAT3 or BCL-X(L) are effectively knocked down by specific CpG(A)-siRNAs in TLR9(+) hematologic tumor cells in vivo. Targeting survival signaling using CpG(A)-siRNAs inhibits the growth of several xenotransplanted multiple myeloma and acute myeloid leukemia tumors. CpG(A)-STAT3 siRNA is immunostimulatory and nontoxic for normal human leukocytes in vitro. The results of the present study show the potential of using tumoricidal/immunostimulatory CpG-siRNA oligonucleotides as a novel 2-pronged therapeutic strategy for hematologic malignancies. PMID:23287859

  14. Of Lion Manes and Human Beards: Some Unusual Effects of the Interaction between Aggression and Sociality

    PubMed Central

    Blanchard, D. Caroline

    2009-01-01

    The function of manes in lions has been a topic of scientific interest since Darwin (1871) suggested that it provides protection in intraspecific fights. Recent experimental studies on wild lions have emphasized the role of female selection, but analyses of specific attack behaviors and targets, and the social consequences of manelessness for lions living in very hot climates suggest that male manes may indeed mitigate the outcomes of intraspecific male attack and thus serve a permissive function for multi-male + female groups, facilitating protection of prides against take-overs and infanticide by nomadic males. Humans also have unusual structural protections for the head, face and neck, areas that are especially accessible during intraspecies attack, and highly vulnerable to damage. One of these, the beard, consists of coarse hairs that grow indefinitely, but only for males, and only during and following puberty; suggesting that it, like the lion's mane, may serve as protection in intraspecies male fights. Such structural protections may reflect a specific combination of lethal weaponry and social life-style, particularly when these are developed so rapidly that they are not accompanied by the evolution of complex attack-inhibiting social behaviors. PMID:20126434

  15. Of Lion Manes and Human Beards: Some Unusual Effects of the Interaction between Aggression and Sociality.

    PubMed

    Blanchard, D Caroline

    2010-01-01

    The function of manes in lions has been a topic of scientific interest since Darwin (1871) suggested that it provides protection in intraspecific fights. Recent experimental studies on wild lions have emphasized the role of female selection, but analyses of specific attack behaviors and targets, and the social consequences of manelessness for lions living in very hot climates suggest that male manes may indeed mitigate the outcomes of intraspecific male attack and thus serve a permissive function for multi-male + female groups, facilitating protection of prides against take-overs and infanticide by nomadic males. Humans also have unusual structural protections for the head, face and neck, areas that are especially accessible during intraspecies attack, and highly vulnerable to damage. One of these, the beard, consists of coarse hairs that grow indefinitely, but only for males, and only during and following puberty; suggesting that it, like the lion's mane, may serve as protection in intraspecies male fights. Such structural protections may reflect a specific combination of lethal weaponry and social life-style, particularly when these are developed so rapidly that they are not accompanied by the evolution of complex attack-inhibiting social behaviors. PMID:20126434

  16. PME-1 protects ERK pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma

    PubMed Central

    Puustinen, Pietri; Junttila, Melissa R.; Vanhatupa, Sari; Sablina, Anna A.; Hector, Melissa E.; Teittinen, Kaisa; Raheem, Olayinka; Ketola, Kirsi; Lin, Shujun; Kast, Juergen; Haapasalo, Hannu; Hahn, William C.; Westermarck, Jukka

    2010-01-01

    ERK/MAPK pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies, however the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here we show that methylesterase PME-1-mediated inhibition of the protein phosphatase 2A (PP2A) promotes basal ERK pathway activity, and is required for efficient growth factor response. Mechanistically PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and PKC. In malignant glioblastoma, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (N=222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells, and suggest important functional role for PME-1 in the disease progression of human astrocytic gliomas. PMID:19293187

  17. Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

    PubMed Central

    Sansone, Pasquale; Bromberg, Jacqueline

    2012-01-01

    The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers. PMID:22355058

  18. DREMECELS: A Curated Database for Base Excision and Mismatch Repair Mechanisms Associated Human Malignancies

    PubMed Central

    Shukla, Ankita; Singh, Tiratha Raj

    2016-01-01

    DNA repair mechanisms act as a warrior combating various damaging processes that ensue critical malignancies. DREMECELS was designed considering the malignancies with frequent alterations in DNA repair pathways, that is, colorectal and endometrial cancers, associated with Lynch syndrome (also known as HNPCC). Since lynch syndrome carries high risk (~40–60%) for both cancers, therefore we decided to cover all three diseases in this portal. Although a large population is presently affected by these malignancies, many resources are available for various cancer types but no database archives information on the genes specifically for only these cancers and disorders. The database contains 156 genes and two repair mechanisms, base excision repair (BER) and mismatch repair (MMR). Other parameters include some of the regulatory processes that have roles in these disease progressions due to incompetent repair mechanisms, specifically BER and MMR. However, our unique database mainly provides qualitative and quantitative information on these cancer types along with methylation, drug sensitivity, miRNAs, copy number variation (CNV) and somatic mutations data. This database would serve the scientific community by providing integrated information on these disease types, thus sustaining diagnostic and therapeutic processes. This repository would serve as an excellent accompaniment for researchers and biomedical professionals and facilitate in understanding such critical diseases. DREMECELS is publicly available at http://www.bioinfoindia.org/dremecels. PMID:27276067

  19. FT-IR Spectroscopic Analysis of Normal and Malignant Human Oral Tissues

    NASA Astrophysics Data System (ADS)

    Krishnakumar, N.; Madhavan, R. Nirmal; Sumesh, P.; Palaniappan, Pl. Rm.; Venkatachalam, P.; Ramachandran, C. R.

    2008-11-01

    FT-IR spectroscopy has been used to explore the changes in the vibrational bands of normal and oral squamous cell carcinoma (OSCC) tissues in the region 4000-400 cm-1. Significant changes in the spectral features were observed. The spectral changes were the results of characteristics structural alterations at the molecular level in the malignant tissues. These alterations include structural changes of proteins and possible increase of its content, an increase in the nucleic-to-cytoplasm ratio, an increase in the relative amount of DNA, an increase in the rate of phosphorylation process induced by carcinogenesis, a loss of hydrogen bonding of the C-OH groups in the amino acid residues of proteins, a decrease in the relative amount of lipids compared to normal epithelial oral tissues. The results of the present study demonstrate that the FT-IR technique has the feasibility of discriminating malignant from normal tissues and other pathological states in a short period of time and may detect malignant transformation earlier than the standard histological examination stage.

  20. Oral malignant melanoma: Report of three cases with literature review

    PubMed Central

    Gupta, Shalini; Tandon, Ankita; Ram, Hari; Gupta, O. P.

    2015-01-01

    Primary oral melanoma is known to be an extremely rare and aggressive neoplasm arising from the mucosal epithelium of the oral cavity especially upper jaw (palate or alveolar gingivae). Malignant melanoma that does not originate in the skin is a very rare disease and is considered one of the most deadly of all human neoplasms. Oral malignant melanoma (OMM) represents about 1% of all melanomas and approximately 0.5% of all oral malignancies. OMM has been reported in patients aged 20 to 80 years and has a male predilection. Because most mucosal melanotic lesions are painless in their early stages, so delayed recognition and subsequent treatment result in worst prognosis. Here, we report three cases with significant heterogeneity in morphological features and biologic behavior. PMID:26668465

  1. The myth of the aggressive monkey.

    PubMed

    Reinhardt, Viktor

    2002-01-01

    Captive rhesus macaques are not naturally aggressive, but poor husbandry and handling practices can trigger their aggression toward conspecifics and toward the human handler. The myth of the aggressive monkey probably is based on often not taking into account basic ethological principles when managing rhesus macaques in the research laboratory setting. PMID:16221082

  2. Phosphorylation of galectin-3 contributes to malignant transformation of human epithelial cells via modulation of unique sets of genes.

    PubMed

    Mazurek, Nachman; Sun, Yun Jie; Price, Janet E; Ramdas, Latha; Schober, Wendy; Nangia-Makker, Pratima; Byrd, James C; Raz, Avraham; Bresalier, Robert S

    2005-12-01

    Galectin-3 is a multifunctional beta-galactoside-binding protein implicated in apoptosis, malignant transformation, and tumor progression. The mechanisms by which galectin-3 contributes to malignant progression are not fully understood. In this study, we found that the introduction of wild-type galectin-3 into nontumorigenic, galectin-3-null BT549 human breast epithelial cells conferred tumorigenicity and metastatic potential in nude mice, and that galectin-3 expressed by the cells was phosphorylated. In contrast, BT549 cells expressing galectin-3 incapable of being phosphorylated (Ser6-->Glu Ser6-->Ala) were nontumorigenic. A microarray analysis of 10,000 human genes, comparing BT549 transfectants expressing wild-type and those expressing phosphomutant galectin-3, identified 188 genes that were differentially expressed (>2.5-fold). Genes affected by introduction of wild-type phosphorylated but not phosphomutant galectin-3 included those involved in oxidative stress, a novel noncaspase lysosomal apoptotic pathway, cell cycle regulation, transcriptional activation, cytoskeleton remodeling, cell adhesion, and tumor invasion. The reliability of the microarray data was validated by real-time reverse transcription-PCR (RT-PCR) and by Western blot analysis, and clinical relevance was evaluated by real-time RT-PCR screening of a panel of matched pairs of breast tumors. Differentially regulated genes in breast cancers that are also predicted to be associated with phospho-galectin-3 in transformed BT549 cells include C-type lectin 2, insulin-like growth factor-binding protein 5, cathepsins L2, and cyclin D1. These data show the functional diversity of galectin-3 and suggest that phosphorylation of the protein is necessary for regulation (directly or indirectly) of unique sets of genes that play a role in malignant transformation. PMID:16322222

  3. Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors

    PubMed Central

    Duperret, Elizabeth K; Oh, Seung Ja; McNeal, Andrew; Prouty, Stephen M; Ridky, Todd W

    2014-01-01

    Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling. To define the role of FGFR3 in human normal and neoplastic epidermis, and to directly test the hypothesis that FGFR3 antagonizes Ras, we engineered human skin grafts in vivo with mutant active FGFR3 or shRNA FGFR3 knockdown. We show that FGFR3 active mutants drive mild hyperproliferation, but are insufficient to support benign or malignant tumorigenesis, either alone, or in combination with G1–S checkpoint release. This suggests that additional cell-intrinsic or stromal cues are required for formation of benign SKs with FGFR3 mutations. Further, FGFR3 activation does not alter the growth kinetics or differentiation status of engineered human epidermal SCCs driven by Ras, and FGFR3 protein itself is dispensable for Ras-driven SCC. To extend these findings to patients, we examined a uniquely informative human tumor in which SCC developed in continuity with a SK, raising the hypothesis that one of the tumors evolved from the other. However, mutational analysis from each tumor indicates that the overlapping SK and SCC evolved independently and supports our conclusion that FGFR3 activation is insufficient to drive SCC. PMID:24626198

  4. Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies

    PubMed Central

    Peng, Sheng-Bin; Zhang, Xiaoyi; Paul, Donald; Kays, Lisa M.; Ye, Ming; Vaillancourt, Peter; Dowless, Michele; Stancato, Louis F.; Stewart, Julie; Uhlik, Mark T.; Long, Haiyan; Chu, Shaoyou; Obungu, Victor H.

    2016-01-01

    SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin’s lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies. PMID:26954567

  5. Saponin 6 derived from Anemone taipaiensis induces U87 human malignant glioblastoma cell apoptosis via regulation of Fas and Bcl‑2 family proteins.

    PubMed

    Ji, Chen-Chen; Tang, Hai-Feng; Hu, Yi-Yang; Zhang, Yun; Zheng, Min-Hua; Qin, Hong-Yan; Li, San-Zhong; Wang, Xiao-Yang; Fei, Zhou; Cheng, Guang

    2016-07-01

    Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor, and is associated with a poor prognosis. Saponin 6, derived from Anemone taipaiensis, exerts potent cytotoxic effects against the human hepatocellular carcinoma HepG2 cell line and the human promyelocytic leukemia HL‑60 cell line; however, the effects of saponin 6 on glioblastoma remain unknown. The present study aimed to evaluate the effects of saponin 6 on human U87 malignant glioblastoma (U87 MG) cells. The current study revealed that saponin 6 induced U87 MG cell death in a dose‑ and time‑dependent manner, with a half maximal inhibitory concentration (IC50) value of 2.83 µM after treatment for 48 h. However, saponin 6 was needed to be used at a lesser potency in HT‑22 cells, with an IC50 value of 6.24 µM. Cell apoptosis was assessed by flow cytometry using Annexin V‑fluorescein isothiocyanate/propidium iodide double staining. DNA fragmentation and alterations in nuclear morphology were examined by terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling and transmission electron microscopy, respectively. The present study demonstrated that treatment with saponin 6 induced cell apoptosis in U87 MG cells, and resulted in DNA fragmentation and nuclear morphological alterations typical of apoptosis. In addition, flow cytometric analysis revealed that saponin 6 was able to induce cell cycle arrest. The present study also demonstrated that saponin 6‑induced apoptosis of U87 MG cells was attributed to increases in the protein expression levels of Fas, Fas ligand, and cleaved caspase‑3, ‑8 and ‑9, and decreases in the levels of B‑cell lymphoma 2. The current study indicated that saponin 6 may exhibit selective cytotoxicity toward U87 MG cells by activating apoptosis via the extrinsic and intrinsic pathways. Therefore, saponin 6 derived from A. taipaiensis may possess therapeutic potential for the treatment of GBM. PMID

  6. Shortening velocity of skeletal muscle from humans with malignant hyperthermia susceptibility: effects of halothane.

    PubMed

    Etchrivi, T S; Haudecoeur, G; Stix, I; Reyford, H; Tavernier, B; Krivosic-Horber, R M; Adnet, P J

    2000-01-24

    The aim of this investigation was to assess the effect of halothane on the velocity of shortening and lengthening of muscle from normal subjects and from patients with malignant hyperthermia susceptibility. Strips were mounted horizontally at optimal length in normal Krebs-Ringer's solution and mechanical parameters were obtained before and after exposure to 3 vol.% halothane. The maximun shortening velocity at zero load (V(max)) was determined by using Hill's characteristic equation. The contraction and relaxation indices were measured under isotonic and isometric conditions: maximum shortening and lengthening velocities (maxV(c) and maxV(r), respectively); isometric peak twitch tension; peak of the positive (+dP/dt(max)) and negative (-dP/dt(max)) twitch tension derivative; ratio R1=maxV(c)/maxV(r) and ratio R2=(+dP/dt(max))/(-dP/dt(max)). In normal muscle, halothane markedly increased V(max), maxV(c) and peak twitch tension by 30+/-10%, 30+/-5% and 40+/-15%, respectively. The maxV(r) values increased concomitantly with the maxV(c) values, such that no change in the ratio R1 was observed. Both +dP/dt(max) and -dP/dt(max) increased such that the ratio R2 did not vary. In malignant hyperthermia susceptibility muscle, halothane induced a significant decrease in V(max) (-30+/-10%) and maxV(r) (-45+/-15%) without changing maxV(c). The decrease in maxV(r) was greater than that of maxV(c), such that the ratio R1 increased significantly. Peak twitch tension and +dP/dt(max) remained unchanged whereas -dP/dt(max) decreased significantly; the ratio R2 increased by 40+/-10%. These results suggest that halothane alters the contractile properties of malignant hyperthermia susceptibility muscle. PMID:10657553

  7. GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast.

    PubMed

    Scaling, Allison L; Prossnitz, Eric R; Hathaway, Helen J

    2014-06-01

    17β-Estradiol (estrogen), through receptor binding and activation, is required for mammary gland development. Estrogen stimulates epithelial proliferation in the mammary gland, promoting ductal elongation and morphogenesis. In addition to a developmental role, estrogen promotes proliferation in tumorigenic settings, particularly breast cancer. The proliferative effects of estrogen in the normal breast and breast tumors are attributed to estrogen receptor α. Although in vitro studies have demonstrated that the G protein-coupled estrogen receptor (GPER, previously called GPR30) can modulate proliferation in breast cancer cells both positively and negatively depending on cellular context, its role in proliferation in the intact normal or malignant breast remains unclear. Estrogen-induced GPER-dependent proliferation was assessed in the immortalized nontumorigenic human breast epithelial cell line, MCF10A, and an ex vivo organ culture model employing human breast tissue from reduction mammoplasty or tumor resections. Stimulation by estrogen and the GPER-selective agonist G-1 increased the mitotic index in MCF10A cells and proportion of cells in the cell cycle in human breast and breast cancer explants, suggesting increased proliferation. Inhibition of candidate signaling pathways that may link GPER activation to proliferation revealed a dependence on Src, epidermal growth factor receptor transactivation by heparin-bound EGF and subsequent ERK phosphorylation. Proliferation was not dependent on matrix metalloproteinase cleavage of membrane-bound pro-HB-EGF. The contribution of GPER to estrogen-induced proliferation in MCF10A cells and breast tissue was confirmed by the ability of GPER-selective antagonist G36 to abrogate estrogen- and G-1-induced proliferation, and the ability of siRNA knockdown of GPER to reduce estrogen- and G-1-induced proliferation in MCF10A cells. This is the first study to demonstrate GPER-dependent proliferation in primary normal and malignant

  8. GPER mediates estrogen-induced signaling and proliferations in human breast epithelial cells, and normal and malignant breast

    PubMed Central

    Scaling, Allison L.

    2014-01-01

    17β-estradiol (estrogen), through receptor binding and activation, is required for mammary gland development. Estrogen stimulates epithelial proliferation in the mammary gland, promoting ductal elongation and morphogenesis. In addition to a developmental role, estrogen promotes proliferation in tumorigenic settings, particularly breast cancer. The proliferative effects of estrogen in the normal breast and breast tumors are attributed to estrogen receptor α. Although in vitro studies have demonstrated that the G protein-coupled estrogen receptor (GPER, previously called GPR30) can modulate proliferation in breast cancer cells both positively and negatively depending on cellular context, its role in proliferation in the intact normal or malignant breast remains unclear. Estrogen-induced GPER-dependent proliferation was assessed in the immortalized non-tumorigenic human breast epithelial cell line, MCF10A, and an ex vivo organ culture model employing human breast tissue from reduction mammoplasty or tumor resections. Stimulation by estrogen and the GPER-selective agonist G-1 increased the mitotic index in MCF10A cells and proportion of cells in the cell cycle in human breast and breast cancer explants, suggesting increased proliferation. Inhibition of candidate signaling pathways that may link GPER activation to proliferation revealed a dependence on Src, epidermal growth factor receptor transactivation by heparin-bound EGF and subsequent ERK phosphorylation. Proliferation was not dependent on matrix metalloproteinase cleavage of membrane bound pro-HB-EGF. The contribution of GPER to estrogen-induced proliferation in MCF10A cells and breast tissue was confirmed by the ability of GPER-selective antagonist G36 to abrogate estrogen- and G-1-induced proliferation, and the ability of siRNA knockdown of GPER to reduce estrogen- and G-1-induced proliferation in MCF10A cells. This is the first study to demonstrate GPER-dependent proliferation in primary normal and malignant

  9. EGFR and microvessel density in canine malignant mammary tumours.

    PubMed

    Carvalho, Maria Isabel; Guimarães, Maria João; Pires, Isabel; Prada, Justina; Silva-Carvalho, Ricardo; Lopes, Carlos; Queiroga, Felisbina L

    2013-12-01

    The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor which has been shown to have an important role in human breast cancer. Its role appears to be associated with increased angiogenesis and metastasis. In order to clarify its role in canine mammary tumours (CMT), 61 malignant neoplasms were studied by using immunohistochemistry, comparing expression of EGFR, microvessel density (MVD) by CD31 immunolabelling and characteristics of tumour aggressiveness. High EGFR immunoexpression was statistically significantly associated with tumour size, tumour necrosis, mitotic grade, histological grade of malignancy and clinical stage. High CD31 immunoreactivity was statistically significantly associated with tubule formation, histological grade of malignancy and clinical stage. A positive correlation between EGFR and CD31 immunoexpression (r = 0.843; P < 0.001) was also observed. Results suggest that an over-expression of EGFR may contribute to increased angiogenesis and aggression in malignant CMT, presenting the possibility of using EGFR inhibitors in the context of metastatic disease treatment. PMID:24091029

  10. Capsaicin-Induced Death of Human Haematological Malignant Cell Lines Is Independent of TRPV1 Activation.

    PubMed

    Omari, Sofia A; Adams, Murray J; Kunde, Dale A; Geraghty, Dominic P

    2016-01-01

    The effect of the plant-derived vanilloid, capsaicin (CAP), on the metabolic activity of THP-1, U266B1 and U937 hematological malignancy cells was determined. CAP reduced metabolic activity in a concentration-dependent manner in the three cell lines. A biphasic effect was observed on THP-1 cells (EC50: IC50 (95% CI) 32.9 (19.9-54.3)/219 (144-246) µmol/l). U266B1 cells were more resistant to CAP than THP-1 and U937. Metabolic activity was significantly inhibited by CAP in U937 compared to U266B1 cells (IC50: 197 versus 431 µmol/l, respectively, p < 0.008). Transient receptor potential vanilloid-1 (TRPV1) and CB1 antagonists (SB452533 and AM251, respectively) suppressed the CAP-induced increase in THP-1 cell metabolic activity (p < 0.001). AM251 and SB452533 appeared to act as partial agonists and displayed a synergistic effect with CAP in U937 cells. CAP inhibits the metabolic activity of malignant hematological cells through non-TRPV1-dependent mechanisms. PMID:27160991

  11. NANOG promoter methylation and expression correlation during normal and malignant human germ cell development

    PubMed Central

    Nettersheim, Daniel; Bierman, Katharina; Gillis, Ad JM; Steger, Klaus; Looijenga, Leendert HJ

    2011-01-01

    Testicular germ cell tumors are the most frequent malignant tumors in young Caucasian males, with increasing incidence. The actual model of tumorigenesis is based on the theory that a block in maturation of fetal germ cells lead to formation of the intratubular germ cell neoplasia unclassified. Early fetal germ cells and undifferentiated germ cell tumors express pluripotency markers such as the transcription factor NANOG. It has been demonstrated that epigenetic modifications, such as promoter DNA methylation, are able to silence gene expression in normal and cancer cells. Here we show that OCT3/4-SOX2 mediated expression of NANOG can be silenced by methylation of promoter CpG-sites. We found that global methylation of DNA decreased from fetal spermatogonia to mature sperm. In contrast, CpGs in the NANOG promoter were found hypomethylated in spermatogonia and hypermethylated in sperm. This selective repression might reflect the cells need to suppress pluripotency in order to prevent malignant transformation. Finally, methylation of CpGs in the NANOG promoter in germ cell tumors and derived cell lines correlated to differentiation state. PMID:20930529

  12. Repair of chromosome damage induced by X-irradiation during G2 phase in a line of normal human fibroblasts and its malignant derivative

    SciTech Connect

    Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

    1982-08-01

    A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. The gaps may represent single-strand breaks. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or beta-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

  13. A Dimeric Mutant of Human Pancreatic Ribonuclease with Selective Cytotoxicity toward Malignant Cells

    NASA Astrophysics Data System (ADS)

    Piccoli, Renata; di Gaetano, Sonia; de Lorenzo, Claudia; Grauso, Michela; Monaco, Carmen; Spalletti-Cernia, Daniela; Laccetti, Paolo; Cinatl, Jaroslav; Matousek, Josef; D'Alessio, Giuseppe

    1999-07-01

    Monomeric human pancreatic RNase, devoid of any biological activity other than its RNA degrading ability, was engineered into a dimeric protein with a cytotoxic action on mouse and human tumor cells, but lacking any appreciable toxicity on mouse and human normal cells. This dimeric variant of human pancreas RNase selectively sensitizes to apoptotic death cells derived from a human thyroid tumor. Because of its selectivity for tumor cells, and because of its human origin, this protein represents a potentially very attractive, novel tool for anticancer therapy.

  14. Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy.

    PubMed

    Lambert, D W; Wood, I S; Ellis, A; Shirazi-Beechey, S P

    2002-04-22

    Healthy colonocytes derive 60-70% of their energy supply from short-chain fatty acids, particularly butyrate. Butyrate has profound effects on differentiation, proliferation and apoptosis of colonic epithelial cells by regulating expression of various genes associated with these processes. We have previously shown that butyrate is transported across the luminal membrane of the colonic epithelium via a monocarboxylate transporter, MCT1. In this paper, using immunohistochemistry and in situ hybridisation histochemistry, we have determined the profile of MCT1 protein and mRNA expression along the crypt to surface axis of healthy human colonic tissue. There is a gradient of MCT1 protein expression in the apical membrane of the cells along the crypt-surface axis rising to a peak in the surface epithelial cells. MCT1 mRNA is expressed along the crypt-surface axis and is most abundant in cells lining the crypt. Analysis of healthy colonic tissues and carcinomas using immunohistochemistry and Western blotting revealed a significant decline in the expression of MCT1 protein during transition from normality to malignancy. This was reflected in a corresponding reduction in MCT1 mRNA expression, as measured by Northern analysis. Carcinoma samples displaying reduced levels of MCT1 were found to express the high affinity glucose transporter, GLUT1, suggesting that there is a switch from butyrate to glucose as an energy source in colonic epithelia during transition to malignancy. The expression levels of MCT1 in association with GLUT1 could potentially be used as determinants of the malignant state of colonic tissue. PMID:11953883

  15. Targeting ID2 expression triggers a more differentiated phenotype and reduces aggressiveness in human salivary gland cancer cells.

    PubMed

    Sumida, Tomoki; Ishikawa, Akiko; Nakano, Hiroyuki; Yamada, Tomohiro; Mori, Yoshihide; Desprez, Pierre-Yves

    2016-08-01

    Inhibitors of DNA-binding (ID) proteins are negative regulators of basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. We previously determined that ID1 was highly expressed in aggressive salivary gland cancer (SGC) cells in culture. Here, we show that ID2 is also expressed in aggressive SGC cells. ID2 knockdown triggers important changes in cell behavior, that is, it significantly reduces the expression of N-cadherin, vimentin and Snail, induces E-cadherin expression and leads to a more differentiated phenotype exemplified by changes in cell shape. Moreover, ID2 knockdown almost completely suppresses invasion and the expression of matrix metalloproteinase 9. In conclusion, ID2 expression maintains an aggressive phenotype in SGC cells, and ID2 repression triggers a reduction in cell aggressiveness. ID2 therefore represents a potential therapeutic target during SGC progression. ID proteins are negative regulators of basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. ID2 knockdown triggers important changes in cell behavior, that is, it significantly reduces the expression of N-cadherin, vimentin and Snail, induces E-cadherin expression and leads to a more differentiated phenotype exemplified by changes in cell shape. ID2 therefore represents a potential therapeutic target during SGC progression. PMID:27364596

  16. Construction of Ang2-siRNA chitosan magnetic nanoparticles and the effect on Ang2 gene expression in human malignant melanoma cells

    PubMed Central

    LIU, ZHAO-LIANG; YOU, CAI-LIAN; WANG, BIAO; LIN, JIAN-HONG; HU, XUE-FENG; SHAN, XIU-YING; WANG, MEI-SHUI; ZHENG, HOU-BING; ZHANG, YAN-DING

    2016-01-01

    The aim of the present study was to construct angiopoietin-2 (Ang2)-small interfering (si)RNA chitosan magnetic nanoparticles and to observe the interference effects of the nanoparticles on the expression of the Ang2 gene in human malignant melanoma cells. Ang2-siRNA chitosan magnetic nanoparticles were constructed and transfected into human malignant melanoma cells in vitro. Red fluorescent protein expression was observed, and the transfection efficiency was analyzed. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess the inhibition efficiency of Ang2 gene expression. Ang2-siRNA chitosan magnetic nanoparticles were successfully constructed, and at a mass ratio of plasmid to magnetic chitosan nanoparticles of 1:100, the transfection efficiency into human malignant melanoma cells was the highest of the ratios assessed, reaching 61.17%. RT-qPCR analysis showed that the magnetic chitosan nanoparticles effectively inhibited Ang2 gene expression in cells, and the inhibition efficiency reached 59.56% (P<0.05). Ang2-siRNA chitosan magnetic nanoparticles were successfully constructed. The in vitro studies showed that the nanoparticles inhibited Ang2 gene expression in human malignant melanoma tumor cells, which laid the foundation and provided experimental evidence for additional future in vivo studies of intervention targeting malignant melanoma tumor growth in nude mice. PMID:27313729

  17. A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

    PubMed Central

    Zhang, Yonghong; Sun, Xinlin; Huang, Min; Ke, Yiquan; Wang, Jihui; Liu, Xiao

    2015-01-01

    Background In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs) exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas. Materials and methods In the present study, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF165-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo. Results In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs (P<0.01). In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model. Conclusion The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic. PMID:26089644

  18. Inhibition of transient receptor potential canonical channels impairs cytokinesis in human malignant gliomas

    PubMed Central

    Bomben, V. C.; Sontheimer, H. W.

    2009-01-01

    Objectives Glial-derived primary brain tumours, gliomas, are among the fastest growing malignancies and present a huge clinical challenge. Research suggests an important, yet poorly understood, role of ion channels in growth control of normal and malignant cells. In this study, we sought to functionally characterize Transient Receptor Potential Canoncial (TRPC) channels in glioma cell proliferation. TRPC channels form non-selective cation channels that have been suggested to represent a Ca2+ influx pathway impacting cellular growth. Materials and Methods Employing a combination of molecular, biochemical and biophysical techniques, we characterized TRPC channels in glioma cells. Results We showed consistent expression of four channel family members (TRPC-1, -3, -5, -6) in glioma cell lines and acute patient-derived tissues. These channels gave rise to small, non-voltage-dependent cation currents that were blocked by the TRPC inhibitors GdCl3, 2-APB, or SKF96365. Importantly, TRPC channels contributed to the resting conductance of glioma cells and their acute pharmacological inhibition caused an ~10 mV hyperpolarization of the cells’ resting potential. Additionally, chronic application of the TRPC inhibitor SKF96365 caused near complete growth arrest. A detailed analysis, by fluorescence-activated cell sorting and time-lapse microscopy, showed that growth inhibition occurred at the G2 + M phase of the cell cycle with cytokinesis defects. Cells underwent incomplete cell divisions and became multinucleate, enlarged cells. Conclusions Nuclear atypia and enlarged cells are histopathological hallmarks for glioblastoma multiforme, the highest grade glioma, suggesting that a defect in TRPC channel function may contribute to cellular abnormalities in these tumours. PMID:18211288

  19. Photodynamic therapy of human malignant tumors: a comparative study between photohem and tetrasulfonated aluminum phthalocyanine

    NASA Astrophysics Data System (ADS)

    Stranadko, Eugeny P.; Skobelkin, Oleg K.; Litvin, Grigory D.; Astrakhankina, Tamara A.

    1996-01-01

    The analysis of the results of photodynamic therapy (PDT) for treating malignant neoplasms of the skin, mammary glands, tongue, oral mucous, lower lip, larynx, lungs, urinary bladder, rectum and other locations has been made. During 1992-1995 543 tumoral foci in 146 patients have been treated with PDT. All patients were previously treated with conventional techniques without effect or they were not treated due to contraindications either because of severe accompanying diseases or because of old age. A part of the patients had PDT because of recurrences or intradermal metastases in 1-2 years after surgical, radial or combined treatment. Two home-made preparations were used as photosensitizers: Photohem (hematoporphyrine derivative) and Photosense (aluminum sulfonated phthalocyanine). Light sources were: the argon pumped dye laser ('Innova-200,' 'Coherent') and home-made laser devices: copper-vapor laser-pumped dye laser ('Yakhroma-2,' Frjazino), gas-discharge unit 'Xenon' (wavelength 630 nm), gold-vapor laser (wavelength 627.8 nm) for Photohem; while for Photosense sessions we used solid-state laser on ittrium aluminate 'Poljus-1' (wavelength 670 mn). Up to now we have follow-up control data within 2 months and 3 years. Positive effect of PDT was seen in 92.4% of patients including complete regression of tumors in 62.3% and partial -- in 30.1%. Currently, this new perspective technique of treating malignant neoplasms is successfully being used in Russia; new photosensitizers and light sources for PDT and fluorescent tumour diagnostics are being developed as well.

  20. Activation of endogenous human stem cell-associated retroviruses (SCARs) and therapy-resistant phenotypes of malignant tumors.

    PubMed

    Glinsky, Gennadi V

    2016-07-01

    Recent reports revealed consistent activation of specific endogenous retroviral elements in human preimplantation embryos and embryonic stem cells. Activity of stem cell associated retroviruses (SCARs) has been implicated in seeding thousands of human-specific regulatory sequences in the hESC genome. Activation of specific SCARs has been demonstrated in patients diagnosed with multiple types of cancer, autoimmune diseases, and neurodegenerative disorders, and appears associated with clinically lethal therapy resistant death-from-cancer phenotypes in a sub-set of cancer patients diagnosed with different types of malignant tumors. A hallmark feature of human-specific SCAR integration sites is deletions of ancestral DNA. Analysis of human-specific genetic loci of SCARs' stemness networks in tumor samples of TCGA cohorts representing 29 cancer types suggests that this approach may facilitate identification of pan-cancer genomic signatures of clinically-lethal disease defined by the presence of somatic non-silent mutations, gene-level copy number changes, and transcripts and proteins' expression of SCAR-regulated host genes. Present analyses indicate that multiple lines of strong circumstantial evidence support the hypothesis that activation of SCARs' networks may play an important role in cancer progression and metastasis, perhaps contributing to the emergence of clinically-lethal therapy-resistant death-from-cancer phenotypes. PMID:27084523

  1. Genetics of Aggression in Voles

    PubMed Central

    Gobrogge, Kyle L.; Wang, Zuoxin

    2016-01-01

    Prairie voles (Microtus ochrogaster) are socially monogamous rodents that form pair bonds—a behavior composed of several social interactions including attachment with a familiar mate and aggression toward conspecific strangers. Therefore, this species has provided an excellent opportunity for the study of pair bonding behavior and its underlying neural mechanisms. In this chapter, we discuss the utility of this unique animal model in the study of aggression and review recent findings illustrating the neurochemical mechanisms underlying pair bonding-induced aggression. Implications of this research for our understanding of the neurobiology of human violence are also discussed. PMID:22078479

  2. Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression.

    PubMed

    Mittelbronn, Michel; Platten, Michael; Zeiner, Pia; Dombrowski, Yvonne; Frank, Brigitte; Zachskorn, Cornelia; Harter, Patrick N; Weller, Michael; Wischhusen, Jörg

    2011-09-01

    Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced in neoplastic astrocytes in WHO grade II glioma and increased significantly in higher tumour grades (III-IV). MIF expression was further assessed in 12 glioma cell lines in vitro. Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. This translated into high protein levels as assessed by immunoblotting of total cell lysates and by ELISA-based measurement of secreted MIF. Wild-type p53-retaining glioma cell lines expressed higher levels of MIF, which may be connected with the previously described role of MIF as a negative regulator of wild-type p53 signalling in tumour cells. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. Furthermore, supernatant from mock-transfected cells, but not from MIF knockdown cells, induced downregulation of the activating immune receptor NKG2D on NK and CD8+ T cells. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance. Considering its further cell-intrinsic and extrinsic tumour-promoting effects and the availability of small molecule inhibitors, MIF seems to be a promising candidate for future glioma therapy. PMID:21773885

  3. Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D2 Against Human Malignant Melanoma Cell Lines

    PubMed Central

    Piotrowska, Anna; Wierzbicka, Justyna; Nadkarni, Sharmin; Brown, Geoffrey; Kutner, Andrzej; Żmijewski, Michał A.

    2016-01-01

    Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM) analogs of 1,25-dihydroxyvitamin D2 (1,25(OH)2D2) induced differentiation of the vitamin D receptor (VDR) positive A375 and VDR negative SK-MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH)2D2 required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH)2D3. To evaluate the impact of the modification in the side chain (additional 22-hydroxyl) and in the A-ring (5,6-trans modification), the regular side-chain of vitamin D2 or D3 was retained in the structure of our analogs. As expected, 5,6-trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM). Very unexpectedly, the additional 22-hydroxyl in the side-chain reduced significantly the anti-proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was observed to sensitized cells to the effect of vitamin D analogs. PMID:26760999

  4. Involvement of autophagy in recombinant human arginase-induced cell apoptosis and growth inhibition of malignant melanoma cells.

    PubMed

    Wang, Ziyu; Shi, Xunlong; Li, Yubin; Zeng, Xian; Fan, Jiajun; Sun, Yun; Xian, Zongshu; Zhang, Guoping; Wang, Shaofei; Hu, Haifeng; Ju, Dianwen

    2014-03-01

    Recombinant human arginase (rhArg) has been developed for arginine derivation therapy of cancer and is currently in clinical trials for a variety of malignant solid tumors. In this study, we reported for the first time that rhArg could induce obvious autophagy in human melanoma cells; inhibition of autophagy by chloroquine (CQ) significantly increased rhArg-induced cell apoptosis and growth inhibition of A375 cells. A significant increase in mitochondrial membrane potential loss and elevated intracellular reactive oxygen species (ROS) levels were detected in A375 cells after rhArg treatment when compared with control. Membrane transition inhibitor cyclosporine A blocked autophagy and accelerated cell death induced by rhArg, indicating that rhArg induced autophagy via mitochondria pathway. Furthermore, antioxidant N-acetyl-L-cysteine suppressed rhArg-induced autophagy and rescued cells from cell growth inhibition, suggesting that ROS played an important role in rhArg-induced A375 cell growth inhibition and autophagy. Akt/mTOR signaling pathway was involved in autophagy induced by rhArg in a time-dependent manner. Moreover, rhArg could induce ERK1/2 activation in a dose- and time-dependent manner and rhArg-induced autophagy was attenuated when p-ERK1/2 was inhibited by MEK 1/2 inhibitor, U0126. Taken together, this study provides new insight into the molecular mechanism of autophagy involved in rhArg-induced cell apoptosis and growth inhibition, which facilitates the development of rhArg in combination with CQ as a potential therapy for malignant melanoma. PMID:23917632

  5. Down-regulation of malignant potential by alpha linolenic acid in human and mouse colon cancer cells.

    PubMed

    Chamberland, John P; Moon, Hyun-Seuk

    2015-03-01

    Omega-3 fatty acids (also called ω-3 fatty acis or n-3 fatty acid) are polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Numerous test tube and animal studies have shown that omega-3 fatty acids may prevent or inhibit the growth of cancers, suggesting that omega-3 fatty acids are important in cancer physiology. Alpha-linolenic acid (ALA) is one of an essential omega-3 fatty acid and organic compound found in seeds (chia and flaxseed), nuts (notably walnuts), and many common vegetable oils. ALA has also been shown to down-regulate cell proliferation of prostate, breast, and bladder cancer cells. However, direct evidence that ALA suppresses to the development of colon cancer has not been studied. Also, no previous studies have evaluated whether ALA may regulate malignant potential (adhesion, invasion and colony formation) in colon cancer cells. In order to address the questions above, we conducted in vitro studies and evaluated whether ALA may down-regulate malignant potential in human (HT29 and HCT116) and mouse (MCA38) colon cancer cell lines. We observed that treatment with 1-5 mM of ALA inhibits cell proliferation, adhesion and invasion in both human and mouse colon cancer cell lines. Interestingly, we observed that ALA did not decrease total colony numbers when compared to control. By contrast, we found that size of colony was significantly changed by ALA treatment when compared to control in all colon cancer cell lines. We suggest that our data enhance our current knowledge of ALA's mechanism and provide crucial information to further the development of new therapies for the management or chemoprevention of colon cancer. PMID:25336096

  6. siRNA Knockdown of Ribosomal Protein Gene RPL19 Abrogates the Aggressive Phenotype of Human Prostate Cancer

    PubMed Central

    Bee, Alix; Brewer, Daniel; Beesley, Carol; Dodson, Andrew; Forootan, Shiva; Dickinson, Timothy; Gerard, Patricia; Lane, Brian; Yao, Sheng; Cooper, Colin S.; Djamgoz, Mustafa B. A.; Gosden, Christine M.; Ke, Youqiang; Foster, Christopher S.

    2011-01-01

    We provide novel functional data that posttranscriptional silencing of gene RPL19 using RNAi not only abrogates the malignant phenotype of PC-3M prostate cancer cells but is selective with respect to transcription and translation of other genes. Reducing RPL19 transcription modulates a subset of genes, evidenced by gene expression array analysis and Western blotting, but does not compromise cell proliferation or apoptosis in-vitro. However, growth of xenografted tumors containing the knocked-down RPL19 in-vivo is significantly reduced. Analysis of the modulated genes reveals induction of the non-malignant phenotype principally to involve perturbation of networks of transcription factors and cellular adhesion genes. The data provide evidence that extra-ribosomal regulatory functions of RPL19, beyond protein synthesis, are critical regulators of cellular phenotype. Targeting key members of affected networks identified by gene expression analysis raises the possibility of therapeutically stabilizing a benign phenotype generated by modulating the expression of an individual gene and thereafter constraining a malignant phenotype while leaving non-malignant tissues unaffected. PMID:21799931

  7. The dopaminergic system and aggression in laying hens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  8. An alpha-fetoprotein-producing human gallbladder carcinoma cell line (KMG-C) shows more aggressive biologic behavior than an alpha-fetoprotein-non-producing cell line.

    PubMed

    Maruiwa, M; Yano, H; Fukuda, K; Ogasawara, S; Hisaka, T; Yamaguchi, R; Kojiro, M

    1996-06-01

    We have established a new human alphafetoprotein (AFP)-producing gallbladder carcinoma (GBC) cell line, termed KMG-C, from a 67-year-old Japanese male. KMG-C and its reconstituted tumors in nude mice showed the morphological features of an adenocarcinoma. Functionally, KMG-C secreted AFP, carcinoembryonic antigen, and carbohydrate antigen 19-9, as well as 7 serum proteins, including albumin and C-reactive protein. KMG-C showed more malignant biological behavior than an AFP-nonproducing GBC cell line, KMG-A, established originally from the tumor of the same patient; KMG-C had a shorter doubling time, higher tumorigenicity, and an aneuploid DNA index. Our results suggest that AFP-producing GBC cells may have more malignant biological characteristics than AFP-non-producing GBC cells in GBCs having both of these components. PMID:21544480

  9. Microwave-induced local hyperthermia in combination with radiotherapy of human malignant tumors

    SciTech Connect

    U, R.; Noell, K.T.; Woodward, K.T.; Worde, B.T.; Fishburn, R.I.; Miller, L.S.

    1980-02-15

    Since 1976, two groups of patients have been treated with local microwave hyperthermia immediately following ionizing radiation. Group A patients had measurable multiple lesions assigned radiotherapy only, microwave hyperthermia only, or combined treatment. Ionizing radiation in 200 to 600 rad fractions was used 2 to 5 times per week to a total of 1800 to 4200 rad in 5 to 14 fractions. Group B patients had combination treatment only, with radiation fractions of 200 to 600 rad 2 to 5 times per week to a total of 200 to 4800 rad total in 6 to 20 fractions. Both groups received hyperthermia (42 to 44 C) 2 to 3 times per week, maximum ten sessions in four weeks. The 19 patients treated have had squamous cell carcinoma, adenocarcinoma, malignant melanoma, plasmacytoma, epithelioid sarcoma, and undifferentiated carcinoma. After more than 150 hyperthermia sessions, we find: (1) local hyperthermia with microwave alone or in combination with ionizing radiation can be used with excellent normal tissue tolerance provided local tissue temperatures are carefully monitored and controlled; (2) a higher level of heat induction in tumor tissue as compared to surrounding normal tissues; and (3) repeated hyperthermia at 42 to 43.5 C for 45 minutes per session immediately following photon irradiation yields a favorable therapeutic result, occasionally dramatic. Local microwave hyperthermia in combination withradiotherapy offers the possibility of substantial impact on clinical cancer therapy, whether of curative or palliative intent.

  10. Genistein enhances the cisplatin-induced inhibition of cell growth and apoptosis in human malignant melanoma cells.

    PubMed

    Tamura, Shingo; Bito, Toshinori; Ichihashi, Masamitsu; Ueda, Masato

    2003-10-01

    Genistein, a naturally occurring isoflavone found chiefly in soybeans, has been reported to be a potent antitumor agent. Genistein is presumed to exert multiple effects related to the inhibition of cancer growth. Metastatic melanoma is a chemotherapy-refractory neoplasm. The present study was designed to explore the possible activity of genistein to inhibit the aberrant proliferation and to induce apoptosis of human malignant melanoma cells in cooperation with cisplatin treatment. Five human melanoma cell lines were utilized for these experiments. Genistein at physiologic concentrations (20 microM) did not induce apoptosis by itself but did enhance cisplatin-induced apoptosis in all five human melanoma cell lines tested. The enhanced susceptibility among the cell lines was diverse. Changes in the expression of two anti-apoptotic proteins, bcl-2 and bcl-xL, and one pro-apoptotic protein, apoptotic protease activating factor-1 (Apaf-1), were examined. Genistein alone or cisplatin alone generally did not alter bcl-2 expression or bcl-xL expression, but slightly increased Apaf-1 in some cell lines. The combined treatment with genistein and cisplatin significantly reduced bcl-2 and bcl-xL protein and increased Apaf-1 protein expression. These data suggest that genistein therapy may enhance the chemosensitivity of melanoma patients. PMID:12950722

  11. Primary malignant melanoma

    PubMed Central

    Mısır, A. Ferhat; Durmuşlar, Mustafa C.; Zerener, Tamer; Gün, Banu D.

    2016-01-01

    Malignant melanomas (MM) of the oral cavity are extremely rare, accounting for 0.2% to 8.0% of all malignant melanomas. Malignant melanomas is more frequently seen at the level of the hard palate and gingiva. Early diagnosis and treatment are important for reducing morbidity. Malignant melanoma cells stain positively with antibodies to human melanoma black 45, S-100 protein, and vimentin; therefore, immunohistochemistry can play an important role in evaluating the depth of invasion and the location of metastases. A 76-year-old man developed an oral malignant melanoma, which was originally diagnosed as a bluish reactive denture hyperplasia caused by an ill-fitting lower denture. The tumor was removed surgically, and histopathological examination revealed a nodular-type MM. There was no evidence of recurrence over a 4-year follow-up period. PMID:27052289

  12. Zingipain, A cysteine protease from Zingiber ottensii Valeton rhizomes with antiproliferative activities against fungi and human malignant cell lines.

    PubMed

    Karnchanatat, Aphichart; Tiengburanatam, Nathachai; Boonmee, Apaporn; Puthong, Songchan; Sangvanich, Polkit

    2011-01-01

    The objective of this study was to investigate the activity of a protein identified as cysteine protease, purified from Zingiber ottensii Valeton rhizomes, in terms of antiproliferation against fungi, bacteria, and human malignant cell lines. By means of buffer extraction followed by (NH(4))(2)SO(4) precipitation and ion-exchange chromatography, the obtained dominant protein (designated F50) was submitted to non-denaturing and reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), where a single band and three bands were revealed from eletrophoretic patterns, respectively. It could be concluded at this point that the F50 was potentially a heterotrimer or heterodimer composed of either two small (∼13.8 and ∼15.2 kD) subunits or these two together with a larger (∼32.5 kD) one. In-gel digestion was carried out for the most intense band from reducing SDS-PAGE, and to the resulting material was applied liquid chromatography (LC)-mass spectroscopy (MS)/MS. The main F50 subunit was found to contain fragments with 100% similarity to zingipain-1, a cysteine protease first discovered in Zingiber officinale. The activity corresponding to the identified data, cysteine protease, was then confirmed in the F50 by azocasein assay and a positive result was obtained. The F50 then was further investigated for antiproliferation against three plant pathogenic fungi species by disk diffusion test, four bacterial species by direct exposure in liquid culture and dish diffusion tests, and five human malignant cell lines by tissue culture assay. It was found that a dose of 23.6 µg F50/0.3 cm(2) of paper disk exhibited the best inhibitory effect against Collectotrichum cassiicola, while lesser effects were found in Exserohilum turicicum and Fusarium oxysporum, respectively. No inhibitory effect against bacterial proliferation was detected in all studied bacterial strains. However, relatively strong antiproliferative effects were found against five human

  13. Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate

    PubMed Central

    Chung, Ivy; Montecinos, Viviana P.; Buttyan, Ralph; Johnson, Candace S.; Smith, Gary J.

    2013-01-01

    Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients. PMID:23548616

  14. Cystathionine β-synthase-derived hydrogen sulfide is involved in human malignant hyperthermia.

    PubMed

    Vellecco, Valentina; Mancini, Antonio; Ianaro, Angela; Calderone, Vincenzo; Attanasio, Chiara; Cantalupo, Anna; Andria, Barbara; Savoia, Gennaro; Panza, Elisabetta; Di Martino, Antonietta; Cirino, Giuseppe; Bucci, Mariarosaria

    2016-01-01

    Hydrogen sulfide is an endogenous gasotransmitter and its mechanism of action involves activation of ATP-sensitive K(+) channels and phosphodiesterase inhibition. As both mechanisms are potentially involved in malignant hyperthermia (MH), in the present study we addressed the involvement of the L-cysteine/hydrogen sulfide pathway in MH. Skeletal muscle biopsies obtained from 25 MH-susceptible (MHS) and 56 MH-negative (MHN) individuals have been used to perform the in vitro contracture test (IVCT). Quantitative real-time PCR (qPCR) and Western blotting studies have also been performed. Hydrogen sulfide levels are measured in both tissue samples and plasma. In MHS biopsies an increase in cystathionine β-synthase (CBS) occurs, as both mRNA and protein expression compared with MHN biopsies. Hydrogen sulfide biosynthesis is increased in MHS biopsies (0.128±0.12 compared with 0.943±0.13 nmol/mg of protein per min for MHN and MHS biopsies, respectively; P<0.01). Addition of sodium hydrosulfide (NaHS) to MHS samples evokes a response similar, in the IVCT, to that elicited by either caffeine or halothane. Incubation of MHN biopsies with NaHS, before caffeine or halothane challenge, switches an MHN to an MHS response. In conclusion we demonstrate the involvement of the L-cysteine/hydrogen sulfide pathway in MH, giving new insight into MH molecular mechanisms. This finding has potential implications for clinical care and could help to define less invasive diagnostic procedures. PMID:26460077

  15. Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging

    PubMed Central

    Miyata, Akinori; Ishizawa, Takeaki; Kamiya, Mako; Shimizu, Atsushi; Kaneko, Junichi; Ijichi, Hideaki; Shibahara, Junji; Fukayama, Masashi; Midorikawa, Yutaka; Urano, Yasuteru; Kokudo, Norihiro

    2014-01-01

    Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n = 10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed

  16. Expression of vimentin filaments in canine malignant mammary gland tumors: A simulation of clinicopathological features of human breast cancer.

    PubMed

    Rismanchi, Sanaz; Yadegar, Orly; Muhammadnejad, Samad; Amanpour, Saeid; Taghizadeh-Jahed, Masoud; Muhammadnejad, Ahad

    2014-09-01

    Canine malignant mammary gland tumors (CMMGTs) are the most common malignancies observed in females. Several biological similarities have been reported between CMMGTs and human breast cancer (HBC). The present study aimed to assess the correlation of vimentin filaments overexpression, as part of the process of epithelial-mesenchymal transition (EMT) and the clinicopathological characteristics in CMMGTs. The clinicopathological characteristics of 42 CMMGTs were collected. Paraffin-embedded blocks underwent immunohistochemistry staining, which was performed using vimentin (to assess the evolution of the EMT process), Ki-67 (for evaluation of tumor proliferation) and cluster of differentiation 34 (CD34) (for evaluation of angiogenesis) antibodies. The tumor stage, grade, vascular invasion, margin status, rate of expression of the vimentin filaments, microvessel density-CD34 and proliferation rate data were obtained. Finally, the association between the expression of the vimentin filaments and those parameters was resolved statistically. A significant association was shown between the overexpression of the vimentin filaments and tumor size (r=0.71, P=0.03), tumor grade (r=0.80, P=0.021), angiogenesis (r=0.57, P=0.043), proliferation coefficient (r=0.06, P=0.001) and vascular invasion (r=0.76, P=0.043). Vimentin overexpression did not statistically correlate with the tumor stage or the margin status. Similar to the findings of the present study, certain recent studies have indicated that vimentin filament expression in HBC and CMMGTs is associated with the severity of cancer. Thus, spontaneous canine mammary tumor models appear to be an appropriate animal model for breast cancer research, and the results of the present study could aid to reinforce the association. PMID:25054018

  17. Expression of vimentin filaments in canine malignant mammary gland tumors: A simulation of clinicopathological features of human breast cancer

    PubMed Central

    RISMANCHI, SANAZ; YADEGAR, ORLY; MUHAMMADNEJAD, SAMAD; AMANPOUR, SAEID; TAGHIZADEH-JAHED, MASOUD; MUHAMMADNEJAD, AHAD

    2014-01-01

    Canine malignant mammary gland tumors (CMMGTs) are the most common malignancies observed in females. Several biological similarities have been reported between CMMGTs and human breast cancer (HBC). The present study aimed to assess the correlation of vimentin filaments overexpression, as part of the process of epithelial-mesenchymal transition (EMT) and the clinicopathological characteristics in CMMGTs. The clinicopathological characteristics of 42 CMMGTs were collected. Paraffin-embedded blocks underwent immunohistochemistry staining, which was performed using vimentin (to assess the evolution of the EMT process), Ki-67 (for evaluation of tumor proliferation) and cluster of differentiation 34 (CD34) (for evaluation of angiogenesis) antibodies. The tumor stage, grade, vascular invasion, margin status, rate of expression of the vimentin filaments, microvessel density-CD34 and proliferation rate data were obtained. Finally, the association between the expression of the vimentin filaments and those parameters was resolved statistically. A significant association was shown between the overexpression of the vimentin filaments and tumor size (r=0.71, P=0.03), tumor grade (r=0.80, P=0.021), angiogenesis (r=0.57, P=0.043), proliferation coefficient (r=0.06, P=0.001) and vascular invasion (r=0.76, P=0.043). Vimentin overexpression did not statistically correlate with the tumor stage or the margin status. Similar to the findings of the present study, certain recent studies have indicated that vimentin filament expression in HBC and CMMGTs is associated with the severity of cancer. Thus, spontaneous canine mammary tumor models appear to be an appropriate animal model for breast cancer research, and the results of the present study could aid to reinforce the association. PMID:25054018

  18. Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition

    SciTech Connect

    Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

    2007-04-06

    Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.

  19. Loss of estrogen receptor beta expression in malignant human prostate cells in primary cultures and in prostate cancer tissues.

    PubMed

    Pasquali, D; Rossi, V; Esposito, D; Abbondanza, C; Puca, G A; Bellastella, A; Sinisi, A A

    2001-05-01

    The aim of this study was to investigate the expression of estrogen receptor (ER) beta and alpha genes in normal (N) and malignant (C) primary cultures of human prostate epithelial cells (PEC) and fibroblasts (PFC) and in the prostate tissue donors. Both ERbeta and ERalpha messenger ribonucleic acids were found by RT-PCR analysis in six NPECs and normal prostate tissues and in only one of six CPECs and in the respective cancer tissue donor. The other five CPECs and related cancer tissue donors and all normal and cancer PFCs expressed ERalpha messenger ribonucleic acid alone. Immunoblot analysis, using a polyclonal anti-ERbeta (C-terminal) antibody, demonstrated ERbeta protein in all NPEC lysates and in one of the six CPECS: ERalpha protein was expressed in both NPECs and CPECs when a polyclonal antibody directed against the ERalpha N-terminal domain was used. In contrast, ERalpha protein was not detected in two of the six CPEC lysates when ERalpha C-terminal monoclonal antibodies were used. Using a set of primers designed to amplify the region from exons 6-8, RT-PCR analysis demonstrated the absence of the expected transcript in these cells. The present study shows that the ERbeta gene is expressed together with ERalpha in normal prostates and NPECs, whereas it is barely detectable in prostate cancer and CPECS: Moreover, in some CPECs, the ERalpha gene may be transcribed in a changed protein, resulting from the expression of a deletion variant. Together, these data suggest that prostate malignancy is associated with a potential disorder of ER-mediated pathways. PMID:11344205

  20. CONCEPT ANALYSIS: AGGRESSION

    PubMed Central

    Liu, Jianghong

    2006-01-01

    The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

  1. Concept analysis: aggression.

    PubMed

    Liu, Jianghong

    2004-01-01

    The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

  2. Prognostic Role of MicroRNA-200c-141 Cluster in Various Human Solid Malignant Neoplasms

    PubMed Central

    Li, Xiao-yang; Li, Hui; Bu, Jie; Xiong, Liang; Guo, Hong-bin; Liu, Li-hong; Xiao, Tao

    2015-01-01

    The miR-200 family has emerged recently as a noticeable marker for predicting cancer prognosis and tumor progression. We aimed to review the evidence of miR-200c-141 genomic cluster as prognostic biomarkers in cancers. The results suggested that high level of miR-200c had no significant impact on OS (HR = 1.14 [0.77–1.69], P = 0.501) and DFS/PFS (HR = 0.72 [0.45–1.14], P = 0.161). Stratified analyses revealed that high miR-200c expression was significantly related to poor OS in serum/plasma (HR = 2.12 [1.62–2.77], P = 0.000) but not in tissues (HR = 0.89 [0.58–1.37], P = 0.599). High miR-200c expression was significantly associated with favorable DFS/PFS in tissues (HR = 0.56 [0.43–0.73], P = 0.000) but worse DFS/PFS in serum/plasma (HR = 1.90 [1.08–3.36], P = 0.027). For miR-141, we found that high miR-141 expression predicted no significant impact on OS (HR = 1.18 [0.74–1.88], P = 0.482) but poor DFS/PFS (HR = 1.11 [1.04–1.20], P = 0.003). Similarly, subgroup analyses showed that high miR-141 expression predicted poor OS in serum/plasma (HR = 4.34 [2.30–8.21], P = 0.000) but not in tissues (HR = 1.00 [0.92–1.09], P = 0.093). High miR-141 expression was significantly associated with worse DFS/PFS in tissues (HR = 1.12 [1.04–1.20], P = 0.002) but not in serum/plasma (HR = 0.90 [0.44–1.83], P = 0.771). Our findings indicated that, compared to their tissue counterparts, the expression level of miR-200c and miR-141 in peripheral blood may be more effective for monitoring cancer prognosis. High miR-141 expression was better at predicting tumor progression than survival for malignant tumors. PMID:26556949

  3. Esculetin, a Coumarin Derivative, Exhibits Anti-proliferative and Pro-apoptotic Activity in G361 Human Malignant Melanoma

    PubMed Central

    Jeon, Young-Joo; Jang, Jeong-Yun; Shim, Jung-Hyun; Myung, Pyung Keun; Chae, Jung-Il

    2015-01-01

    Background: Although esculetin, a coumarin compound, is known to induce apoptosis in human cancer cells, the effects and molecular mechanisms on the apoptosis in human malignant melanoma (HMM) cells are not well understood yet. In this study, we investigated the anti-proliferative effects of esculetin on the G361 HMM cells. Methods: We analyzed the anti-proliferative effects and molecular mechanisms of esculetin on G361 cells by a 3-(4,5-dimethylthiazol- 2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, 4′,6-diamidino-2-phenylindole staining and Western blotting. Results: Esculetin exhibited significant anti-proliferative effects on the HMM cells in a dose-dependent manner. Interestingly, we found that esculetin induced nuclear shrinkage and fragmentation, typical apoptosis markers, by suppression of Sp1 transcription factor (Sp1). Notably, esculetin modulated Sp1 downstream target genes including p27, p21 and cyclin D1, resulted in activation of apoptosis signaling molecules such as caspase-3 and PARP in G361 HMM cells. Conclusions: Our results clearly demonstrated that esculetin induced apoptosis in the HMM cells by downregulating Sp1 protein levels. Thus, we suggest that esculetin may be a potential anti-proliferative agent that induces apoptotic cell death in G361 HMM cells. PMID:26151043

  4. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.

    PubMed

    Bauer, Alexander T; Suckau, Jan; Frank, Kathrin; Desch, Anna; Goertz, Lukas; Wagner, Andreas H; Hecker, Markus; Goerge, Tobias; Umansky, Ludmila; Beckhove, Philipp; Utikal, Jochen; Gorzelanny, Christian; Diaz-Valdes, Nancy; Umansky, Viktor; Schneider, Stefan W

    2015-05-14

    Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation. PMID:25977583

  5. T24 human bladder carcinoma cells with activated Ha-ras protooncogene: Nontumorigenic cells susceptible to malignant transformation with carcinogen

    SciTech Connect

    Senger, D.R.; Perruzzi, C.A.; Ali, I.U. )

    1988-07-01

    A comparative analysis of T24 human bladder carcinoma cells and N-methyl-N{prime}-nitro-N-nitrosoguanidine (MeNNG)-transformed derivatives (MeNNG-T24) revealed the following: (i) The presence of an activated c-Ha-ras gene (in the absence of the normal allele) is sufficient to confer upon T24 cells a tumor-associated phenotype. (ii) MeNNG-transformed T24 cells not only acquire tumor-associated (in vitro) traits (growth in soft agar and rhodamine retention) but, are highly tumorigenic in nude mice. (iii) It is possible to render T24 cells tumorigenic by chemical transformation; therefore, the reason that T24 cells lack tumorigenicity is not because of possible incompatibilities between these cells and nude mice but, in fact, because T24 cells are not malignant. (iv) The loss of expression of a transformation-related M{sub r} 67,000 phosphoprotein by MeNNG-T24 cells after explanation of these cells from nude mouse tumors to in vitro culture indicates that culture conditions can be responsible for rapid phenotypic conversion of human tumor cell lines.

  6. Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells

    SciTech Connect

    Li Hongzhen; Zhou Jianjun; Miki, Jun; Furusato, Bungo; Gu Yongpeng; Srivastava, Shiv; McLeod, David G.; Vogel, Jonathan C.; Rhim, Johng S.

    2008-01-01

    Understanding prostate stem cells may provide insight into the origin of prostate cancer. Primary cells have been cultured from human prostate tissue but they usually survive only 15-20 population doublings before undergoing senescence. We report here that RC-170N/h/clone 7 cells, a clonal cell line from hTERT-immortalized primary non-malignant tissue-derived human prostate epithelial cell line (RC170N/h), retain multipotent stem cell properties. The RC-170N/h/clone 7 cells expressed a human embryonic stem cell marker, Oct-4, and potential prostate epithelial stem cell markers, CD133, integrin {alpha}2{beta}1{sup hi} and CD44. The RC-170N/h/clone 7 cells proliferated in KGM and Dulbecco's Modified Eagle Medium with 10% fetal bovine serum and 5 {mu}g/ml insulin (DMEM + 10% FBS + Ins.) medium, and differentiated into epithelial stem cells that expressed epithelial cell markers, including CK5/14, CD44, p63 and cytokeratin 18 (CK18); as well as the mesenchymal cell markers, vimentin, desmin; the neuron and neuroendocrine cell marker, chromogranin A. Furthermore the RC170 N/h/clone 7 cells differentiated into multi tissues when transplanted into the sub-renal capsule and subcutaneously of NOD-SCID mice. The results indicate that RC170N/h/clone 7 cells retain the properties of multipotent stem cells and will be useful as a novel cell model for studying the mechanisms of human prostate stem cell differentiation and transformation.

  7. Procaine in Malignant Hyperpyrexia

    PubMed Central

    Moulds, R. F. W.; Denborough, M. A.

    1972-01-01

    The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture. The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine. These experiments support the therapeutic use of procaine in malignant hyperpyrexia. PMID:4642792

  8. Basic and clinical aspects of malignant melanoma

    SciTech Connect

    Nathanson, L. )

    1987-01-01

    This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignant melanoma by fast neutrons.

  9. Human BK Polyomavirus—The Potential for Head and Neck Malignancy and Disease

    PubMed Central

    Burger-Calderon, Raquel; Webster-Cyriaque, Jennifer

    2015-01-01

    Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV) has conclusively been linked to human cancer, all members of the polyomavirus (PyV) family encode the oncoprotein T antigen and may be potentially carcinogenic. Studies focusing on PyV pathogenesis in humans have become more abundant as the number of PyV family members and the list of associated diseases has expanded. BK polyomavirus (BKPyV) in particular has emerged as a new opportunistic pathogen among HIV positive individuals, carrying harmful implications. Increasing evidence links BKPyV to HIV-associated salivary gland disease (HIVSGD). HIVSGD is associated with elevated risk of lymphoma formation and its prevalence has increased among HIV/AIDS patients. Determining the relationship between BKPyV, disease and tumorigenesis among immunosuppressed individuals is necessary and will allow for expanding effective anti-viral treatment and prevention options in the future. PMID:26184314

  10. Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma

    PubMed Central

    Phillips, Joanna J.; Huillard, Emmanuelle; Robinson, Aaron E.; Ward, Anna; Lum, David H.; Polley, Mei-Yin; Rosen, Steven D.; Rowitch, David H.; Werb, Zena

    2012-01-01

    Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways, presenting a major challenge to effective therapy. The activation of many RTK pathways is regulated by extracellular heparan sulfate proteoglycans (HSPG), suggesting these molecules may be effective targets in the tumor microenvironment. In this study, we demonstrated that the extracellular sulfatase, SULF2, an enzyme that regulates multiple HSPG-dependent RTK signaling pathways, was expressed in primary human GBM tumors and cell lines. Knockdown of SULF2 in human GBM cell lines and generation of gliomas from Sulf2–/– tumorigenic neurospheres resulted in decreased growth in vivo in mice. We found a striking SULF2 dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. Interestingly, in a survey of SULF2 levels in different subtypes of GBM, the proneural subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. Therefore, in addition to its potential as an upstream target for therapy of GBM, SULF2 may help identify a subset of GBMs that are more dependent on exogenous growth factor–mediated signaling. Our results suggest the bioavailability of growth factors from the microenvironment is a significant contributor to tumor growth in a major subset of human GBM. PMID:22293178

  11. Repair of chromosome damage induced by X-irradiation during G/sub 2/ phase in a line of normal human fibroblasts and its malignant derivative

    SciTech Connect

    Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

    1982-08-01

    A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G/sub 2/ phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or ..beta..-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G/sub 2/ phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, which destroys H/sub 2/O/sub 2/, or mannitol, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G/sub 2/ phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

  12. Epidermal growth factor receptor (EGFR) antisense transfection reduces the expression of EGFR and suppresses the malignant phenotype of a human ovarian cancer cell line.

    PubMed

    Brader, K R; Wolf, J K; Chakrabarty, S; Price, J E

    1998-01-01

    An EGFR-expressing clone of the human ovarian cancer line 2774 was transfected with an antisense construct of EGFR to test how suppression of this gene modulates the malignant phenotype. Transfected clones were screened for EGFR expression by Western blot and FACS analysis. Anchorage-independent growth was used to assess the effect of reduced EGFR on the malignant behavior of the cells. Several transfected clones with decreased EGFR (40-50% reduction) were identified. A correlation was noted between reduced EGFR and decreased anchorage-independent growth, with the transfected clones losing the ability to grow in agarose and responsiveness to exogenous EGF. These results suggest that EGFR may be an important factor in the malignant behavior of this ovarian cancer cell line. PMID:9683849

  13. Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy.

    PubMed

    Pelizzaro-Rocha, Karin Juliane; de Jesus, Marcelo Bispo; Ruela-de-Sousa, Roberta Regina; Nakamura, Celso Vataru; Reis, Fabiano Souza; de Fátima, Angelo; Ferreira-Halder, Carmen Veríssima

    2013-12-01

    Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix[6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix[6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix[6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix[6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix[6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics. PMID:23872419

  14. Malignant external otitis: CT evaluation

    SciTech Connect

    Curtin, H.D.; Wolfe, P.; May, M.

    1982-11-01

    Malignant external otitis is an aggressive infection caused by Pseudomonas aeruginosa that most often occurs in elderly diabetics. Malignant external otitis often spreads inferiorly from the external canal to involve the subtemporal area and progresses medially towards the petrous apex leading to multiple cranial nerve palsies. The computed tomographic (CT) findings in malignant external otitis include obliteration of the normal fat planes in the subtemporal area as well as patchy destruction of the bony cortex of the mastoid. The point of exit of the various cranial nerves can be identified on CT scans, and the extent of the inflammatory mass correlates well with the clinical findings. Four cases of malignant external otitis are presented. In each case CT provided a good demonstration of involvement of the soft tissues at the base of the skull.

  15. Up-regulation of microRNA-15b correlates with unfavorable prognosis and malignant progression of human glioma

    PubMed Central

    Pang, Chao; Guan, Yanlei; Zhao, Kai; Chen, Ling; Bao, Yijun; Cui, Run; Li, Guangyu; Wang, Yunjie

    2015-01-01

    Recent studies have demonstrated that microRNA-15b (miR-15b) regulates cell cycle progression, proliferationnd apoptosis in glioma cells by targeting Cyclins. However, the clinical significance of miR-15b in human glioma remains unclear. Therefore, the aim of this study was to investigate the significance of miR-15b expression in diagnosis, prognosis and malignant progression of glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-15b expression levels in 76 glioma tissues (13 grade II, 13 grade III and 50 grade IV gliomas) and seven glioma cell lines, as well as 10 non-neoplastic brain tissues and human astrocyte as control. MiR-15b showed significant increased expression in high-grade gliomas (P ≤ 0.001) and glioma cells (fold change 2.8-7.6) relative to non-neoplastic brains and astrocyte, respectively. Additionally, high miR-15b expression was significantly associated with advanced WHO grade (P ≤ 0.001), advanced patient age (P ≤ 0.001) and low Karnofsky performance score (KPS, P ≤ 0.001). Furthermore, Kaplan-Meier survival analysis and Cox regression analysis showed that patients with high miR-15b expression had significantly poor overall survival rate (P ≤ 0.001) and miR-15b expression was an independent prognosis-predicting factor for glioma patients (P ≤ 0.001; risk ratio = 5.6), respectively. Moreover, miR-15b expression was examined in seven independent patients with primary grade II or III gliomas that spontaneously progressed to grade III or IV gliomas. Statistically significant higher expression (P = 0.01) in the recurrent tumor compared with the corresponding primary tumor was observed in all of the seven patients. Our results suggest that miR-15b may be a prognostic predictor and be involved in malignant progression of glioma. PMID:26191187

  16. Knowledge of human papillomavirus and its association with head and neck benign and malignant lesions in a group of dental patients in pakistan.

    PubMed

    Gichki, Abdul Samad; Buajeeb, Waranun; Doungudomdacha, Sombhun; Khovidhunkit, Siribang-On Pibooniyom

    2015-01-01

    Human papillomaviruses (HPVs) remain a serious world health problem due to their association with cervical and head and neck cancers. While over 100 HPV types have been identified, only a few subtypes are associated with malignancies. HPV 16 and 18 are the most prevalent oncogenic types in head and neck cancers. Although it has been proven that some subsets of benign and malignant head and neck lesions are associated with HPV, the general population have very little awareness and knowledge of their association with HPV. Therefore, the purpose of this study was to determine the knowledge of HPV and its links with head and neck benign and malignant lesions in a group of Pakistani dental patients who attended the Dental Department of the Sandeman provincial hospital in Quetta, Pakistan. One hundred and ninety-two patients were recruited and requested to answer a questionnaire. It was revealed that there was a low level of knowledge about HPV and its association with head and neck benign and malignant lesions among the participants. This result suggested that more education regarding the relationship of HPV in inducing head and neck benign and malignant lesions is required in this group of patients. PMID:25743835

  17. Analysis of Mammalian Septin Expression in Human Malignant Brain Tumors1

    PubMed Central

    Kim, Dong-Seok; Hubbard, Sherri-Lynn; Peraud, Aurelia; Salhia, Bodour; Sakai, Keiichi; Rutka, James T

    2004-01-01

    Abstract Septins are a highly conserved subfamily of GTPases that play an important role in the process of cytokinesis. To increase our understanding of the expression and localization of the different mammalian septins in human brain tumors, we used antibodies against septins 2, 3, 4, 5, 6, 7, 9, and 11 in immunofluorescence and Western blot analyses of astrocytomas and medulloblastomas. We then characterized the expression and subcellular distribution of the SEPT2 protein in aphidicolin-synchronized U373 MG astrocytoma cells by immunofluorescence and fluorescence-activated cell sorter analysis. To determine the role of SEPT2 in astrocytoma cytokinesis, we inducibly expressed a dominant-negative (DN) SEPT2 mutant in U373 MG astrocytoma cells. We show variable levels and expression patterns of the different septins in brain tissue, brain tumor specimens, and human brain tumor cell lines. SEPT2 was abundantly expressed in all brain tumor samples and cell lines studied. SEPT3 was expressed in medulloblastoma specimens and cell lines, but not in astrocytoma specimens or cell lines. SEPT2 expression was cell cycle-related, with maximal levels in G2-M. Immunocytochemical analysis showed endogenous levels of the different septins within the perinuclear and peripheral cytoplasmic regions. In mitosis, SEPT2 was concentrated at the cleavage furrow. By immunocytochemistry and flow cytometry, we show that a DN SEPT2 mutant inhibits the completion of cell division and results in the accumulation of multinucleated cells. These results suggest that septins are variably expressed in human brain tumors. Stable expression of the DN SEPT2 mutant leads to a G2-M cell cycle block in astrocytoma cells. PMID:15140406

  18. Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

    PubMed

    Maund, Sophia Lisette; Nolley, Rosalie; Peehl, Donna Mae

    2014-02-01

    Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies. Problems encountered include degeneration of differentiated secretory cells, basal cell hyperplasia, and poor survival of PCa. Here, we optimized, characterized, and applied a TSC model of primary human PCa and benign prostate tissue that overcomes many deficiencies of current in vitro models. Tissue cores from fresh prostatectomy specimens were precision-cut at 300 μm and incubated in a rotary culture apparatus. The ability of varied culture conditions to faithfully maintain benign and cancer cell and tissue structure and function over time was evaluated by immunohistological and biochemical assays. After optimization of the culture system, molecular and cellular responses to androgen ablation and to piperlongumine (PL), purported to specifically reduce androgen signaling in PCa, were investigated. Optimized culture conditions successfully maintained the structural and functional fidelity of both benign and PCa TSCs for 5 days. TSCs exhibited androgen dependence, appropriately undergoing ductal degeneration, reduced proliferation, and decreased prostate-specific antigen expression upon androgen ablation. Further, TSCs revealed cancer-specific reduction of androgen receptor and increased apoptosis upon treatment with PL, validating data from cell lines. We demonstrate a TSC model that authentically recapitulates the structural, cellular, and genetic characteristics of the benign and malignant human prostate, androgen dependence of the native tissue, and cancer-specific response

  19. Monitoring the Bystander Killing Effect of Human Multipotent Stem Cells for Treatment of Malignant Brain Tumors.

    PubMed

    Leten, Cindy; Trekker, Jesse; Struys, Tom; Roobrouck, Valerie D; Dresselaers, Tom; Vande Velde, Greetje; Lambrichts, Ivo; Verfaillie, Catherine M; Himmelreich, Uwe

    2016-01-01

    Tumor infiltrating stem cells have been suggested as a vehicle for the delivery of a suicide gene towards otherwise difficult to treat tumors like glioma. We have used herpes simplex virus thymidine kinase expressing human multipotent adult progenitor cells in two brain tumor models (hU87 and Hs683) in immune-compromised mice. In order to determine the best time point for the administration of the codrug ganciclovir, the stem cell distribution and viability were monitored in vivo using bioluminescence (BLI) and magnetic resonance imaging (MRI). Treatment was assessed by in vivo BLI and MRI of the tumors. We were able to show that suicide gene therapy using HSV-tk expressing stem cells can be followed in vivo by MRI and BLI. This has the advantage that (1) outliers can be detected earlier, (2) GCV treatment can be initiated based on stem cell distribution rather than on empirical time points, and (3) a more thorough follow-up can be provided prior to and after treatment of these animals. In contrast to rodent stem cell and tumor models, treatment success was limited in our model using human cell lines. This was most likely due to the lack of immune components in the immune-compromised rodents. PMID:26880961

  20. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by alpha particles

    PubMed Central

    Zhang, Suping; Wen, Gengyun; Huang, Sarah XL; Wang, Jianrong; Tong, Jian; Hei, Tom K.

    2012-01-01

    Human small airway epithelial cells (SAECs) immortalized with human telomerase reverse transcriptase (h-TERT) were exposed to either a single or multiple doses of α particles. Irradiated cells showed a dose-dependent cytotoxicity and progressive neoplastic transformation phenotype. These included an increase in saturation density of growth, a greater resistance to PALA, faster anchorage-independent growth, reinforced cell invasion and c-Myc expression. In addition, the transformed cells formed progressively growing tumors upon inoculation into athymic nude mice. Specifically, α-irradiation induced damage to both mitochondrial DNA (mtDNA) and mitochondrial functions in transformed cells as evidenced by increased mtDNA copy number and common deletion, decreased oxidative phosphorylation (OXPHOS) activity as measured by cytochrome C oxidase (COX) activity and oxygen consumption. There was a linear correlation between mtDNA copy number, common deletion, COX activity and cellular transformation represented by soft agar colony formation and c-Myc expression. These results suggest that mitochondria are associated with neoplastic transformation of SAEC cells induced by α particles, and that the oncogenesis process may depend not only on the genomes inside the nucleus, but also on the mitochondrial DNA outside the nucleus. PMID:22644783

  1. Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro.

    PubMed

    Ren, Suping; Chai, Lina; Wang, Chunyan; Li, Changlan; Ren, Qiquan; Yang, Lihua; Wang, Fumei; Qiao, Zhixin; Li, Weijing; He, Min; Riker, Adam I; Han, Ying; Yu, Qun

    2015-01-01

    Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. PMID:25785839

  2. Malignant human cell transformation of Marcellus Shale gas drilling flow back water.

    PubMed

    Yao, Yixin; Chen, Tingting; Shen, Steven S; Niu, Yingmei; DesMarais, Thomas L; Linn, Reka; Saunders, Eric; Fan, Zhihua; Lioy, Paul; Kluz, Thomas; Chen, Lung-Chi; Wu, Zhuangchun; Costa, Max; Zelikoff, Judith

    2015-10-01

    The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining. PMID:26210350

  3. Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies

    PubMed Central

    LUO, LINGQING; CHEN, YAN; CHENG, XIAO; LIN, YAZHEN; FU, XIAODAN; LI, DAN; CUI, ZHAOLEI; LIN, DONGHONG

    2016-01-01

    The role of the WW domain-containing oxidoreductase (WWOX) gene in multiple types of solid human cancers has been documented extensively thus far. Recently, we investigated the in vitro effects of WWOX overexpression and observed marked growth arrest in human leukemia cells; however, the clinical characterization of WWOX in leukemia remains poorly investigated. The present study evaluated the WWOX expression profiles of 182 patients with leukemia of different types and 5 leukemic cell lines, using reverse transcription-polymerase chain reaction and immunofluorescence analysis. The results found that WWOX mRNA and WWOX protein expression was significantly reduced or absent in the leukemia cases and cell lines compared with paired controls. The WWOX-positive rate was also lower in the leukemia cases compared with the rate of the normal controls. Notably, the WWOX level was reduced in newly diagnosed and relapsed cases, or in chronic myelogenous leukemia in the blastic phase, yet elevated in remission samples. Moreover, WWOX-negative cases exhibited WWOX expression restoration following induced remission. These findings suggest that WWOX may contribute to the occurrence and development of leukemia, and that it has potential to be a good biomarker or predictor for leukemia therapy. PMID:27313745

  4. Monitoring the Bystander Killing Effect of Human Multipotent Stem Cells for Treatment of Malignant Brain Tumors

    PubMed Central

    Leten, Cindy; Trekker, Jesse; Struys, Tom; Roobrouck, Valerie D.; Dresselaers, Tom; Vande Velde, Greetje; Lambrichts, Ivo; Verfaillie, Catherine M.; Himmelreich, Uwe

    2016-01-01

    Tumor infiltrating stem cells have been suggested as a vehicle for the delivery of a suicide gene towards otherwise difficult to treat tumors like glioma. We have used herpes simplex virus thymidine kinase expressing human multipotent adult progenitor cells in two brain tumor models (hU87 and Hs683) in immune-compromised mice. In order to determine the best time point for the administration of the codrug ganciclovir, the stem cell distribution and viability were monitored in vivo using bioluminescence (BLI) and magnetic resonance imaging (MRI). Treatment was assessed by in vivo BLI and MRI of the tumors. We were able to show that suicide gene therapy using HSV-tk expressing stem cells can be followed in vivo by MRI and BLI. This has the advantage that (1) outliers can be detected earlier, (2) GCV treatment can be initiated based on stem cell distribution rather than on empirical time points, and (3) a more thorough follow-up can be provided prior to and after treatment of these animals. In contrast to rodent stem cell and tumor models, treatment success was limited in our model using human cell lines. This was most likely due to the lack of immune components in the immune-compromised rodents. PMID:26880961

  5. Malignant transformation of diploid human fibroblasts by transfection of oncogenes. Part 2, Progress report, July 1989--June 1992

    SciTech Connect

    McCormick, J.J.

    1992-12-31

    This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

  6. Multiple dispersed spontaneous mutations: A novel pathway of mutation in a malignant human cell line

    SciTech Connect

    Harwood, J.; Tachibana, Akira; Meuth, M. )

    1991-06-01

    The authors analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in part hemizygotes derived from SW620, largely as a result of base substitutions at G {center dot} C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells.

  7. MicroRNA-495 suppresses human renal cell carcinoma malignancy by targeting SATB1

    PubMed Central

    Lv, Cai; Bai, Zhiming; Liu, Zhenxiang; Luo, Pengcheng; Zhang, Jie

    2015-01-01

    Deregulated expression of miRNAs is related to progression and initiation of human cancers. Although miR-495 has identified in various tumors, its expression and function in renal cell carcinoma (RCC) is still unknown. In this study, we found that the expression of miR-495 was downregulated in RCC cell lines and tissues. Ectopic expression of miR-495 induced G0/G1 phase arrest and suppressed cell proliferation and migration in RCC cell lines. We further validated SATB1 was a direct target of miR-495 in RCC. In addition, re-expression of SATB1 reversed the miR-495-induced inhibition of cell proliferation and migration. These data suggest that miR-495 functions as a tumor suppressor and may be a promising therapeutic target in RCC in the future. PMID:26692942

  8. Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells

    SciTech Connect

    Yasumoto, S.; Burkhardt, A.L.; Doniger, J.; DiPaolo, J.A.

    1986-02-01

    A biological function for human papillomavirus 16 (HPV 16) DNA was demonstrated by transformation of NIH 3T3 cells. HPV 16 DNA has been found frequently in genital cancer and has been classified as a papillomavirus on the basis of DNA homology. A recombinant HPV 16 DNA (pSHPV16d), which contains a head-to-tail dimer of the full-length HPV 16 genome, induced morphologic transformation; the transformed cells were tumorigenic in nude mice. Expression of transforming activity was unique because of the long latency period (more than 4 weeks) required for induction of morphologic transformation and because the transfected DNA existed primarily in a multimeric form with some rearrangement. Furthermore, virus-specific RNAs were expressed in the transformants. The transformation of NIH 3T3 cells provides a model for analyzing the functions of HPV 16, which is associated with cervical carcinomas.

  9. Characterization of 17beta-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate.

    PubMed

    Elo, J P; Akinola, L A; Poutanen, M; Vihko, P; Kyllönen, A P; Lukkarinen, O; Vihko, R

    1996-03-28

    In the present study, expressions of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1, 2, and 3, 5alpha-reductase type 2 and human androgen receptor mRNAs were determined in 12 benign prostatic hyperplasia and 17 prostatic carcinoma specimens. 17HSD type 2 was found to be the principle isoenzyme expressed in the prostate. Significantly higher expressions of 17HSD type 2 and 5alpha-reductase type 2 were detected in benign prostatic hyperplasia compared with the carcinoma specimens. Expression of the androgen receptor in the 2 groups was not significantly different. 17HSD type 3 mRNA was not detected in any of the specimens investigated. Only low constructive expression of the 2.3 kb mRNA of 17HSD type 1 was seen. Immunohistochemical analysis indicated that this did not lead to significant enzyme expression, only faint staining for the enzyme protein being detected, mainly in uroepithelial cells. No significant correlation was found between any of the mRNAs analysed, but the data on 5alpha-reductase type 2 mRNA support the presence of an increased proportion of 5alpha-dihydrotesterone in the hyperplastic prostate. In cultured PC-3 prostatic cancer cells and in the transiently transfected human embryonic kidney 293 cells, 17HSD type 2 was found exclusively to convert 5alpha-dihydrotestosterone and testosterone into the less potent 17-keto compounds 5alpha-androstanedione and 4-androstenedione, respectively. We suggest that the 17HSD type 2 isoenzyme plays a part in the metabolic pathway, resulting in the inactivation of testosterone and 5alpha-dihydrotestosterone locally in the prostate. The enzyme expressed in the prostate could, therefore, protect cells from excessive androgen action. PMID:8608963

  10. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse

    PubMed Central

    Li, Catherine F; MacDonald, Jeffrey R; Wei, Robert Y; Ray, Jocelyn; Lau, Kimberly; Kandel, Christopher; Koffman, Rachel; Bell, Sherilyn; Scherer, Stephen W; Alman, Benjamin A

    2007-01-01

    Background Neoplasia can be driven by mutations resulting in dysregulation of transcription. In the mesenchymal neoplasm, aggressive fibromatosis, subtractive hybridization identified sterile alpha motif domain 9 (SAMD9) as a substantially down regulated gene in neoplasia. SAMD9 was recently found to be mutated in normophosphatemic familial tumoral calcinosis. In this study, we studied the gene structure and function of SAMD9, and its paralogous gene, SAMD9L, and examined these in a variety of species. Results SAMD9 is located on human chromosome 7q21.2 with a paralogous gene sterile alpha motif domain 9 like (SAMD9L) in the head-to-tail orientation. Although both genes are present in a variety of species, the orthologue for SAMD9 is lost in the mouse lineage due to a unique genomic rearrangement. Both SAMD9 and SAMD9L are ubiquitously expressed in human tissues. SAMD9 is expressed at a lower level in a variety of neoplasms associated with β-catenin stabilization, such as aggressive fibromatosis, breast, and colon cancers. SAMD9 and SAMD9L contain an amino-terminal SAM domain, but the remainder of the predicted protein structure does not exhibit substantial homology to other known protein motifs. The putative protein product of SAMD9 localizes to the cytoplasm. In vitro data shows that SAMD9 negatively regulates cell proliferation. Over expression of SAMD9 in the colon cancer cell line, SW480, reduces the volume of tumors formed when transplanted into immune-deficient mice. Conclusion SAMD9 and SAMD9L are a novel family of genes, which play a role regulating cell proliferation and suppressing the neoplastic phenotype. This is the first report as far as we know about a human gene that exists in rat, but is lost in mouse, due to a mouse specific rearrangement, resulting in the loss of the SAMD9 gene. PMID:17407603

  11. Curcumin inhibits AP-2γ-induced apoptosis in the human malignant testicular germ cells in vitro

    PubMed Central

    Zhou, Chang; Zhao, Xiao-meng; Li, Xiao-feng; Wang, Cheng; Zhang, Xiao-ting; Liu, Xi-zhi; Ding, Xiao-feng; Xiang, Shuang-lin; Zhang, Jian

    2013-01-01

    Aim: To investigate the effects of curcumin on proliferation and apoptosis in testicular cancer cells in vitro and to investigate its molecular mechanisms of action. Methods: NTera-2 human malignant testicular germ cell line and F9 mouse teratocarcinoma stem cell line were used. The anti-proliferative effect was examined using MTT and colony formation assays. Hoechst 33258 staining, TUNEL and Annexin V-FITC/PI staining assays were used to analyze cell apoptosis. Protein expression was examined with Western blot analysis and immunocytochemical staining. Results: Curcumin (5, 10 and 15 μmol/L) inhibited the viability of NTera-2 cells in dose- and time-dependent manners. Curcumin significantly inhibited the colony formation in both NTera-2 and F9 cells. Curcumin dose-dependently induced apoptosis of NTera-2 cells by reducing FasL expression and Bcl-2-to-Bax ratio, and activating caspase-9, -8 and -3. Furthermore, curcumin dose-dependently reduced the expression of AP transcription factor AP-2γ in NTera-2 cells, whereas the pretreatment with the proteasome inhibitor MG132 blocked both the curcumin-induced reduction of AP-2γ and antiproliferative effect. Curcumin inhibited ErbB2 expression, and decreased the phosphorylation of Akt and ERK in NTera-2 cells. Conclusion: Curcumin induces apoptosis and inhibits proliferation in NTera-2 cells via the inhibition of AP-2γ-mediated downstream cell survival signaling pathways. PMID:23685957

  12. Comparative Genomic Hybridization of Human Malignant Gliomas Reveals Multiple Amplification Sites and Nonrandom Chromosomal Gains and Losses

    PubMed Central

    Schròck, Evelin; Thiel, Gundula; Lozanova, Tanka; du Manoir, Stanislas; Meffert, Marie-Christine; Jauch, Anna; Speicher, Michael R.; Nürnberg, Peter; Vogel, Siegfried; Janisch, Werner; Donis-Keller, Helen; Ried, Thomas; Witkowski, Regine; Cremer, Thomas

    1994-01-01

    Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue ImagesFigure 1Figure 4Figure 6 PMID:8203461

  13. Optimization of radioimmunotherapy using human malignant melanoma multicell spheroids as a model

    SciTech Connect

    Kwok, C.S.; Crivici, A.; MacGregor, W.D.; Unger, M.W. )

    1989-06-15

    In vitro multicell spheroids from a human melanoma cell line and the human colon cancer cell line HT29, used as control, have been established as a model of poorly vascularized micrometastases in vivo. The antimelanoma monoclonal antibody 96.5 was radiolabeled with 131I at specific radioactivities from 1.85 to 3.96 GBq/mg. Cytotoxicity of 131I-96.5 to the spheroids, at an initial size of 300 microns in diameter, was investigated as a function of concentration of 131I-96.5 in the incubation medium, specific radioactivity, and treatment time. Spheroid growth delay and clonogenic survival of cells disaggregated from the spheroids at various times after treatment were used as end points. Therapeutic effects increased with the concentration of 131I-96.5 within the range 0.2 to 2 mg/liter (0.34 to 3.4 GBq/liter) at a fixed specific radioactivity. The effects increased with specific radioactivity at a fixed concentration of 131I-96.5. Difference in therapeutic effect was also observed between treatment times of 8 and 24 h. Radiation doses to the melanoma spheroids varied from 10 to 16 Gy. Unlabeled 96.5 at 2 mg/liter or 131I-iodide at 1.7 GBq/liter did not affect the growth of the melanoma spheroids. The HT29 spheroids, however, only suffered slight cytotoxicity at 1 or 2 mg/liter of 131I-96.5 and for a treatment time of 24 h despite comparable radiosensitivity of HT29 cells and melanoma cells to high-dose-rate radiation. Similar cytotoxicity was observed in the HT29 group treated with 131I-iodide at 1.7 GBq/liter. Present findings therefore demonstrate preferential and adequate killing of the melanoma spheroids by 131I-96.5 at 0.5 mg/liter and 3.96 GBq/mg in 8 h.

  14. Health Disparities in the Immunoprevention of Human Papillomavirus Infection and Associated Malignancies

    PubMed Central

    Bakir, Amira H.; Skarzynski, Martin

    2015-01-01

    Human papillomavirus (HPV) causes roughly 1.6% of the plus 1.6 million cases of cancer that are diagnosed in the United States each year. Despite the proven safety and efficacy of available vaccines, HPV remains the most common sexually transmitted infection. Underlying the high prevalence of HPV infection is the poor adherence to the Centers for Disease Control recommendation to vaccinate all 11- to 12-year-old males and females. In fact, only about 38 and 14% of eligible females and males, respectively, receive the complete, three-dose immunization. The many factors associated with missed HPV vaccination opportunities – including race, age, family income, and patient education – contribute to widespread disparities in vaccine completion and related health outcomes. Beyond patient circumstance, however, research indicates that the rigor and consistency of recommendation by primary care providers also plays a significant role in uptake of HPV immunization. Health disparities data are of vital importance to HPV vaccination campaigns because they can provide insight into how to address current problems and allocate limited resources where they are most needed. Furthermore, even modest gains in populations with low vaccination rates may yield great benefits because HPV immunization has been shown to provide herd immunity, indirect protection for non-immunized individuals achieved by limiting the spread of an infectious agent through a population. However, the impact of current HPV vaccination campaigns is hindered by stagnant immunization rates, which remain far below target levels despite a slow overall increase. Furthermore, gains in immunization are not equally distributed across gender, age, demographic, and socioeconomic divisions within the recommended group of vaccine recipients. To achieve the greatest impact, public health campaigns should focus on improving immunization coverage where it is weakest. They should also explore more subtle but potentially

  15. New pterocarpanquinones: synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-alpha modulation in human PBMC cells.

    PubMed

    Netto, Chaquip D; da Silva, Alcides J M; Salustiano, Eduardo J S; Bacelar, Thiago S; Riça, Ingred G; Cavalcante, Moises C M; Rumjanek, Vivian M; Costa, Paulo R R

    2010-02-15

    A new pterocarpanquinone (5a) was synthesized through a palladium catalyzed oxyarylation reaction and was transformed, through electrophilic substitution reaction, into derivatives 5b-d. These compounds showed to be active against human leukemic cell lines and human lung cancer cell lines. Even multidrug resistant cells were sensitive to 5a, which presented low toxicity toward peripheral blood mononuclear cells (PBMC) cells and decreased the production of TNF-alpha by these cells. In the laboratory these pterocarpanquinones were reduced by sodium dithionite in the presence of thiophenol at physiological pH, as NAD(P)H quinone oxidoredutase-1 (NQO1) catalyzed two-electron reduction, and the resulting hydroquinone undergo structural rearrangements, leading to the formation of Michael acceptors, which were intercepted as adducts of thiophenol. These results suggest that these compounds could be activated by bioreduction. PMID:20117936

  16. The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers.

    PubMed Central

    Pyke, C.; Rømer, J.; Kallunki, P.; Lund, L. R.; Ralfkiaer, E.; Danø, K.; Tryggvason, K.

    1994-01-01

    All known laminin isoforms are cross-shaped heterotrimeric molecules, consisting of one heavy alpha chain and two light beta and gamma chains. Recently, a cDNA encoding a new gamma chain from laminin 5 (also known as kalinin) was sequenced. This chain, named gamma 2, showed extended homology to the classical gamma 1 chain but differed from this by lacking the terminal globular domain. Recent data, indicating an important role of the gamma 2 chain gene in establishing adhesion contacts between epithelial cells and basement membranes, prompted us to investigate whether the gamma 2 chain gene is aberrantly expressed in cancer tissue, and if so whether its localization could provide clues to its possible role in cancer dissemination. Routinely processed tissue specimens from 36 cases of human cancer were investigated, including 16 cases of colon adenocarcinoma, 7 ductal mammary carcinomas, 4 squamous cell carcinomas, 3 malignant melanomas and 6 sarcomas. In situ hybridization for the detection of mRNAs for the gamma 2 chain and for the classical laminin chains alpha 1, beta 1, and gamma 1 was performed using S-35 labeled antisense RNA probes. As positive control of the specificity of the gamma 2 chain mRNA detection, two different anti-sense probes derived from two nonoverlapping cDNA clones were used. Malignant cells were found to express the gamma 2 chain in 29 of the 30 carcinomas studied and the expression was particularly high in cancer cells located at the invasion front. In contrast, mesenchymally derived cancer cells in three different types of sarcomas did not express the gamma 2 chain. In colon cancer there was a clear histological correlation between the expression of gamma 2 chain by cancer cells and their engagement in tumor budding processes. Laminin chains alpha 1, beta 1, and gamma 1 were weakly expressed throughout cancerous areas with no apparent correlation to sites of invasion. The aberrant expression of the gamma 2 chain gene seen in invasively

  17. Isolation and genome-wide expression and methylation characterization of CD31+ cells from normal and malignant human prostate tissue

    PubMed Central

    Luo, Wei; Hu, Qiang; Wang, Dan; Deeb, Kristin K.; Ma, Yingyu; Morrison, Carl D.; Liu, Song; Johnson, Candace S.; Trump, Donald L.

    2013-01-01

    Endothelial cells (ECs) are an important component involved in the angiogenesis. Little is known about the global gene expression and epigenetic regulation in tumor endothelial cells. The identification of gene expression and epigenetic difference between human prostate tumor-derived endothelial cells (TdECs) and those in normal tissues may uncover unique biological features of TdEC and facilitate the discovery of new anti-angiogenic targets. We established a method for isolation of CD31+ endothelial cells from malignant and normal prostate tissues obtained at prostatectomy. TdECs and normal-derived ECs (NdECs) showed >90% enrichment in primary culture and demonstrated microvascular endothelial cell characteristics such as cobblestone morphology in monolayer culture, diI-acetyl-LDL uptake and capillary-tube like formation in Matrigel®. In vitro primary cultures of ECs maintained expression of endothelial markers such as CD31, von Willebrand factor, intercellular adhesion molecule, vascular endothelial growth factor receptor 1, and vascular endothelial growth factor receptor 2. We then conducted a pilot study of transcriptome and methylome analysis of TdECs and matched NdECs from patients with prostate cancer. We observed a wide spectrum of differences in gene expression and methylation patterns in endothelial cells, between malignant and normal prostate tissues. Array-based expression and methylation data were validated by qRT-PCR and bisulfite DNA pyrosequencing. Further analysis of transcriptome and methylome data revealed a number of differentially expressed genes with loci whose methylation change is accompanied by an inverse change in gene expression. Our study demonstrates the feasibility of isolation of ECs from histologically normal prostate and prostate cancer via CD31+ selection. The data, although preliminary, indicates that there exist widespread differences in methylation and transcription between TdECs and NdECs. Interestingly, only a small

  18. Culture in Animals: The Case of a Non-human Primate Culture of Low Aggression and High Affiliation

    ERIC Educational Resources Information Center

    Sapolsky, Robert M.

    2006-01-01

    Philosophers often consider what it is that makes individuals human. For biologists considering the same, the answer is often framed in the context of what are the key differences between humans and other animals. One vestige of human uniqueness still often cited by anthropologists is culture. However, this notion has been challenged in recent…

  19. Argon laser phototherapy of human malignancies using rhodamine-123 as a new laser dye: The intracellular role of oxygen

    SciTech Connect

    Castro, D.J.; Saxton, R.E.; Markley, J.; Foote, C.S.; Fetterman, H.R.; Castro, D.J.; Ward, P.H. )

    1990-08-01

    Recent studies demonstrated that the cationic, mitochondrial-specific dye Rhodamine-123 (Rh-123), is an efficient tumor photosensitizer for Argon laser treatment of human cancer cells both in vitro and in tumors grown as xenografts in athymic mice. To demonstrate the photodynamic mechanism of action of this reaction, the intracellular role of oxygen and temperature changes in treated cells have to be defined. In the current study, a large panel of human tumor cell lines of diverse histologic origin were tested for in vitro sensitivity to Rh-123 and the Argon laser (514.5 nm) in oxygen, deuterium oxide (D2O), and nitrogen (N2) environment. Tumor cells in suspension were first sensitized to Rh-123 (1 or 20 micrograms/ml for 1 hour), cooled on ice to 4 degrees C, and then exposed to the Argon laser (delta T = 14 +/- 1 degree C). Cell proliferation measured by (3H)-thymidine uptake 24 hours after sensitization with Rh-123 and laser treatment was significantly decreased in tumor cells kept in oxygen and D2O atmospheres. No decrease in DNA synthesis was seen in Rh-123 and laser treated cells kept in an N2 environment. Control tumor cells treated with Rh-123 or the Argon laser separately did not show any decreased (3H)-thymidine uptake in oxygen, D2O or N2 environment. These results provide evidence of a photodynamic process since Rh-123 sensitization and Argon laser activation occur at nonthermal levels of energy and are oxygen dependent. The high effectiveness of this technique of photodynamic therapy with the Argon laser, and low toxicity of Rh-123 could make its clinical use very attractive for the treatment of superficial malignancies.

  20. Household Chemical Exposures and the Risk of Canine Malignant Lymphoma, a Model for Human Non-Hodgkin’s Lymphoma

    PubMed Central

    Takashima-Uebelhoer, Biki B.; Barber, Lisa G.; Zagarins, Sofija E.; Procter-Gray, Elizabeth; Gollenberg, Audra L.; Moore, Antony S.; Bertone-Johnson, Elizabeth R.

    2011-01-01

    Background Epidemiologic studies of companion animals offer an important opportunity to identify risk factors for cancers in animals and humans. Canine malignant lymphoma (CML) has been established as a model for non-Hodgkin’s lymphoma (NHL). Previous studies have suggested that exposure to environmental chemicals may relate to development of CML. Methods We assessed the relation of exposure to flea and tick control products and lawn-care products and risk of CML in a case-control study of dogs presented to a tertiary-care veterinary hospital (2000–2006). Cases were 263 dogs with biopsy-confirmed CML. Controls included 240 dogs with benign tumors and 230 dogs undergoing surgeries unrelated to cancer. Dog owners completed a 10-page questionnaire measuring demographic, environmental, and medical factors. Results After adjustment for age, weight, and other factors, use of specific lawn care products was associated with greater risk of CML. Specifically, the use of professionally applied pesticides was associated with a significant 70% higher risk of CML (odds ratio(OR)=1.7; 95% confidence interval (CI)=1.1–2.7). Risk was also higher in those reporting use of self-applied insect growth regulators (OR = 2.7; 95% CI=1.1–6.8). The use of flea and tick control products was unrelated to risk of CML. Conclusions Results suggest that use of some lawn care chemicals may increase the risk of CML. Additional analyses are needed to evaluate whether specific chemicals in these products may be related to risk of CML, and perhaps to human NHL as well. PMID:22222006

  1. UDP-GlcNAc2-epimerase regulates cell surface sialylation and ceramide-induced cell death in human malignant lymphoma.

    PubMed

    Suzuki, Osamu; Tasaki, Kazuhiro; Kusakabe, Takashi; Abe, Masafumi

    2008-09-01

    Stress signals induce ceramide (cer) through sphingomyelinase activation, and metabolites of cer such as sphingosine (Sph) and sphingosine-1-phoshate (S-1-P) play a significant role in many biological processes. This study aimed to elucidate the association between the alteration in cell surface sialylation and ceramide-induced cell death in the human Burkitt's lymphoma cell line, HBL-8. The highly sialylated 3G3 clone was less sensitive to C6-ceramide-induced cell death. On the other hand, the hyposialylated 3D2 clone was more sensitive to C6-ceramide-induced cell death. Neuraminidase treatment or knockdown by siRNA of uridine diphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc2-epimerase), which is a key enzyme of sialic acid biosynthesis, enhanced the amount of cell death induced by C6-ceramide in the highly sialylated 3G3 clone. Sialic acid metabolic complementation assays using several precursors of sialic acid showed that cell surface resialylation by N-acetyl-D-mannosamine (ManNAc) inhibited C6-ceramide-induced cell death. The amount of cell death by C6-ceramide was enhanced after pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002 in both clones. In addition, clone 3G3 was less sensitive to Sph than the 3D2 clone. In conclusion, in human malignant lymphoma, ceramide and its metabolite-induced cell death is regulated by the amount of sialic acid on the cell surface which in turn is regulated by mRNA expression of UDP-GlcNAc2-epimerase. PMID:18698493

  2. Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells.

    PubMed

    Rappa, Germana; Mercapide, Javier; Anzanello, Fabio; Le, Thuc T; Johlfs, Mary G; Fiscus, Ronald R; Wilsch-Bräuninger, Michaela; Corbeil, Denis; Lorico, Aurelio

    2013-04-01

    Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1-positive structures appeared in three sizes (small, ≤40 nm; intermediates ~40-80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1-containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. PMID:23318676

  3. Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas

    PubMed Central

    Harn, Horng-Jyh; Lin, Shinn-Zong; Lin, Po-Cheng; Liu, Cyong-Yue; Liu, Po-Yen; Chang, Li-Fu; Yen, Ssu-Yin; Hsieh, Dean-Kuo; Liu, Fu-Chen; Tai, Dar-Fu; Chiou, Tzyy-Wen

    2011-01-01

    We have shown that the natural compound z-butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the Bdph dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with Bdph incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects. On the basis of in vitro release kinetics, we demonstrated that the Bdph-Wafer released 50% of the available Bdph by the sixth day, and the release reached a plateau phase (90% of Bdph) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models—F344 rats (for rat GBM) and nude mice (for human GBM)—which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with Bdph-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of Bdph on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of Bdph in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our Bdph-Wafer significantly reduced tumor size in a dose-dependent manner. In summary, our study showed that p(CPP-SA) containing Bdph delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma. PMID:21565841

  4. Malignant cancer and invasive placentation: A case for positive pleiotropy between endometrial and malignancy phenotypes.

    PubMed

    D'Souza, Alaric W; Wagner, Günter P

    2014-01-01

    Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971; 47: :1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness. PMID:25324490

  5. A multilevel study of neighborhoods and parent-to-child physical aggression: results from the project on human development in Chicago neighborhoods.

    PubMed

    Molnar, Beth E; Buka, Stephen L; Brennan, Robert T; Holton, John K; Earls, Felton

    2003-05-01

    The majority of children in the United States experience parent-to-child physical aggression (PCPA), a disciplinary strategy out of favor with many experts. Several decades of research have documented a link between community characteristics and severe child maltreatment. None have taken a multilevel approach to study whether neighborhoods affect the amount of corporal punishment and/or physical abuse used by individual families. Data for this article come from the Project on Human Development in Chicago Neighborhoods and were analyzed using hierarchical linear modeling. An interval scale of PCPA was developed. Values obtained show that several neighborhood characteristics were associated with PCPA. Immigrant concentration remained significant after controlling for family composition. A cross-level interaction was found between neighborhood social networks and Hispanic race/ethnicity. The article's conclusion is that neighborhood characteristics may influence the amount of PCPA used by families. Neighborhood intervention strategies hold promise. PMID:12735711

  6. Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells

    SciTech Connect

    Rappa, Germana; Mercapide, Javier; Anzanello, Fabio; Le, Thuc T.; Johlfs, Mary G.; Fiscus, Ronald R.; Wilsch-Bräuninger, Michaela; Corbeil, Denis; Lorico, Aurelio

    2013-04-01

    Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1–positive structures appeared in three sizes (small, ≤40 nm; intermediates ∼40–80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1–containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. - Highlights: ► First report of release of prominin-1–containing microvesicles from cancer cells. ► Pro-metastatic role of prominin-1–containing microvesicles in

  7. Epigenetic control of group V phospholipase A2 expression in human malignant cells.

    PubMed

    Menschikowski, Mario; Hagelgans, Albert; Nacke, Brit; Jandeck, Carsten; Mareninova, Olga A; Asatryan, Liana; Siegert, Gabriele

    2016-06-01

    Secreted phospholipases A2 (sPLA2) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA2s expression in cancer cells, but group V sPLA2 (GV-PLA2) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA2 expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA2 transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA2 transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA2 promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA2 (r = -0.697; p = 0.01). The effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA2 transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA2 gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA2 resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA2 on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in

  8. Problems in the study of rodent aggression.

    PubMed

    Blanchard, Robert J; Wall, Philip M; Blanchard, D Caroline

    2003-09-01

    Laboratory research has produced detailed descriptions of aggression and defense patterns in the rat, mouse, and hamster, showing strong similarities, but also some differences, across these species. Research on target sites for attack, in conjunction with analyses of the situational antecedents of attack behaviors and of responsivity of these to conditions that elicit fear, has also provided a strong basis for analysis of offensive and defensive aggression strategies and for identification of combinations of these modalities such as may occur in maternal aggression. These patterns have been empirically differentiated from phenomena such as play fighting or predation and compared for laboratory rodents and their wild ancestors. An array of tasks, suitable for use with pharmacological and experimental manipulations, is available for analysis of both aggression and defense. These developments should produce a firm basis for research using animal models to analyze a broad array of aggression-related phenomena, including systematic approaches to understanding the normal antecedents and consequences of each of several differentiable types of aggressive behavior. Despite this strong empirical and analytic background, laboratory animal aggression research has been in a period of decline, spanning several decades, relative to comparable research focusing on areas such as sexual behavior or stress. Problems that may have contributed to the relative neglect of aggression research include confusion about the interpretation of different tasks for eliciting aggression; difficulties and labor intensiveness of observational measures needed for an adequate differentiation of offensive and defensive behaviors; analytic difficulties stemming from the sensitivity of offensive aggression to the inhibitory effects of fear or defensiveness; lack of a clear relationship between categories of aggressive behavior as defined in animal studies and those used in human aggression research; and

  9. Transcription analysis in the MeLiM swine model identifies RACK1 as a potential marker of malignancy for human melanocytic proliferation

    PubMed Central

    Egidy, Giorgia; Julé, Sophia; Bossé, Philippe; Bernex, Florence; Geffrotin, Claudine; Vincent-Naulleau, Silvia; Horak, Vratislav; Sastre-Garau, Xavier; Panthier, Jean-Jacques

    2008-01-01

    Background Metastatic melanoma is a severe disease. Few experimental animal models of metastatic melanoma exist. MeLiM minipigs exhibit spontaneous melanoma. Cutaneous and metastatic lesions are histologically similar to human's. However, most of them eventually spontaneously regress. Our purpose was to investigate whether the MeLiM model could reveal markers of malignancy in human melanocytic proliferations. Results We compared the serial analysis of gene expression (SAGE) between normal pig skin melanocytes and melanoma cells from an early pulmonary metastasis of MeLiM minipigs. Tag identification revealed 55 regulated genes, including GNB2L1 which was found upregulated in the melanoma library. In situ hybridisation confirmed GNB2L1 overexpression in MeLiM melanocytic lesions. GNB2L1 encodes the adaptor protein RACK1, recently shown to influence melanoma cell lines tumorigenicity. We studied the expression of RACK1 by immunofluorescence and confocal microscopy in tissues specimens of normal skin, in cutaneous and metastatic melanoma developped in MeLiM minipigs and in human patients. In pig and human samples, the results were similar. RACK1 protein was not detected in normal epidermal melanocytes. By contrast, RACK1 signal was highly increased in the cytoplasm of all melanocytic cells of superficial spreading melanoma, recurrent dermal lesions and metastatic melanoma. RACK1 partially colocalised with activated PKCαβ. In pig metastases, additional nuclear RACK1 did not associate to BDNF expression. In human nevi, the RACK1 signal was low. Conclusion RACK1 overexpression detected in situ in human melanoma specimens characterized cutaneous and metastatic melanoma raising the possibility that RACK1 can be a potential marker of malignancy in human melanoma. The MeLiM strain provides a relevant model for exploring mechanisms of melanocytic malignant transformation in humans. This study may contribute to a better understanding of melanoma pathophysiology and to

  10. What lies beneath the face of aggression?

    PubMed

    Carré, Justin M; Murphy, Kelly R; Hariri, Ahmad R

    2013-02-01

    Recent evidence indicates that a sexually dimorphic feature of humans, the facial width-to-height ratio (FWHR), is positively correlated with reactive aggression, particularly in men. Also, predictions about the aggressive tendencies of others faithfully map onto FWHR in the absence of explicit awareness of this metric. Here, we provide the first evidence that amygdala reactivity to social signals of interpersonal challenge may underlie the link between aggression and the FWHR. Specifically, amygdala reactivity to angry faces was positively correlated with aggression, but only among men with relatively large FWHRs. The patterns of association were specific to angry facial expressions and unique to men. These links may reflect the common influence of pubertal testosterone on craniofacial growth and development of neural circuitry underlying aggression. Amygdala reactivity may also represent a plausible pathway through which FWHR may have evolved to represent an honest indicator of conspecific threat, namely by reflecting the responsiveness of neural circuitry mediating aggressive behavior. PMID:22198969

  11. Induction of ovarian function by using short-term human menopausal gonadotrophin in patients with ovarian failure following cytotoxic chemotherapy for haematological malignancy.

    PubMed

    Chatterjee, R; Mills, W; Katz, M; McGarrigle, H H; Goldstone, A H

    1993-07-01

    Currently no treatment has proved successful in inducing ovarian steroidogenic and/or gametogenic recovery in patients with haematological malignancies treated by cytotoxic chemotherapy once biochemical failure becomes manifest i.e., when FSH levels exceed 40 IU/L. This paper reports two such cases with classical biochemical ovarian failure in which ovarian function was induced by brief stimulation with Human Menopausal Gonadotrophin (HMG). PMID:7693105

  12. Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells

    SciTech Connect

    Hossain, Md. Motarab; Banik, Naren L.; Ray, Swapan K.

    2012-08-01

    network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. -- Highlights: Black-Right-Pointing-Pointer Survivin shRNA + EGCG controlled growth of human malignant neuroblastoma cells. Black-Right-Pointing-Pointer Survivin knockdown induced neuronal differentiation in neuroblastoma cells. Black-Right-Pointing-Pointer Survivin shRNA + EGCG induced morphological and biochemical features of apoptosis. Black-Right-Pointing-Pointer Combination therapy inhibited invasion, proliferation, and angiogenesis as well. Black-Right-Pointing-Pointer So, combination therapy showed multiple anti-cancer mechanisms in neuroblastoma.

  13. Mucosal malignant melanoma of the maxillary sinus.

    PubMed

    Norhafizah, M; Mustafa, W M B W; Sabariah, A R; Shiran, M S; Pathmanathan, R

    2010-09-01

    Mucosal malignant melanoma (MMM) is an aggressive tumour occurring in the upper respiratory tract. It is rare compared to malignant melanoma of the skin. We report a case of a 53-year-old man with left paranasal swelling. A biopsy showed high-grade spindle cell tumour. Subsequently a subtotal maxillectomy was performed. Histopathological examination revealed a hypercellular tumour composed of mixed spindle and epitheloid cells with very occasional intracytoplasmic melanin pigment. The malignant cells were immunopositive for vimentin, S-100 protein and HMB-45. It was diagnosed as mucosal malignant melanoma (MMM). This article illustrates a rare case of MMM where the diagnosis may be missed or delayed without proper histopathological examination that include meticulous search for melanin pigment and appropriate immunohistochemical stains to confirm the diagnosis. Malignant melanoma can mimic many other types of high-grade malignancy and should be considered as a differential diagnosis in many of these instances. PMID:21939172

  14. MicroRNA-93 promotes the malignant phenotypes of human glioma cells and induces their chemoresistance to temozolomide

    PubMed Central

    Chen, Rui; Liu, Huan; Cheng, Quan; Jiang, Bing; Peng, Renjun; Zou, Qin; Yang, Wenren; Yang, Xiaosheng; Wu, Xiaobing; Chen, Zigui

    2016-01-01

    ABSTRACT MicroRNAs (miRNAs), a class of small non-coding RNAs, can induce mRNA degradation or repress translation by binding to the 3′-untranslated region (UTR) of its target mRNA. Recently, some specific miRNAs, e.g. miR-93, have been found to be involved in pathological processes by targeting some oncogenes or tumor suppressors in glioma. However, the regulatory mechanism of miR-93 in the biological behaviors and chemoresistance of glioma cells remains unclear. In the present study, in situ hybridization and real-time RT-PCR data indicated that miR-93 was significantly upregulated in glioma patients (n=43) compared with normal brain tissues (n=8). Moreover, the upregulated miR-93 level was significantly associated with the advanced malignancy. We also found that upregulation of miR-93 promoted the proliferation, migration and invasion of glioma cells, and that miR-93 was involved in the regulation of cell cycle progression by mediating the protein levels of P21, P27, P53 and Cyclin D1. P21 was further identified as a direct target of miR-93. Knockdown of P21 attenuated the suppressive effects of miR-93 inhibition on cell cycle progression and colony formation. In addition, inhibition of miR-93 enhanced the chemosensitization of glioma cells to temozolomide (TMZ). Based on these above data, our study demonstrates that miR-93, upregulated in glioma, promotes the proliferation, cell cycle progression, migration and invasion of human glioma cells and suppresses their chemosensitivity to TMZ. Therefore, miR-93 may become a promising diagnostic marker and therapeutic target for glioma. PMID:27185265

  15. Mechanisms differentiating normal from abnormal aggression: glucocorticoids and serotonin.

    PubMed

    Haller, Jozsef; Mikics, Eva; Halász, József; Tóth, Máthé

    2005-12-01

    Psychopathology-associated human aggression types are induced by a variety of conditions, are behaviorally variable, and show a differential pharmacological responsiveness. Thus, there are several types of abnormal human aggression. This diversity was not reflected by conventional laboratory approaches that focused on the quantitative aspects of aggressive behavior. Recently, several laboratory models of abnormal aggression were proposed, which mainly model hyperarousal-driven aggressiveness (characteristic to intermittent explosive disorder, post-traumatic stress disorder, depression, chronic burnout, etc.) and hypoarousal-driven aggressiveness (characteristic mainly to antisocial personality disorder and its childhood antecedent conduct disorder). Findings obtained with these models suggest that hyperarousal-driven aggressiveness has at its roots an excessive acute glucocorticoid stress response (and probably an exaggerated response of other stress-related systems), whereas chronic hypoarousal-associated aggressiveness is due to glucocorticoid deficits that affect brain function on the long term. In hypoarousal-driven aggressiveness, serotonergic neurotransmission appears to lose its impact on aggression (which it has in normal aggression), certain prefrontal neurons are weakly activated, whereas the central amygdala (no, or weakly involved in the control of normal aggression) acquires important roles. We suggest that the specific study of abnormal aspects of aggressive behavior would lead to important developments in understanding the specific mechanisms underlying different forms of aggression, and may ultimately lead to the development of better treatment approaches. PMID:16280125

  16. What Is Aggressive Violence?

    ERIC Educational Resources Information Center

    Singer, Dorothy G.; Luca, Wendy

    1985-01-01

    Responses to a questionnaire dealing with what constitutes aggressive violence on television indicate that health care providers tend to rate items describing acts on television as more aggressive than television writers, producers, and executives do. (MBR)

  17. Cytostatic and cytotoxic effects of recombinant tumor necrosis factor-alpha on sensitive human melanoma cells in vitro may result in selection of cells with enhanced markers of malignancy.

    PubMed

    Zouboulis, C C; Schröder, K; Garbe, C; Krasagakis, K; Krüger, S; Orfanos, C E

    1990-12-01

    Monolayer cultures of the human melanoma cell lines StML-12, StML-11, StML-14 (third, respectively, twenty-fifth subculture), and SKMel-28 derived from specimens representing different stages of tumor progression were treated with 10-10,000 U/ml rTNF-alpha applied for 72 h. The effects of rTNF-alpha on cell proliferation, DNA synthesis, cell viability, cloning efficiency, cell division, cell morphology, and the immunophenotype were studied in triplicate experiments. The cell line StML-14(3) revealed a significantly dose-dependent reduction of growth due to both cytostatic and cytotoxic activities of rTNF-alpha as well as a decrease of CE. Increased numbers of cells in prophase were observed 24 h after addition of r-TNF-alpha. In addition, dislocation of chromosomes in the metaphase, formation of micronuclei, and dose-dependent increases of cells exhibiting micronuclei and the DNA amount per cell were detected at the end of treatment. On the other hand, only a slight sensitivity to the anti-proliferative effect of rTNF-alpha was observed with StML-14(25) and SKMel-28, whereas StML-12 and StML-11 were significantly resistant. The last four cell lines were serially subcultivated and presented common phenotypic patterns with more malignant characteristics than the cell line StML-14(3) before treatment. Overall, rTNF-alpha enhanced the malignant immunophenotype of the cell lines tested. It increased the expression of the "late" melanoma progression markers A.10.33 and A.1.43, and Ki67, and it decreased the expression of the "early" progression marker K.1.2. The expression of HLA-I, HLA-DR, and ICAM-1 was also enhanced after rTNF-alpha treatment, whereas in contrast to other cytokines, rTNF-alpha did not induce the de novo expression of HLA-DR in HLA-DR-negative melanoma cell lines. These findings indicate that rTNF-alpha induces cytostasis and decreases cell viability of certain rTNF-alpha-sensitive melanoma cells. These effects may result in selection of r

  18. Neurobiological Patterns of Aggression.

    ERIC Educational Resources Information Center

    Hunt, Robert D.

    1993-01-01

    Describes chemical model for patterns of aggressive behavior. Addresses cultural, neurobiological, and cognitive factors that affect violent children. Identifies five patterns of aggression (overaroused, impulsive, affective, predatory, and instrumental) and examines these dimensions of aggression for each pattern: baseline, precipitators,…

  19. Aquaporins: Their role in gastrointestinal malignancies.

    PubMed

    Nagaraju, Ganji Purnachandra; Basha, Riyaz; Rajitha, Balney; Alese, Olatunji Boladale; Alam, Afroz; Pattnaik, Subasini; El-Rayes, Bassel

    2016-04-01

    Aquaporins (AQPs) are small (~30 kDa monomers) integral membrane water transport proteins that allow water to flow through cell membranes in reaction to osmotic gradients in cells. In mammals, the family of AQPs has thirteen (AQP0-12) unique members that mediate critical biological functions. Since AQPs can impact cell proliferation, migration and angiogenesis, their role in various human cancers is well established. Recently, AQPs have been explored as potential diagnostic and therapeutic targets in gastrointestinal (GI) cancers. GI cancers encompass multiple sites including the colon, esophagus, stomach and pancreas. Research in the last three decades has revealed biological aspects and signaling pathways critical for the development of GI cancers. Since the majority of these cancers are very aggressive and rapidly metastasizes, identifying effective targets is crucial for treatment. Preclinical studies have utilized inhibitors of specific AQPs and knock down of AQP expression using siRNA. Although several studies have explored the role of AQPs in colorectal, esophageal, gastric, hepatocellular and pancreatic cancers, there is no comprehensive review compiling the available information on GI cancers as has been published for other malignancies such as ovarian cancer. Due to the similarities and association of various sites of GI cancers, it is helpful to consider these results collectively in order to better understand the role of specific AQPs in critical GI cancers. This review summarizes the current knowledge of the role of AQPs in GI malignancies with particular focus on diagnosis and therapeutic applications. PMID:26780474

  20. Prolonged treatment response in aggressive natural killer cell leukemia.

    PubMed

    Osuji, N; Matutes, E; Morilla, A; Del Giudice, I; Wotherspoon, A; Catovsky, D

    2005-05-01

    We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders. PMID:16019515

  1. The effect of television-mediated aggression and real-life aggression on the behavior of Lebanese children.

    PubMed

    Day, R C; Ghandour, M

    1984-08-01

    This study investigated the effect of television-mediated aggression and real-life aggression on the behavior of Lebanese children. The sample consisted of 48 boys and 48 girls of Lebanese origin who were students in an elementary school in Beirut, Lebanon. After controlling for pre-experimental aggression, the subjects were randomly assigned to one of the following treatment conditions: human-film aggression, cartoon-film aggression, neutral film, or real-life (act of war) aggression. The results indicated that boys as a group were more aggressive than girls and exhibited more imitative aggression after viewing both violent film and real-life violence. Girls were not more violent after viewing filmed aggression but were affected by the real-life violence. Comparisons of Bandura's work within the Lebanese culture are made. PMID:6470621

  2. Maternal Defense: Breast Feeding Increases Aggression by Reducing Stress

    PubMed Central

    Hahn-Holbrook, Jennifer; Holt-Lunstad, Julianne; Holbrook, Colin; Coyne, Sarah M.; Lawson, E. Thomas

    2012-01-01

    Mothers in numerous species exhibit heightened aggression in defense of their young. This shift typically coincides with the duration of lactation in nonhuman mammals, which suggests that human mothers may display similarly accentuated aggressiveness while breast feeding. Here we report the first behavioral evidence for heightened aggression in lactating humans. Breast-feeding mothers inflicted louder and longer punitive sound bursts on unduly aggressive confederates than did formula-feeding mothers or women who had never been pregnant. Maternal aggression in other mammals is thought to be facilitated by the buffering effect of lactation on stress responses. Consistent with the animal literature, our results showed that while lactating women were aggressing, they exhibited lower systolic blood pressure than did formula-feeding or never-pregnant women while they were aggressing. Mediation analyses indicated that reduced arousal during lactation may disinhibit female aggression. Together, our results highlight the contributions of breast feeding to both protecting infants and buffering maternal stress. PMID:21873570

  3. [Development of New Therapy for Malignant Mesothelioma Based on CD26 Molecule].

    PubMed

    Morimoto, Chikao; Ohnuma, Kei

    2016-07-01

    CD26 is a 110 kDa, type II transmembrane glycoprotein with dipeptidyl peptidase IV activity and is capable of cleaving Nterminal dipeptides with either L-proline or L-alanine at the penultimate position. Malignant mesothelioma(MM)is an aggressive malignancy arising from the mesothelial cells. It is generally associated with a history of asbestos exposure and has a very poor prognosis. Due to lack of efficacy of conventional treatments, novel therapeutic strategies are urgently needed to improve outcomes. Recently we showed that CD26 is preferentially expressed on epithelial type of MM cells but not on normal mesothelial cells. We have developed a highly biological active humanized anti-CD26 monoclonal antibody(mAb)and have published previously extensive in vivo data demonstrating the anti-tumor activity of humanized anti-CD26 mAb(YS110)in mouse xenograft models. The use of a humanized anti-CD26 mAb may therefore be a rational therapy for patients with MM. The first-in-human(FIH)phase I study performed in France demonstrates that humanized anti-CD26 therapy is generally well-tolerated with preliminary evidence of activity in patients with advanced/refractory CD26-expressing cancers, particularly refractory malignant mesothelioma. From the above results, the phase I clinical trial for malignant mesothelioma in Japan is to be started in the very near future. PMID:27431629

  4. Long-term low-dose α-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway

    SciTech Connect

    Liu, Weili; Xiao, Linlin; Dong, Chen; He, Mingyuan; Pan, Yan; Xie, Yuexia; Tu, Wenzhi; Fu, Jiamei; Shao, Chunlin

    2014-05-09

    Highlights: • Multi-exposures of 25 mGy α-ray enhanced cell proliferation, adhesion, and invasion. • MAPK/Akt but not JNK/P66 was positively correlated with cell invasive phenotypes. • LDR of α-irradiation triggers cell malignant transformation through MAPK/Akt. - Abstract: Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy α-particles for 8 times in total and then further cultured for 1–2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1–2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of α-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway.

  5. Novel ZnO:Ag nanocomposites induce significant oxidative stress in human fibroblast malignant melanoma (Ht144) cells

    PubMed Central

    Arooj, Syeda; Nazir, Samina; Nadhman, Akhtar; Ahmad, Nafees; Muhammad, Bakhtiar; Ahmad, Ishaq; Mazhar, Kehkashan

    2015-01-01

    Summary The use of photoactive nanoparticles (NPs) such as zinc oxide (ZnO) and its nanocomposites has become a promising anticancer strategy. However, ZnO has a low photocatalytic decomposition rate and the incorporation of metal ions such as silver (Ag) improves their activity. Here different formulations of ZnO:Ag (1, 3, 5, 10, 20 and 30% Ag) were synthesized by a simple co-precipitation method and characterized by powder X-ray diffraction, scanning electron microscopy, Rutherford back scattering and diffuse reflectance spectroscopy for their structure, morphology, composition and optical band gap. The NPs were investigated with regard to their different photocatalytic cytotoxic effects in human malignant melanoma (HT144) and normal (HCEC) cells. The ZnO:Ag nanocomposites killed cancer cells more efficiently than normal cells under daylight exposure. Nanocomposites having higher Ag content (10, 20 and 30%) were more toxic compared to low Ag content (1, 3 and 5%). For HT144, under daylight exposure, the IC50 values were ZnO:Ag (10%): 23.37 μg/mL, ZnO:Ag (20%): 19.95 μg/mL, and ZnO:Ag (30%): 15.78 μg/mL. ZnO:Ag (30%) was toxic to HT144 (IC50: 23.34 μg/mL) in dark as well. The three nanocomposites were further analyzed with regard to their ability to generate reactive oxygen species (ROS) and induce lipid peroxidation. The particles led to an increase in levels of ROS at cytotoxic concentrations, but only HT144 showed strongly induced MDA level. Finally, NPs were investigated for the ROS species they generated in vitro. A highly significant increase of 1O2 in the samples exposed to daylight was observed. Hydroxyl radical species, HO•, were also generated to a lesser extent. Thus, the incorporation of Ag into ZnO NPs significantly improves their photo-oxidation capabilities. ZnO:Ag nanocomposites could provide a new therapeutic option to selectively target cancer cells. PMID:25821698

  6. Novel ZnO:Ag nanocomposites induce significant oxidative stress in human fibroblast malignant melanoma (Ht144) cells.

    PubMed

    Arooj, Syeda; Nazir, Samina; Nadhman, Akhtar; Ahmad, Nafees; Muhammad, Bakhtiar; Ahmad, Ishaq; Mazhar, Kehkashan; Abbasi, Rashda

    2015-01-01

    The use of photoactive nanoparticles (NPs) such as zinc oxide (ZnO) and its nanocomposites has become a promising anticancer strategy. However, ZnO has a low photocatalytic decomposition rate and the incorporation of metal ions such as silver (Ag) improves their activity. Here different formulations of ZnO:Ag (1, 3, 5, 10, 20 and 30% Ag) were synthesized by a simple co-precipitation method and characterized by powder X-ray diffraction, scanning electron microscopy, Rutherford back scattering and diffuse reflectance spectroscopy for their structure, morphology, composition and optical band gap. The NPs were investigated with regard to their different photocatalytic cytotoxic effects in human malignant melanoma (HT144) and normal (HCEC) cells. The ZnO:Ag nanocomposites killed cancer cells more efficiently than normal cells under daylight exposure. Nanocomposites having higher Ag content (10, 20 and 30%) were more toxic compared to low Ag content (1, 3 and 5%). For HT144, under daylight exposure, the IC50 values were ZnO:Ag (10%): 23.37 μg/mL, ZnO:Ag (20%): 19.95 μg/mL, and ZnO:Ag (30%): 15.78 μg/mL. ZnO:Ag (30%) was toxic to HT144 (IC50: 23.34 μg/mL) in dark as well. The three nanocomposites were further analyzed with regard to their ability to generate reactive oxygen species (ROS) and induce lipid peroxidation. The particles led to an increase in levels of ROS at cytotoxic concentrations, but only HT144 showed strongly induced MDA level. Finally, NPs were investigated for the ROS species they generated in vitro. A highly significant increase of (1)O2 in the samples exposed to daylight was observed. Hydroxyl radical species, HO(•), were also generated to a lesser extent. Thus, the incorporation of Ag into ZnO NPs significantly improves their photo-oxidation capabilities. ZnO:Ag nanocomposites could provide a new therapeutic option to selectively target cancer cells. PMID:25821698

  7. Aggression in Replacement Grower and Finisher Gilts fed a High-Tryptophan Diet and the Effect of Long-term Human-Animal Interaction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aggression is a major problem for swine production as it negatively impacts the pigs’ health and welfare. Dietary approaches such as increasing tryptophan (TRP) ingestion to raise cerebral serotonin (5-HT) – a key neurotransmitter for aggression control, and long-term positive social handling have b...

  8. Relational aggression in marriage.

    PubMed

    Carroll, Jason S; Nelson, David A; Yorgason, Jeremy B; Harper, James M; Ashton, Ruth Hagmann; Jensen, Alexander C

    2010-01-01

    Drawing from developmental theories of relational aggression, this article reports on a study designed to identify if spouses use relationally aggressive tactics when dealing with conflict in their marriage and the association of these behaviors with marital outcomes. Using a sample of 336 married couples (672 spouses), results revealed that the majority of couples reported that relationally aggressive behaviors, such as social sabotage and love withdrawal, were a part of their marital dynamics, at least to some degree. Gender comparisons of partner reports of their spouse's behavior revealed that wives were significantly more likely to be relationally aggressive than husbands. Structural equation modeling demonstrated that relational aggression is associated with lower levels of marital quality and greater marital instability for both husbands and wives. Implications are drawn for the use of relational aggression theory in the future study of couple conflict and marital aggression. PMID:20698028

  9. Sternal Resection and Reconstruction for Malignant Phylloides Tumor.

    PubMed

    Selvakumar, Veda Padma Priya; Poonia, Dharmaram; Agrawal, Juhi; Goel, Ashish; Mehta, Sandeep; Kumar, Kapil

    2015-08-01

    Malignant phylloides tumor is a locally aggressive breast neoplasm constituting less than 1 % of all breast cancers. It has a tendency for local recurrence and management is multidisciplinary. We hereby report a case of total sternal resection and reconstruction using Biopore HDPE prosthesis for Malignant Phylloides tumor. PMID:26702245

  10. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model

    PubMed Central

    Couronné, Lucile; Scourzic, Laurianne; Pilati, Camilla; Valle, Véronique Della; Duffourd, Yannis; Solary, Eric; Vainchenker, William; Merlio, Jean-Philippe; Beylot-Barry, Marie; Damm, Frederik; Stern, Marc-Henri; Gaulard, Philippe; Lamant, Laurence; Delabesse, Eric; Merle-Beral, Hélène; Nguyen-Khac, Florence; Fontenay, Michaëla; Tilly, Hervé; Bastard, Christian; Zucman-Rossi, Jessica; Bernard, Olivier A.; Mercher, Thomas

    2013-01-01

    STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies. PMID:23872306

  11. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer.

    PubMed

    Wang, Tianzhen; Wang, Guangyu; Hao, Dapeng; Liu, Xi; Wang, Dong; Ning, Ning; Li, Xiaobo

    2015-01-01

    RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed. PMID:26123544

  12. Hematologic malignancies

    SciTech Connect

    Hoogstraten, B.

    1986-01-01

    The principle aim of this book is to give practical guidelines to the modern treatment of the six important hematologic malignancies. Topics considered include the treatment of the chronic leukemias; acute leukemia in adults; the myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis/agnogenic myeloid metaplasia; Hodgkin's Disease; non-Hodgkin's lymphoma; and Multiple Myeloma.

  13. ATR-FTIR spectroscopy coupled with chemometric analysis discriminates normal, borderline and malignant ovarian tissue: classifying subtypes of human cancer.

    PubMed

    Theophilou, Georgios; Lima, Kássio M G; Martin-Hirsch, Pierre L; Stringfellow, Helen F; Martin, Francis L

    2016-01-21

    Surgical management of ovarian tumours largely depends on their histo-pathological diagnosis. Currently, screening for ovarian malignancy with tumour markers in conjunction with radiological investigations has a low specificity for discriminating benign from malignant tumours. Also, pre-operative biopsy of ovarian masses increases the risk of intra-peritoneal dissemination of malignancy. Intra-operative frozen section, although sufficiently accurate in differentiating tumours according to their histological type, increases operation times. This results in increased surgery-related risks to the patient and additional burden to resource allocation. We set out to determine whether attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, combined with chemometric analysis can be applied to discriminate between normal, borderline and malignant ovarian tumours and classify ovarian carcinoma subtypes according to the unique spectral signatures of their molecular composition. Formalin-fixed, paraffin-embedded ovarian tissue blocks were de-waxed, mounted on Low-E slides and desiccated before being analysed using ATR-FTIR spectroscopy. Chemometric analysis in the form of principal component analysis (PCA), successive projection algorithm (SPA) and genetic algorithm (GA), followed by linear discriminant analysis (LDA) of the obtained spectra revealed clear segregation between benign versus borderline versus malignant tumours as well as segregation between different histological tumour subtypes, when these approaches are used in combination. ATR-FTIR spectroscopy coupled with chemometric analysis has the potential to provide a novel diagnostic approach in the accurate diagnosis of ovarian tumours assisting surgical decision making to avoid under-treatment or over-treatment, with minimal impact to the patient. PMID:26090781

  14. Malignant mammary tumor in female dogs: environmental contaminants

    PubMed Central

    2010-01-01

    Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adjacent adipose tissue of canine mammary tumor. High Precision Liquid Chromatography - HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in nine female dogs, without predilection for breed or age. After surgery, masses were carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected to detect of environmental contaminants. The identified pyrethroids were allethrin, cyhalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 33.3%. Histopathology demonstrated six female dogs (66.7%) as having complex carcinoma and three (33.3%) with simple carcinoma. From these tumors, seven (77.8%) presented aggressiveness degree III and two (22.2%) degree I. Five tumors were positive for estrogen receptors in immunohistochemical analysis. The contamination level was observed in more aggressive tumors. This was the first report in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis. Hence, the dog may be used as a sentinel animal for human breast cancer, since human beings share the same environment and basically have the same eating habits. PMID:20587072

  15. Canine aggression toward people: a guide for practitioners.

    PubMed

    Sueda, Karen Lynn C; Malamed, Rachel

    2014-05-01

    This article reviews the various causes of human-directed aggression in dogs and provides a step-by-step plan guiding the general practitioner through history taking, behavior observations, diagnosis, consultation, treatment, and follow-up care. Charts summarizing how to obtain behavioral information, the client's management options, treatment recommendations, diagnosis and treatment of human-directed aggression, and the clinician's role in preventing human-directed aggression are included. A graphic illustration of canine body language is also provided. PMID:24766702

  16. The mitogenic effect of KGF and the expression of its cell surface receptor on cultured normal and malignant human oral keratinocytes and on contiguous fibroblasts.

    PubMed

    Drugan, C S; Stone, A; Game, S M; Prime, S S

    1997-08-01

    This study examined the mitogenic response to keratinocyte growth factor (KGF) of normal and tumour-derived human oral keratinocytes in which the degree of cellular differentiation was known and in contiguous fibroblast cultures derived from the malignant epithelial cultures. Keratinocytes, but not fibroblasts, were stimulated by KGF, thereby demonstrating epithelial target cell specificity of the ligand. KGF-induced stimulation of the tumour-derived keratinocytes cultured in the absence of the 3T3 fibroblast support broadly correlated with the degree of cellular differentiation; well-differentiated keratinocytes were stimulated more by KGF than their less differentiated counterparts. Malignant oral keratinocytes expressed KGF cell surface receptors (KD 451-709 pM; receptors/cell 2306-13645), but KGF receptor mRNA did not correlate with either KGF-induced mitogenesis or the degree of epithelial cell differentiation. When the tumour-derived keratinocytes were cultured in the presence of 3T3 fibroblasts, the mitogenic response to KGF was comparable to normal epithelial cells. The results suggest that KGF-mediated growth stimulation may not be significant in providing a selective advantage for the growth of malignant keratinocytes. PMID:9250933

  17. Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis.

    PubMed

    Egas-Bejar, Daniela; Anderson, Pete M; Agarwal, Rishi; Corrales-Medina, Fernando; Devarajan, Eswaran; Huh, Winston W; Brown, Robert E; Subbiah, Vivek

    2014-03-12

    The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3.Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis. PMID:25126591

  18. Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: the human fingerprint hypothesis

    PubMed Central

    Egas-Bejar, Daniela; Anderson, Pete M.; Agarwal, Rishi; Corrales-Medina, Fernando; Devarajan, Eswaran; Huh, Winston W.; Brown, Robert E; Subbiah, Vivek

    2014-01-01

    The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3. Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/ mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis. PMID:25126591

  19. A catalogue of treatment and technologies for malignant pleural mesothelioma.

    PubMed

    Schunselaar, Laurel M; Quispel-Janssen, Josine M M F; Neefjes, Jacques J C; Baas, Paul

    2016-04-01

    Malignant pleural mesothelioma is an aggressive fatal malignancy with a prognosis that has not significantly improved in the last decades. This review summarizes the current state of treatment and the various attempts that are made to improve overall survival for patients with malignant pleural mesothelioma. It also discusses technologies and protocols to test new and hopefully more effective compounds in a more individualized manner. These developments are expected to improve the prognosis for this group of patients. PMID:26943000

  20. Determination of hyperglycosylated human chorionic gonadotropin produced by malignant gestational trophoblastic neoplasias and male germ cell tumors using a lectin-based immunoassay and surface plasmon resonance

    PubMed Central

    Kelly, Lisa S.; Birken, Steven; Puett, David

    2007-01-01

    The ability to reliably detect aberrant glycosylation of human chorionic gonadotropin (hCG) may have profound implications for the diagnosis and monitoring of malignant gestational trophoblastic neoplasia, germ cell tumors, other malignancies, and pregnancy complications. To become a clinically useful assay, however, this discrimination of glycoforms should be possible on minimally treated biological specimens. Towards this end, we have developed a lectin-based sandwich-type immunoassay to compare the glycosylation patterns of hCG among urine specimens from patients presenting with a normal pregnancy, invasive mole, choriocarcinoma, and male germ cell tumors using carbohydrate-free antibody fragments as capture reagents and a panel of eight lectins, five recognizing neutral sugars and three recognizing sialic acid. There was no significant difference in the binding of any of the lectins to hCG in the urine of women over the gestational range of 6 – 38 weeks. Three lectins, however, exhibited differential binding to urinary hCG derived from these normal pregnant controls and that from patients with malignant forms of gestational trophoblastic disease and male germ cell tumors. Galanthus nivalis agglutinin and Maackia amurensis lectin, which bind terminal mannose and α(2–3)sialic acid, respectively, preferentially bound pregnancy-derived hCG, whereas the lectin, wheat germ agglutinin, which binds sialic acid and β(1–4)N-acetylglucosamine, exhibited decreased binding to pregnancy-derived hCG compared to that from patients with male germ cell tumors and malignant gestational trophoblastic neoplasia. The differential binding observed with these three promising lectins is most encouraging and warrants further examination. The experimental paradigm also holds promise for the development of comparable assays for other glycosylated tumor markers. PMID:17081681

  1. Serum (1-3)-beta-D-glucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy.

    PubMed

    Desmet, Stefanie; Van Wijngaerden, Eric; Maertens, Johan; Verhaegen, Jan; Verbeken, Eric; De Munter, Paul; Meersseman, Wouter; Van Meensel, Britt; Van Eldere, Johan; Lagrou, Katrien

    2009-12-01

    (1-3)-Beta-D-Glucan (BG) reactivity was tested in serum samples from 28 patients with human immunodeficiency virus infection or a hematological malignancy and Pneumocystis jirovecii pneumonia (PCP) and 28 control patients. The sensitivity and specificity of BG detection with the Fungitell assay for PCP were 100 and 96.4%, respectively, using a cutoff value of 100 pg/ml. Serum BG testing looks promising for the noninvasive diagnosis of PCP. Our data suggest that a higher cutoff value for the diagnosis of PCP than for the diagnosis of invasive aspergillosis or candidiasis could be used safely and will improve the specificity of the test. PMID:19846641

  2. Mapping Brain Development and Aggression

    PubMed Central

    Paus, Tomás

    2005-01-01

    Introduction This article provides an overview of the basic principles guiding research on brain-behaviour relationships in general, and as applied to studies of aggression during human development in particular. Method Key literature on magnetic resonance imaging of the structure and function of a developing brain was reviewed. Results The article begins with a brief introduction to the methodology of techniques used to map the developing brain, with a special emphasis on magnetic resonance imaging (MRI). It then reviews briefly the current knowledge of structural maturation, assessed by MRI, of the human brain during childhood and adolescence. The last part describes some of the results of neuroimaging studies aimed at identifying neural circuits involved in various aspects of aggression and social cognition. Conclusion The article concludes by discussing the potential and limitations of the neuroimaging approach in this field. PMID:19030495

  3. Distinct Splice Variants and Pathway Enrichment in the Cell Line Models of Aggressive Human Breast Cancer Subtypes

    PubMed Central

    Menon, Rajasree; Im, Hogune; Zhang, Emma (Yue); Wu, Shiaw-Lin; Chen, Rui; Snyder, Michael; Hancock, William S.; Omenn, Gilbert S.

    2013-01-01

    This study was conducted as a part of the Chromosome-Centric Human Proteome Project (C-HPP) of the Human Proteome Organization. The United States team of C-HPP is focused on characterizing the protein-coding genes in chromosome 17. Despite its small size, chromosome 17 is rich in protein-coding genes, it contains many cancer-associated genes, including BRCA1, ERBB2 (Her2/neu), and TP53. The goal of this study was to examine the splice variants expressed in three ERBB2 expressed breast cancer cell line models of hormone receptor negative breast cancers by integrating RNA-Seq and proteomic mass spectrometry data. The cell-lines represent distinct phenotypic variations subtype: SKBR3 (ERBB2+ (over-expression)/ ER−/PR−; adenocarcinoma), SUM190 (ERBB2+ (over-expression)/ER−/PR−; inflammatory breast cancer) and SUM149 (ERBB2 (low expression) ER−/PR −; inflammatory breast cancer). We identified more than one splice variant for 1167 genes expressed in at least one of the three cancer cell lines. We found multiple variants of genes that are in the signaling pathways downstream of ERBB2 along with variants specific to one cancer cell line compared to the other two cancer cell lines and to normal mammary cells. The overall transcript profiles based on read counts indicated more similarities between SKBR3 and SUM190. The top-ranking Gene Ontology and BioCarta pathways for the cell-line specific variants pointed to distinct key mechanisms including: amino sugar metabolism, caspase activity, and endocytosis in SKBR3; different aspects of metabolism, especially of lipids in SUM190; cell- to-cell adhesion, integrin and ERK1/ERK2 signaling, and translational control in SUM149. The analyses indicated an enrichment in the electron transport chain processes in the ERBB2 over-expressed cell line models; and an association of nucleotide binding, RNA splicing and translation processes with the IBC models, SUM190 and SUM149. Detailed experimental studies on the distinct

  4. Neurogenetics of Aggressive Behavior – Studies in Rodents

    PubMed Central

    Takahashi, Aki; Miczek, Klaus A.

    2014-01-01

    Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals’ survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques e.g. immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), major inhibitory and excitatory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie

  5. Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas

    PubMed Central

    2012-01-01

    Background Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL). Methodology The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL). Results αIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by αIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The αIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses

  6. Authoritarianism and sexual aggression.

    PubMed

    Walker, W D; Rowe, R C; Quinsey, V L

    1993-11-01

    In Study 1, 198 men completed the Right Wing Authoritarianism, Sex Role Ideology, Hostility Towards Women, Acceptance of Interpersonal Violence, Adversarial Sexual Beliefs, and Rape Myth Acceptance scales, as well as measures of past sexually aggressive behavior and likelihood of future sexual aggression. As predicted, authoritarianism and sex role ideology were as closely related to self-reported past and potential future sexually aggressive behavior as were the specifically sexual and aggression-related predictors. Among 134 men in Study 2, authoritarianism and sex guilt positively correlated with each other and with self-reported past sexual aggression. In both studies, the relationship of authoritarianism and sexual aggression was larger in community than in university samples. PMID:8246111

  7. Epigenetic alteration by DNA-demethylating treatment restores apoptotic response to glucocorticoids in dexamethasone-resistant human malignant lymphoid cells

    PubMed Central

    2014-01-01

    Background Glucocorticoids (GCs) are often included in the therapy of lymphoid malignancies because they kill several types of malignant lymphoid cells. GCs activate the glucocorticoid receptor (GR), to regulate a complex genetic network, culminating in apoptosis. Normal lymphoblasts and many lymphoid malignancies are sensitive to GC-driven apoptosis. Resistance to GCs can be a significant clinical problem, however, and correlates with resistance to several other major chemotherapeutic agents. Methods We analyzed the effect of treatment with the cytosine analogue 5 aza-2’ deoxycytidine (AZA) on GC resistance in two acute lymphoblastic leukemia (T or pre-T ALL) cell lines- CEM and Molt-4- and a (B-cell) myeloma cell line, RPMI 8226. Methods employed included tissue culture, flow cytometry, and assays for clonogenicity, cytosine extension, immunochemical identification of proteins, and gene transactivation. High throughput DNA sequencing was used to confirm DNA methylation status. Conclusions Treatment of these cells with AZA resulted in altered DNA methylation and restored GC-evoked apoptosis in all 3 cell lines. In CEM cells the altered epigenetic state resulted in site-specific phosphorylation of the GR, increased GR potency, and GC-driven induction of the GR from promoters that lie in CpG islands. In RPMI 8226 cells, expression of relevant coregulators of GR function was altered. Activation of p38 mitogen-activated protein kinase (MAPK), which is central to a feed-forward mechanism of site-specific GR phosphorylation and ultimately, apoptosis, occurred in all 3 cell lines. These data show that in certain malignant hematologic B- and T-cell types, epigenetically controlled GC resistance can be reversed by cell exposure to a compound that causes DNA demethylation. The results encourage studies of application to in vivo systems, looking towards eventual clinical applications. PMID:24795534

  8. Preventing aggressive behaviour in dogs.

    PubMed

    Orritt, Rachel

    2016-07-01

    Delegates from around the world met at the University of Lincoln on June 11 and 12 for the third annual UK Dog Bite Prevention and Behaviour conference. The conference, hosted by dog trainer Victoria Stilwell, brings together dog behaviour experts to discuss possible solutions to this public health issue. Rachel Orritt, who has been examining the perceptions, assessment and management of human-directed aggressive behaviour in dogs for her PhD, reports. PMID:27389748

  9. Malignant Peripheral Nerve Sheath Tumor -A Rare Malignancy in Mandible

    PubMed Central

    Majumdar, Sumit; Kotina, Sreekanth; Uppala, Divya; Kumar, Singam Praveen

    2016-01-01

    Malignant Peripheral Nerve Sheath Tumor (MPNST) is biologically an aggressive tumor that is usually found in the extremities, trunk and infrequently found in the head and neck area particularly in the jaws, arising from the cells allied with nerve sheath. Mandibular MPNST may either arise from a preexisting neurofibroma or develop de novo. Because of the greater variability from case to case in overall appearance both clinically and histologically, a case of MPNST of the mandible in a 25-year-old female patient is reported. The lesion was excised and immunohistological studies (S-100 & Neuron specific enolase) were conducted to confirm the neural origin. PMID:27504425

  10. Malignant Peripheral Nerve Sheath Tumor -A Rare Malignancy in Mandible.

    PubMed

    Majumdar, Sumit; Kotina, Sreekanth; Mahesh, Nirujogi; Uppala, Divya; Kumar, Singam Praveen

    2016-06-01

    Malignant Peripheral Nerve Sheath Tumor (MPNST) is biologically an aggressive tumor that is usually found in the extremities, trunk and infrequently found in the head and neck area particularly in the jaws, arising from the cells allied with nerve sheath. Mandibular MPNST may either arise from a preexisting neurofibroma or develop de novo. Because of the greater variability from case to case in overall appearance both clinically and histologically, a case of MPNST of the mandible in a 25-year-old female patient is reported. The lesion was excised and immunohistological studies (S-100 & Neuron specific enolase) were conducted to confirm the neural origin. PMID:27504425

  11. Microbiome and Malignancy

    PubMed Central

    Plottel, Claudia S.; Blaser, Martin J.

    2011-01-01

    Current knowledge is insufficient to explain why only a proportion of individuals exposed to environmental carcinogens or carrying a genetic predisposition to cancer develop disease. Clearly, other factors must be important and one such element that has recently received attention is the human microbiome, the residential microbes including Bacteria, Archaea, Eukaryotes, and viruses that colonize humans. Here, we review principles and paradigms of microbiome-related malignancy, as illustrated by three specific microbial-host interactions. We review the effects of the microbiota on local and adjacent-neoplasia, present the estrobolome model of distant effects, and discuss the complex interactions with a latent virus leading to malignancy. These are separate facets of a complex biology interfacing all the microbial species we harbor from birth onward toward early reproductive success and eventual senescence. PMID:22018233

  12. Malignant transformation of human gastric epithelium cells via reactive oxygen species production and Wnt/β-catenin pathway activation following 40-week exposure to ochratoxin A.

    PubMed

    Jia, Xin; Cui, Jinfeng; Meng, Xinxing; Xing, Lingxiao; Shen, Haitao; Wang, Juan; Liu, Jing; Wang, Yuan; Lian, Weiguang; Zhang, Xianghong

    2016-03-01

    Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogenic to humans. We previously demonstrated that OTA treatment induced oxidative damage in human gastric epithelium cells (GES-1) in vitro. In this study, we found that long-term OTA treatment could result in increased proliferation, migration, and invasion abilities of GES-1 cells and induce anchorage-independent growth of cells in soft agar. Inoculation of OTA-treated GES-1 cells resulted in the formation of tumor xenografts in Balb/c nude mice in vivo, confirming that long-term OTA treatment can induce the malignant transformation of GES-1 cells. In addition, we found that long-term OTA treatment induced oxidative stress and activated the Wnt/β-catenin pathway, including the nuclear transition of β-catenin and the upregulation of the downstream molecules of the pathway. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) inhibited ROS formation and activation of the Wnt pathway in OTA-transformed GES-1 cells, which decreased the tumor formation abilities of these cells after inoculation in nude mice. These findings suggest that long-term OTA exposure induces the malignant transformation of GES-1 cells via intracellular ROS production and activation of the Wnt/β-catenin signaling pathway. PMID:26721203

  13. Galectin-3 as a Potential Therapeutic Target in Tumors Arising from Malignant Endothelia1

    PubMed Central

    Johnson, Kim D; Glinskii, Olga V; Mossine, Valeri V; Turk, James R; Mawhinney, Thomas P; Anthony, Douglas C; Henry, Carolyn J; Huxley, Virginia H; Glinsky, Gennadi V; Pienta, Kenneth J; Raz, Avraham; Glinsky, Vladislav V

    2007-01-01

    Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-l-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 antiapoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells. PMID:17786185

  14. Sialylation and glycosylation modulate cell adhesion and invasion to extracellular matrix in human malignant lymphoma: Dependency on integrin and the Rho GTPase family

    PubMed Central

    SUZUKI, OSAMU; ABE, MASAFUMI; HASHIMOTO, YUKO

    2015-01-01

    To determine the biological roles of cell surface glycosylation, we modified the surface glycosylation of human malignant lymphoma cell lines using glycosylation inhibitors. The O-glycosylation inhibitor, benzyl-α-GalNAc (BZ) enhanced the fibronectin adhesion of HBL-8 cells, a human Burkitt's lymphoma cell line, and of H-ALCL cells, a human anaplastic large cell lymphoma cell line, both of which were established in our laboratory. The N-glycosylation inhibitor, tunicamycin (TM) inhibited the surface expression of Phaseolus vulgaris leukoagglutinating (L-PHA) lectin- and Canavalia ensiformis (ConA) lectin-reactive oligosaccharides in the HBL-8 cell line. Assay of the adhesion of HBL-8 cells to fibronectin showed that fibronectin adhesion is mediated by the integrin very late antigen (VLA)-4 and that not only BZ but also TM treatment enhanced HBL-8 cell adhesion to fibronectin. Furthermore, although BZ treatment also enhanced H-ALCL cell adhesion to fibronectin, this effect was not mediated by VLA-5 or the RGD sequence of fibronectin. We also showed that H-ALCL cell adhesion to galectin-3 was enhanced by pre-treatment with neuraminidase, which cleaves cell surface sialic acid. Additionally, H-ALCL cell adhesion to galectin-3 was inhibited by pre-treatment with the RGD peptide suggesting that cell adhesion to galectin-3 is mediated by integrin (VLA-5). Furthermore, H-ALCL cell invasion of galectin-1 and galectin-3 was inhibited by pre-treatment with the RGD peptide. Therefore, cell adhesion to and invasion of galectin-1 and galectin-3 are integrin-dependent. In addition to these findings, cell adhesion to galectin-3 was markedly inhibited by treatment with β-lactose compared to treatment with sucrose. Therefore, interactions between integrins and galectin-3 may be mediated through β-galactose that is linked to glycans of integrins. AZA1, an inhibitor of Ras homolog oncoprotein (Rho) GTPase family proteins, RAS-related C3 botulinus toxin substrate 1 (Rac 1) and Cell

  15. Sialylation and glycosylation modulate cell adhesion and invasion to extracellular matrix in human malignant lymphoma: Dependency on integrin and the Rho GTPase family.

    PubMed

    Suzuki, Osamu; Abe, Masafumi; Hashimoto, Yuko

    2015-12-01

    To determine the biological roles of cell surface glycosylation, we modified the surface glycosylation of human malignant lymphoma cell lines using glycosylation inhibitors. The O-glycosylation inhibitor, benzyl-α-GalNAc (BZ) enhanced the fibronectin adhesion of HBL-8 cells, a human Burkitt's lymphoma cell line, and of H-ALCL cells, a human anaplastic large cell lymphoma cell line, both of which were established in our laboratory. The N-glycosylation inhibitor, tunicamycin (TM) inhibited the surface expression of Phaseolus vulgaris leukoagglutinating (L-PHA) lectin- and Canavalia ensiformis (ConA) lectin-reactive oligosaccharides in the HBL-8 cell line. Assay of the adhesion of HBL-8 cells to fibronectin showed that fibronectin adhesion is mediated by the integrin very late antigen (VLA)-4 and that not only BZ but also TM treatment enhanced HBL-8 cell adhesion to fibronectin. Furthermore, although BZ treatment also enhanced H-ALCL cell adhesion to fibronectin, this effect was not mediated by VLA-5 or the RGD sequence of fibronectin. We also showed that H-ALCL cell adhesion to galectin-3 was enhanced by pre-treatment with neuraminidase, which cleaves cell surface sialic acid. Additionally, H-ALCL cell adhesion to galectin-3 was inhibited by pre‑treatment with the RGD peptide suggesting that cell adhesion to galectin-3 is mediated by integrin (VLA-5). Furthermore, H-ALCL cell invasion of galectin-1 and galectin-3 was inhibited by pre-treatment with the RGD peptide. Therefore, cell adhesion to and invasion of galectin-1 and galectin-3 are integrin-dependent. In addition to these findings, cell adhesion to galectin-3 was markedly inhibited by treatment with β-lactose compared to treatment with sucrose. Therefore, interactions between integrins and galectin-3 may be mediated through β-galactose that is linked to glycans of integrins. AZA1, an inhibitor of Ras homolog oncoprotein (Rho) GTPase family proteins, RAS-related C3 botulinus toxin substrate 1 (Rac 1) and

  16. Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms.

    PubMed

    Csiba, A; Whitwell, H L; Moore, M

    1984-11-01

    Monoclonal antibodies (McAbs) directed against the framework determinants of Class I and Class II products of the major histocompatibility complex (MHC) and against leucocyte differentiation antigens were used in an indirect immunoperoxidase technique to study their expression in normal, benign (adenomatous polyps) and malignant disease of the colon. Class I products (detected by the McAb 2A1) were strongly expressed on all cell types in normal and benign tissues but some carcinomas exhibited a heterogenous pattern of epithelial cell staining and 4/15 were completely negative. Class II products (detected by TDR31.1) were strongly expressed on cells (mainly B lymphocytes) within the lamina propria. In carcinomas TDR31.1 staining was mainly interstitial, but in 2/15, DR + epithelial cells were also detected. In normal and benign tissues, leucocytes (reactive with 2D1) found predominantly in the lamina propria, comprised T cells mainly of the helper/inducer (OKT4) subset, DR + cells in approx. equivalent proportion and a few OKM1+ cells mostly of macrophage morphology. Occasional intraepithelial lymphocytes were of cytotoxic/suppressor (OKT8) phenotype. In malignant neoplasms, there was wide inter and intra-tumour variation in the proportion of leucocytes which were heterogeneous with respect to cell type and confined mainly to the stroma. T cells were consistently predominant, but B cells and macrophages were also present. Two neoplasms showed unequivocal evidence of a shift (relative to peripheral blood) in favour of the OKT8+ subset, but in the majority of tumours OKT4+; and OKT8+ cells were present in roughly similar proportions. Natural killer cells (monitored with Leu7, HNK1) were virtually undetectable in both normal and malignant tissues. There were no apparent correlations between the extent and type of leucocyte infiltration, tumour differentiation or expression of MHC products. Some implications for the extrapolation of in vitro data on leucocyte function

  17. Angry and Aggressive Students

    ERIC Educational Resources Information Center

    Larson, Jim

    2008-01-01

    Students who engage in physical aggression in school present a serious challenge to maintaining a safe and supportive learning environment. Unlike other forms of student aggression, fighting is explicit, is violent, and demands attention. A fight between students in a classroom, hallway, or the lunchroom brings every other activity to a halt and…

  18. Girls' Aggressive Behavior

    ERIC Educational Resources Information Center

    Owens, Larry; Shute, Rosalyn; Slee, Phillip

    2004-01-01

    In contrast to boys' bullying behavior which is often overt and easily visible, girls' aggression is usually indirect and covert. Less research has been conducted on the types of bullying that girls usually engage in. Using focus groups composed of teenaged girls, Dr. Owens and colleagues examine the nature of teenage girls' indirect aggression.

  19. Testosterone and Aggression.

    ERIC Educational Resources Information Center

    Archer, John

    1994-01-01

    Studies comparing aggressive and nonaggressive prisoners show higher testosterone levels among the former. While there is limited evidence for a strong association between aggressiveness and testosterone during adolescence, other studies indicate that testosterone levels are responsive to influences from the social environment, particularly those…

  20. Aggression: Psychopharmacologic Management

    PubMed Central

    Conlon, Patrick; Frommhold, Kristine

    1989-01-01

    Aggression may be part of a variety of psychiatric diagnoses. The appropriate treatment requires that the physician recognize the underlying cause. Pharmacologic agents may form part of the overall treatment of the patient. The number of possible drugs for treating aggression has expanded rapidly, and it is important that the physician be familiar with the various options avilable. PMID:21248947

  1. Social Aggression among Girls.

    ERIC Educational Resources Information Center

    Underwood, Marion K.

    Noting recent interest in girls' social or "relational" aggression, this volume offers a balanced, scholarly analysis of scientific knowledge in this area. The book integrates current research on emotion regulation, gender, and peer relations, to examine how girls are socialized to experience and express anger and aggression from infancy through…

  2. Third Person Instigated Aggression.

    ERIC Educational Resources Information Center

    Gaebelein, Jacquelyn

    Since many acts of aggression in society are more than simply an aggressor-victim encounter, the role played by third person instigated aggression also needs examination. The purpose of this study was to develop a laboratory procedure to systematically investigate instigation. In a competitive reaction time task, high and low Machiavellian Males…

  3. Neuropsychiatry of Aggression

    PubMed Central

    Lane, Scott D.; Kjome, Kimberly L.; Moeller, F. Gerard

    2010-01-01

    Synopsis Aggression is a serious medical problem that can place both the patient and the health care provider at risk. Aggression can result from medical, neurologic and or psychiatric disorders. A comprehensive patient evaluation is needed. Treatment options include pharmacotherapy as well as non-pharmacologic interventions, both need to be individualized to the patient. PMID:21172570

  4. Multifunctional Role of Bcl-2 in Malignant Transformation and Tumorigenesis of Cr(VI)-Transformed Lung Cells

    PubMed Central

    Azad, Neelam; Wang, Liying; Jiang, Bing-Hua; Davis, Mary E.; Barnett, John B.; Guo, Lan; Rojanasakul, Yon

    2012-01-01

    B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI). PMID:22666341

  5. Telomerase Activation in Hematological Malignancies.

    PubMed

    Ropio, Joana; Merlio, Jean-Philippe; Soares, Paula; Chevret, Edith

    2016-01-01

    Telomerase expression and telomere maintenance are critical for cell proliferation and survival, and they play important roles in development and cancer, including hematological malignancies. Transcriptional regulation of the rate-limiting subunit of human telomerase reverse transcriptase gen (hTERT) is a complex process, and unveiling the mechanisms behind its reactivation is an important step for the development of diagnostic and therapeutic applications. Here, we review the main mechanisms of telomerase activation and the associated hematologic malignancies. PMID:27618103

  6. Inverted Sinonasal Papilloma Masquerading as a Malignancy - Report of an Unusual Case

    PubMed Central

    Sruthi, Ranganath; Anuthama, Krishnamurthy; Perumal, Mahendra; Parthasarathy, Ranganathan

    2016-01-01

    Inverted sinonasal papilloma (ISP) is a benign epithelial neoplasm arising from the Schneiderian membrane. We report a case of ISP in a 50-year-old male that clinically presented as a polypoid mass in the nasal cavity. Imaging studies revealed it to be an aggressive lesion showing intracranial extension. On histopathological examination of the excised specimen, a diagnosis of ISP was arrived at. However, an extensive sampling of the tissue revealed no evidence of any malignant transformation. Taking into account the suggested viral aetiology for such lesions and the aggressiveness observed in this case, human papillomavirus (HPV) profiling was done but it turned out to be negative. Only one other case of inverted sinonasal papilloma arising from the nasal cavity and involving the brain has been reported in the literature to date. Considering the alarming clinical course in spite of its benign nature, it is important for the pathologist and surgeon to be well informed about this lesion. PMID:27081587

  7. miR-148b-3p inhibits malignant biological behaviors of human glioma cells induced by high HOTAIR expression

    PubMed Central

    Wang, Guan; Li, Zhaohui; Tian, Nan; Han, Liang; Fu, Yao; Guo, Zhigang; Tian, Yu

    2016-01-01

    Increasing evidence suggests that long non coding (lnc)RNA and microRNA (miRNA/miR) both regulate the expression of key genes in tumorigenesis and have considerable theranostic potential. Rapid advances in bioinformatics indicate that miRNA may potentially interact with lncRNA to modulate their regulatory roles. miR-148b-3p has been reported to have a vital role in regulating tumor progression. However, the expression pattern of miR-148b-3p in glioma remains largely unknown, and interactions between miR-148b-3p and lncRNA has yet to be identified. The aim of the present study was to insight into the regulatory role of miR-148b-3p in glioma. Using online software, the HOTAIR gene was identified as a possible lncRNA target of miR-148b-3p in the present study. siRNA was used to suppress the expression of HOTAIR and reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-148b-3p. The results confirmed that HOTAIR mRNA expression was inversely correlated with miR-148b-3p expression in A172 glioma cells. Furthermore, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the viability of cells, flow cytometry was performed to test cell cycle and a matrigel invasion assay was performed to test cell invasion. The results showed that HOTAIR promotes factors associated with malignancy, including cell proliferation, cell cycle progression and invasion, whereas miR-148b-3p suppresses malignancy. Bioinformatics and luciferase reporter assays showed that miR-148b-3p modulates HOTAIR expression by directly targeting the HOTAIR gene sequence. In summary, the results indicated that miR-148b-3p inhibits malignant biological behaviors of glioma cells by directly targeting HOTAIR. The current data provide important evidence for understanding the key roles of the lncRNA miRNA functional network in glioma. PMID:27446363

  8. Artemether Combined with shRNA Interference of Vascular Cell Adhesion Molecule-1 Significantly Inhibited the Malignant Biological Behavior of Human Glioma Cells

    PubMed Central

    Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

    2013-01-01

    Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

  9. Non-AIDS definings malignancies among human immunodeficiency virus-positive subjects: Epidemiology and outcome after two decades of HAART era

    PubMed Central

    Brugnaro, Pierluigi; Morelli, Erika; Cattelan, Francesca; Petrucci, Andrea; Panese, Sandro; Eseme, Franklyn; Cavinato, Francesca; Barelli, Andrea; Raise, Enzo

    2015-01-01

    Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection has been widely available in industrialized countries since 1996; its widespread use determined a dramatic decline in acquired immunodeficiency syndrome (AIDS)-related mortality, and consequently, a significant decrease of AIDS-defining cancers. However the increased mean age of HIV-infected patients, prolonged exposure to environmental and lifestyle cancer risk factors, and coinfection with oncogenic viruses contributed to the emergence of other malignancies that are considered non-AIDS-defining cancers (NADCs) as a relevant fraction of morbidity and mortality among HIV-infected people twenty years after HAART introduction. The role of immunosuppression in the pathogenesis of NADCs is not well defined, and future researches should investigate the etiology of NADCs. In the last years there is a growing evidence that intensive chemotherapy regimens and radiotherapy could be safely administrated to HIV-positive patients while continuing HAART. This requires a multidisciplinary approach and a close co-operation of oncologists and HIV-physicians in order to best manage compliance of patients to treatment and to face drug-related side effects. Here we review the main epidemiological features, risk factors and clinical behavior of the more common NADCs, such as lung cancer, hepatocellular carcinoma, colorectal cancer and anal cancer, Hodgkin’s lymphoma and some cutaneous malignancies, focusing also on the current therapeutic approaches and preventive screening strategies. PMID:26279983

  10. Alterations in vitamin D signaling pathway in gastric cancer progression: a study of vitamin D receptor expression in human normal, premalignant, and malignant gastric tissue

    PubMed Central

    Wen, Yanghui; Da, Mingxu; Zhang, Yongbin; Peng, Lingzhi; Yao, Jibin; Duan, Yaoxing

    2015-01-01

    Amount of studies in cells and animal models have proved vitamin D has multifarious antitumor effects. However, epidemiological studies showed inconsistent result on gastric cancer. The antitumor role is mainly mediated by the vitamin D receptor (VDR). Our hypothesis is that VDR may be abnormally (poorly) expressed in gastric cancer tissue. Present study is aimed at discovering and analyzing VDR expression in a series of human gastric tissues, including normal, premalignant, and malignant gastric tissue, and correlated VDR to the clinicopathological parameters of gastric cancer patients. VDR expression was detected by immunohistochemistry. The χ2 test was used to analyze the VDR expression as well as the relationship between VDR and the clinicopathological factors of gastric cancer patients. Compared with normal (82.61%) and premalignant tissues (73.64%), VDR was lower expressed in cancer tissues (57.61%), with a statistically significant difference (P = 0.001). Among cancer tissues, VDR was higher expressed in well and moderate differentiated tissues contrasted with tissues with poor differentiation, and higher expressed in small tumors (< 5 cm) compared with large tumors (≥ 5 cm), with a statistically significant difference respectively (P = 0.016, P = 0.009). A decline linear trend appeared when analyzing the statistical difference of VDR expression among normal, premalignant, and malignant gastric tissues. VDR expression has been on the decline from the premalignant stage, finally low expressed in gastric cancer tissues, especial in poorly differentiated tissues. VDR could be a potential prognostic factor for patients with gastric cancer. PMID:26722516

  11. Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors

    PubMed Central

    de Paula Mariani, Beatriz Marinho; Trarbach, Ericka Barbosa; Ribeiro, Tamaya Castro; Pereira, Maria Adelaide Albergaria; Mendonca, Berenice Bilharinho; Fragoso, Maria Candida Barisson Villares

    2012-01-01

    OBJECTIVE: Endostatin is a potent endogenous inhibitor of angiogenesis. It is derived from the proteolytic cleavage of collagen XVIII, which is encoded by the COL18A1 gene. A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis. This polymorphism has been previously analyzed in many types of cancer and has been considered a phenotype modulator in some benign and malignant tumors. However, these data are controversial, and different results have been reported for the same tumor types, such as prostate and breast cancer. The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors. METHODS: DNA samples were obtained from 38 pediatric and 56 adult patients (0.6–75 yrs) with adrenocortical tumors. The DNA samples were obtained from peripheral blood, frozen tissue or paraffin-embedded tumor blocks when blood samples or fresh frozen tissue samples were unavailable. Restriction fragment length polymorphism analysis was used to genotype the patients and 150 controls. The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed. RESULTS: Both the patient group and the control group were in Hardy–Weinberg equilibrium. The frequencies of the p.D104N polymorphism in the patient group were 81.9% (DD), 15.9% (DN) and 2.2% (NN). In the controls, these frequencies were 80.6%, 17.3% and 2.0%, respectively. We did not observe any association of this variant with clinical or histopathological features or oncologic outcome in our cohort of pediatric and adult patients with adrenocortical tumors. PMID:22358232

  12. Prognostic role of miR-9 expression in various human malignant neoplasms: a meta-analysis

    PubMed Central

    Liu, Xiaodan; Luo, Ziyan; Peng, Hongxia; Jiang, Hua; Xu, Ling

    2016-01-01

    Emerging evidence has shown that aberrant microRNA expression has the potential to be used for predicting survival and treatment response of malignant neoplasms. In recent years, the role of miR-9 had been investigated in various types of cancers, and it was found that the results were inconsistent and inconclusive. Hence, in this study, a meta-analysis was conducted to assess the prognostic value of miR-9 in various types of tumors. Eligible studies were identified through a systematic search in PubMed and EMBASE and then were assessed by further quality evaluation. Pooled hazard ratios (HRs) with 95% confidence intervals for overall survival (OS) were calculated to investigate the association between miR-9 expression and cancer prognosis. The pooled results of eight published studies showed that elevated miR-9 was a predictor of poor survival of various carcinomas, with pooled HR of 3.04 (95% confidence interval: 1.96–4.73) for OS. Subgroup analysis on the basis of tumor type, sample size, and HR estimate also showed that high levels of miR-9 were also significantly correlated with OS. In addition, when the subgroup analyses were grouped by follow-up time, it was found that the elevated expression of miR-9 was associated with a lower long-term survival when the follow-up time was >60 months, but there was no correlation between the outcomes and those patients whose follow-up time was <60 months. Funnel plots and Egger’s tests revealed that there was no obvious publication bias risk in the meta-analysis. In conclusion, our results demonstrated that higher expression level of miR-9 significantly predicted worse OS in various carcinomas and that miR-9 may act as a novel biomarker in the prognosis of malignant neoplasms. PMID:27284255

  13. Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

    PubMed Central

    Luster, Troy A.; Mukherjee, Ipsita; Carrell, Jeffrey A.; Cho, Yun Hee; Gill, Jeffrey; Kelly, Lizbeth; Garcia, Andy; Ward, Christopher; Oh, Luke; Ullrich, Stephen J.; Migone, Thi-Sau; Humphreys, Robin

    2012-01-01

    B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. The biological activity of BLyS is mediated by three cell surface receptors: BR3/BAFF-R, TACI and BCMA. The expression of these receptors is highly restricted to B cells, both normal and malignant. A BLyS-gelonin fusion toxin (BLyS-gel) was generated consisting of the recombinant plant-derived toxin gelonin fused to the N-terminus of BLyS and tested against a large and diverse panel of B-NHL cell lines. Interestingly, B-NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with low picomolar EC50 values. BLyS receptor expression did not guarantee sensitivity to BLyS-gel, even though the construct was internalized by both sensitive and resistant cells. Resistance to BLyS-gel could be overcome by treatment with the endosomotropic drug chloroquine, suggesting BLyS-gel may become trapped within endosomal/lysosomal compartments in resistant cells. BLyS-gel induced cell death was caspase-independent and shown to be at least partially mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment was shown to localize to sites of disease, rapidly reduce tumor burden, and significantly prolong survival in xenograft mouse models of disseminated BCP-ALL, DLBCL, and MCL. Together, these findings suggest BLyS has significant potential as a targeting ligand for the delivery of cytotoxic “payloads” to malignant B cells. PMID:23056634

  14. Characterization of cancer stem cell properties of CD24 and CD26-positive human malignant mesothelioma cells

    SciTech Connect

    Yamazaki, Hiroto; Naito, Motohiko; Ghani, Farhana Ishrat; Dang, Nam H.; Morimoto, Chikao

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer We focused on CD24 and CD26 for further analysis of CSC properties in MM. Black-Right-Pointing-Pointer Their expressions were correlated with chemoresistance, cell growth, and invasion. Black-Right-Pointing-Pointer Their expressions were also correlated with several cancer related genes. Black-Right-Pointing-Pointer The expression of each marker was correlated with different CSC property in Meso1. Black-Right-Pointing-Pointer Phosphorylation of ERK by EGF was regulated by expression of CD26, but not CD24. -- Abstract: Malignant mesothelioma (MM) is an asbestos-related malignancy characterized by rapid growth and poor prognosis. In our previous study, we have demonstrated that several cancer stem cell (CSC) markers correlated with CSC properties in MM cells. Among these markers, we focused on two: CD24, the common CSC marker, and CD26, the additional CSC marker. We further analyzed the CSC properties of CD24 and CD26-positve MM cells. We established RNAi-knockdown cells and found that these markers were significantly correlated with chemoresistance, proliferation, and invasion potentials in vitro. Interestingly, while Meso-1 cells expressed both CD24 and CD26, the presence of each of these two markers was correlated with different CSC property. In addition, downstream signaling of these markers was explored by microarray analysis, which revealed that their expressions were correlated with several cancer-related genes. Furthermore, phosphorylation of ERK by EGF stimulation was significantly affected by the expression of CD26, but not CD24. These results suggest that CD24 and CD26 differentially regulate the CSC potentials of MM and could be promising targets for CSC-oriented therapy.

  15. Malignant thymoma.

    PubMed

    Wang, L S; Huang, M H; Lin, T S; Huang, B S; Chien, K Y

    1992-07-15

    Sixty-one patients underwent operations for malignant thymomas between 1961 and 1989. Twenty-three patients had associated myasthenia gravis (MG), an incidence of 37.7%. Upon being admitted to the hospital, the patients' most common symptoms included chest pain, MG, cough, and dyspnea. Only 7 of 61 (11.5%) patients had no symptom. Tumor staging of 58 patients with invasive thymomas was performed according to Masaoka classification. The patients were classified as follows: Stage II disease, 5; Stage III, 41; Stage IVa, 8; and Stage IVb, 4. In addition, thymic carcinoma was present in three patients. The series had a resection rate of 55.7%. The incidence of operative complications was 16.3%. Only one patient died of myocardial infarction; the incidence of operative mortality was 1.6%. The patients with MG had a higher rate of resection (69.6%) and a higher incidence of complete thymectomy (14 of 23 patients; 60.9%). Mixed lymphoepithelial tumors and epithelial cell predominant tumors were the most frequent histologic patterns (45.9% and 34.4%, respectively). Fifty-two patients had postoperative radiation therapy, and 10 patients had chemotherapy. The overall cumulative survival rates in the series were 59% and 34% at 5 and 10 years, respectively. The results demonstrated that the factors affecting the prognosis may include resectability, postoperative irradiation or chemotherapy, MG, and tumor staging. The influence of histologic variation on survival rates could not be clearly defined in the series. Surgical resection, particularly complete thymectomy, followed by irradiation is the primary option of therapeutic management for malignant thymoma. PMID:1617594

  16. Spontaneous malignant craniopharyngioma in an aged Wistar rat

    PubMed Central

    Heinrichs, Martin; Ernst, Heinrich

    2016-01-01

    Craniopharyngiomas are extremely rare epithelial tumors of the sellar region in human beings and domestic and laboratory animals. A craniopharyngioma, 0.6 cm in diameter, was observed grossly in the sellar and parasellar regions of an untreated 23-month-old male Wistar-derived rat sacrificed moribund. The tumor was composed of cords, columns, and nests of neoplastic stratified squamous epithelium with marked hyperkeratosis and parakeratosis. Neoplastic cells formed solid or cystic areas, infiltrating the base of the skull, brain, and pituitary gland. Immunocytochemical evaluation revealed a strong cytoplasmic reaction for pan-cytokeratin in all tumor cells. Malignant craniopharyngioma should be considered a differential diagnosis in the rat when a tumor with stratified squamous epithelial features and a locally aggressive growth pattern is observed in the sellar or suprasellar region. PMID:27559246

  17. Spontaneous malignant craniopharyngioma in an aged Wistar rat.

    PubMed

    Heinrichs, Martin; Ernst, Heinrich

    2016-07-01

    Craniopharyngiomas are extremely rare epithelial tumors of the sellar region in human beings and domestic and laboratory animals. A craniopharyngioma, 0.6 cm in diameter, was observed grossly in the sellar and parasellar regions of an untreated 23-month-old male Wistar-derived rat sacrificed moribund. The tumor was composed of cords, columns, and nests of neoplastic stratified squamous epithelium with marked hyperkeratosis and parakeratosis. Neoplastic cells formed solid or cystic areas, infiltrating the base of the skull, brain, and pituitary gland. Immunocytochemical evaluation revealed a strong cytoplasmic reaction for pan-cytokeratin in all tumor cells. Malignant craniopharyngioma should be considered a differential diagnosis in the rat when a tumor with stratified squamous epithelial features and a locally aggressive growth pattern is observed in the sellar or suprasellar region. PMID:27559246

  18. The Origin of Malignant Malaria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasmodium falciparum is the causative agent of malignant malaria, which is among the most severe human infectious diseases. Despite its overwhelming significance to human health, the parasite’s origins remain unclear. The favored origin hypothesis holds that P. falciparum and its closest known rel...

  19. Linkages between Aggression and Children's Legitimacy of Aggression Beliefs.

    ERIC Educational Resources Information Center

    Erdley, Cynthia A.; Asher, Steven R.

    To determine whether Slaby and Guerra's (1988) measure of aggression would reliably assess younger children's belief about aggression and whether children's belief about the legitimacy of aggression relates to their self-reports of it and to their levels of aggression as evaluated by peers, 781 fourth and fifth graders were asked to complete an…

  20. Aggressive Attitudes Predict Aggressive Behavior in Middle School Students.

    ERIC Educational Resources Information Center

    McConville, David W.; Cornell, Dewey G.

    2003-01-01

    This prospective study found that self-reported attitudes toward peer aggression among 403 middle school students were both internally consistent and stable over time (7 months). Aggressive attitudes were correlated with four outcome criteria for aggressive behavior: student self-report of peer aggression; peer and teacher nominations of bullying;…

  1. Aggression in Pretend Play and Aggressive Behavior in the Classroom

    ERIC Educational Resources Information Center

    Fehr, Karla K.; Russ, Sandra W.

    2013-01-01

    Research Findings: Pretend play is an essential part of child development and adjustment. However, parents, teachers, and researchers debate the function of aggression in pretend play. Different models of aggression predict that the expression of aggression in play could either increase or decrease actual aggressive behavior. The current study…

  2. Oral malignant melanomas and other head and neck neoplasms in Danish dogs - data from the Danish Veterinary Cancer Registry

    PubMed Central

    2009-01-01

    Background Head and neck cancers (HNC) are relatively common and often very serious diseases in both dogs and humans. Neoplasms originating in the head and neck region are a heterogeneous group. HNC often has an unfavourable prognosis and the proximity of the tissue structures renders extirpation of tumours with sufficient margins almost incompatible with preservation of functionality. In humans oral malignant melanoma (OMM) is extremely rare, but represents a particular challenge since it is highly aggressive as is the canine counterpart, which thus may be of interest as a spontaneous animal model. Methods Canine cases entered in the Danish Veterinary Cancer Registry (DVCR) from May 15th 2005 through February 29th 2008 were included in this study. Fisher's exact test was used to compare proportions of HNC in dogs and humans as well as proportions of surgically treated cases of OMM and squamous cell carcinomas (SCC). Also the proportions of benign and malignant neoplasms of different locations in dogs were compared using Fisher's exact test. Results A total of 1768 cases of neoplasias (679 malignant, 826 benign, 263 unknown) were submitted. Of all neoplasias HNC accounted for 7.2% (n = 128). Of these, 64 (50%) were malignant and 44 (34%) benign. The most common types of malignant neoplasia were SCC (18; 28% of malignant), OMM (13; 20% of malignant), soft tissue sarcoma (11; 17% of malignant) and adenocarcinoma (5; 11% of malignant). The most common types of benign neoplasms were adenoma (7; 16% of benign), polyps (6; 14% of benign) and fibroma (5; 11% of benign). Conclusions In the current study, the proportion of neoplasia in the head and neck region in dogs in Denmark was similar to other canine studies and significantly more common than in humans with a large proportion of malignancies. Spontaneous HNC in dogs thus, may serve as a model for HNC in humans. Canine OMM is a spontaneous cancer in an outbred, immune-competent large mammal population and could be a

  3. Simultaneous estimation of size, radial and angular locations of a malignant tumor in a 3-D human breast - A numerical study.

    PubMed

    Das, Koushik; Mishra, Subhash C

    2015-08-01

    This article reports a numerical study pertaining to simultaneous estimation of size, radial location and angular location of a malignant tumor in a 3-D human breast. The breast skin surface temperature profile is specific to a tumor of specific size and location. The temperature profiles are always the Gaussian one, though their peak magnitudes and areas differ according to the size and location of the tumor. The temperature profiles are obtained by solving the Pennes bioheat equation using the finite element method based solver COMSOL 4.3a. With temperature profiles known, simultaneous estimation of size, radial location and angular location of the tumor is done using the curve fitting method. Effect of measurement errors is also included in the study. Estimations are accurate, and since in the inverse analysis, the curve fitting method does not require solution of the governing bioheat equation, the estimation is very fast. PMID:26267509

  4. Establishment of a human malignant fibrous histiocytoma cell line, COMA. Characterization By conventional cytogenetics, comparative genomic hybridization, and multiplex fluorescence In situ hybridization.

    PubMed

    Mairal, A; Chibon, F; Rousselet, A; Couturier, J; Terrier, P; Aurias, A

    2000-09-01

    The human COMA cell line has been established from a storiform pleomorphic malignant fibrous histiocytoma (MFH). As expected for this tumor type, a very complex karyotype was observed after R-banding analysis. An extensive analysis by 24-color painting, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) was performed. Twelve complex marker chromosomes recurrently observed were clearly identified; among them, three were systematically present in all analyzed metaphases. Amplifications detected by CGH were refined by FISH with probes specific for various candidate loci. A significant aneuploidy and numerous micronuclei were observed, which could be related to the anomalies of centriole numbers detected in a proportion of cells. Such an analysis, performed on a series of MFH cell lines, would allow the delineation of the genomic alterations specific for the oncogenesis or progression of this complex tumor type or both. PMID:11063793

  5. Chemotherapy and targeted agents for thymic malignancies.

    PubMed

    Girard, Nicolas

    2012-05-01

    Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat. Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection. However, nearly 30% of patients present with locally advanced tumors at time of diagnosis, and chemotherapy is then used to reduce the tumor burden, possibly allowing subsequent surgery and/or radiotherapy. Metastatic and recurrent thymic malignancies may similarly be treated with chemotherapy. More recently, the molecular characterization of thymoma and thymic carcinoma led to the identification of potentially druggable targets, laying the foundations to implement personalized medicine for patients. PMID:22594902

  6. 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.

  7. Is metastatic pancreatic cancer an untargetable malignancy?

    PubMed Central

    Kourie, Hampig Raphael; Gharios, Joseph; Elkarak, Fadi; Antoun, Joelle; Ghosn, Marwan

    2016-01-01

    Metastatic pancreatic cancer (MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies (TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC. PMID:26989465

  8. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders

    SciTech Connect

    Tommerup, N.; Vissing, H.

    1995-05-20

    The authors have isolated and chromosomally fine-mapped 16 novel genes belonging to the human zinc finger Krueppel family (ZNF131-140, 142, 143, 148, 151, 154, and 155), including 1 of the GLI type (ZNF143) and 3 containing a KRAB (Krueppel-associated box) segment (ZNF133, 136, and 140). Based on their map position, several of these ZNF genes are putative candidate genes for both developmental and malignant disorders: ZNF138, ZNF139, and ZNF143 were localized to 7q11.2, 7q21.3-q22.1, and 11p15.3-p15.4, regions involved in deletions and/or translocations associated with Williams syndrome, split hand and foot disease (SHFD1), and Beckwith-Wiedemann syndrome, respectively. ZNF133 was localized to 20p11.2, close to, but probably distinct from, the region deleted in Alagille syndrome. Zinc finger genes mapping to regions commonly deleted in solid tumors included ZNF132, 134, 135, 137, 154, and 155, all located on 19q13 (thyroid adenoma), and ZNF151, at 1p36.1-p36.2 (neuroblastoma, colon cancer, and other tumors). In addition, several of the ZNFs mapped to regions implicated in recurrent chromosomal rearrangements in hematological malignancies (ZNF139, 7q21.3-q22.1; ZNF148, 3q21-q22; ZNF151, 1p36.1-p36.2). The study indicates that the number of ZNF genes in human is large and that systematic isolation and mapping of ZNF genes is a straightforward approach for the identification of novel candidate disease genes. 47 refs., 2 figs., 1 tab.

  9. Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.

    PubMed

    Reber, U; Wüllner, U; Trepel, M; Baumgart, J; Seyfried, J; Klockgether, T; Dichgans, J; Weller, M

    1998-02-01

    Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan. PMID:9484802

  10. Quantitative expression analysis and study of the novel human kallikrein-related peptidase 14 gene (KLK14) in malignant and benign breast tissues.

    PubMed

    Papachristopoulou, Georgia; Avgeris, Margaritis; Charlaftis, Antonios; Scorilas, Andreas

    2011-01-01

    Human kallikrein-related peptidase 14 gene (KLK14) is regulated by androgens and progestins. This gene is expressed in the central nervous system and endocrine tissues such as the breast, prostate and ovary. The differential KLK14 mRNA expression levels are related to several human neoplasias, among them breast cancer. The aim of this study was to analyse the KLK14 expression in breast tissues and to investigate its differential diagnostic and prognostic value in the mammary carcinomas. For this purpose, we isolated total RNA from 70 malignant and 33 benign specimens. After testing RNA quality, we synthesised cDNA by reverse transcription and applied a highly sensitive quantitative real-time PCR (qRT-PCR) method for KLK14 mRNA quantification using the SYBR Green® chemistry. HPRT1 was used as a reference gene and the BT20 breast cancer cell line as a calibrator. Relative quantification analysis was performed using the comparative CT method 2-ΔΔCT. KLK14 expression was detected in both types of breast tumours. However, a statistically significant increase of the KLK14 mRNA level was observed in the malignant, compared to the benign tumour samples (p<0.001), highlighting its value in discriminating these breast lesions. Elevated KLK14 expression profiles were associated with higher tumour grade (p=0.043) and size (p=0.007) in cancerous samples. Furthermore, KLK14 mRNA expression showed negative correlation in a statistically significant manner with estrogen receptor status (p=0.024). In accordance with logistic regression models (p=0.012) and receiver-operating-characteristics analysis (p<0.001), KLK14 gene expression could be evaluated as a putative independent diagnostic biomarker in breast tumour biopsies. PMID:21057706

  11. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    PubMed Central

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2015-01-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. PMID:25448439

  12. Exposure to the polyester PET precursor—terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells

    PubMed Central

    Luciani-Torres, Maria Gloria; Moore, Dan H.; Dairkee, Shanaz H.

    2015-01-01

    Identification of early perturbations induced in cells from non-cancerous breast tissue is critical for understanding possible breast cancer risk from chemical exposure. We have demonstrated previously that exposure to the ubiquitous xenoestrogens, bisphenol A (BPA) and methyl paraben, promotes the hallmarks of cancer in non-malignant human high-risk donor breast epithelial cells (HRBECs) isolated from several donors. Here we show that terephthalic acid (TPA), a major chemical precursor of polyethylene terephthalate (PET) containers used for the storage of food and beverages, increased the ERα: ERβ ratio in multiple HRBEC samples, suggesting an estrogenic effect. Although, like BPA and methyl paraben, TPA also promoted resistance to tamoxifen-induced apoptosis, unlike these chemicals instead of inducing an increased S-phase fraction, TPA treatment arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated indicating induction of DNA strand breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-: pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53pSer15 and H2AXpSer139, indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The propensity for the perpetuation of DNA aberrations that activate DNA damage pathways in non-malignant breast cells justifies careful consideration of human exposure to TPA, particularly at vulnerable life stages. PMID:25411358

  13. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    SciTech Connect

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  14. Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines.

    PubMed

    Jane, Esther P; Premkumar, Daniel R; Cavaleri, Jonathon M; Sutera, Philip A; Rajasekar, Thatchana; Pollack, Ian F

    2016-02-01

    The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-[4,5-dimethylthiazol- 2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263 (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide) or ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor

  15. Aggression and Anxiety: Social Context and Neurobiological Links

    PubMed Central

    Neumann, Inga D.; Veenema, Alexa H.; Beiderbeck, Daniela I.

    2009-01-01

    Psychopathologies such as anxiety- and depression-related disorders are often characterized by impaired social behaviours including excessive aggression and violence. Excessive aggression and violence likely develop as a consequence of generally disturbed emotional regulation, such as abnormally high or low levels of anxiety. This suggests an overlap between brain circuitries and neurochemical systems regulating aggression and anxiety. In this review, we will discuss different forms of male aggression, rodent models of excessive aggression, and neurobiological mechanisms underlying male aggression in the context of anxiety. We will summarize our attempts to establish an animal model of high and abnormal aggression using rats selected for high (HAB) vs. low (LAB) anxiety-related behaviour. Briefly, male LAB rats and, to a lesser extent, male HAB rats show high and abnormal forms of aggression compared with non-selected (NAB) rats, making them a suitable animal model for studying excessive aggression in the context of extremes in innate anxiety. In addition, we will discuss differences in the activity of the hypothalamic–pituitary–adrenal axis, brain arginine vasopressin, and the serotonin systems, among others, which contribute to the distinct behavioural phenotypes related to aggression and anxiety. Further investigation of the neurobiological systems in animals with distinct anxiety phenotypes might provide valuable information about the link between excessive aggression and disturbed emotional regulation, which is essential for understanding the social and emotional deficits that are characteristic of many human psychiatric disorders. PMID:20407578

  16. Reducing proactive aggression through non-invasive brain stimulation.

    PubMed

    Dambacher, Franziska; Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T

    2015-10-01

    Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders. PMID:25680991

  17. Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen.

    PubMed

    Wang, Q; Li, D-C; Li, Z-F; Liu, C-X; Xiao, Y-M; Zhang, B; Li, X-D; Zhao, J; Chen, L-P; Xing, X-M; Tang, S-F; Lin, Y-C; Lai, Y-D; Yang, P; Zeng, J-L; Xiao, Q; Zeng, X-W; Lin, Z-N; Zhuang, Z-X; Zhuang, S-M; Chen, W

    2011-09-01

    The introduction of the Simian virus 40 (SV40) early region, the telomerase catalytic subunit (hTERT) and an oncogenic allele of H-Ras directly transforms primary human cells. SV40 small T antigen (ST), which forms a complex with protein phosphatase 2A (PP2A) and inhibits PP2A activity, is believed to have a critical role in the malignant transformation of human cells. Recent evidence has shown that aberrant microRNA (miRNA) expression patterns are correlated with cancer development. Here, we identified miR-27a as a differentially expressed miRNA in SV40 ST-expressing cells. miR-27a is upregulated in SV40 ST-transformed human bronchial epithelial cells (HBERST). Suppression of miR-27a expression in HBERST cells or lung cancer cell lines (NCI-H226 and SK-MES-1) that exhibited high levels of miR-27a expression lead to cell growth arrested in the G(0)-G(1) phase. In addition, suppression of miR-27a in HBERST cells attenuated the capacity of such cells to grow in an anchorage-independent manner. We also found that suppression of the PP2A B56γ expression resulted in upregulation of miR-27a similar to that achieved by the introduction of ST, indicating that dysregulation of miR-27a expression in ST-expressing cells was mediated by the ST-PP2A interaction. Moreover, we discovered that Fbxw7 gene encoding F-box/WD repeat-containing protein 7 was a potential miR-27a target validated by dual-luciferase reporter system analysis. The inverse correlation between miR-27a expression levels and Fbxw7 protein expression was further confirmed in both cell models and human tumor samples. Fbxw7 regulates cell-cycle progression through the ubiquitin-dependent proteolysis of a set of substrates, including c-Myc, c-Jun, cyclin E1 and Notch 1. Thus, promotion of cell growth arising from the suppression of Fbxw7 by miR-27a overexpression might be responsible for the viral oncoprotein ST-induced malignant transformation. These observations demonstrate that miR-27a functions as an oncogene

  18. Up-regulation of PKM2 promote malignancy and related to adverse prognostic risk factor in human gallbladder cancer

    PubMed Central

    Lu, Wei; Cao, Yang; Zhang, Yijian; Li, Sheng; Gao, Jian; Wang, Xu-An; Mu, Jiasheng; Hu, Yun-Ping; Jiang, Lin; Dong, Ping; Gong, Wei; Liu, Yingbin

    2016-01-01

    Recently, pyruvate kinase M2 (PKM2) has been implicated in the progression of certain cancers and might play pivotal roles in the formation of malignancy. However, the role of PKM2 in gallbladder cancer had not been well investigated. This study analyzed associations between PKM2 expression status with various clinical and pathologic parameters in a large cohort of gallbladder cancer (GBC) patients from a long term follow up results. The expression level of pyruvate kinase isotypes in GBC tissues and their adjacent normal gallbladder tissues were estimated by qRT-PCR and Western blot. PKM2 mRNA level were significantly high in gallbladder cancer tissues than in adjacent noncancerous tissues (P < 0.001). High expression of the PKM2 was detected in 55.71% paraffin-embedded GBC tissue. The high PKM2 expression was independently associated with poorer overall survival in patients with GBC (median survival 11.9 vs 30.1 months; hazard ratio 2.79; 95% CI = 1.18 to 6.55; P = 0.02). These findings indicated elevated expression of PKM2 is a prognostic factor for poor GBC clinical outcomes, implied involving of PKM2 in GBC progression. PMID:27283076

  19. Hypothesis: exertional heat stroke-induced myopathy and genetically inherited malignant hyperthermia represent the same disorder, the human stress syndrome.

    PubMed

    Zhao, Xuesheng; Song, Qing; Gao, Yan

    2014-11-01

    Exertional heat stroke is usually experienced as a result of a prolonged and intensive exercise. It is a life-threatening condition that is characterized by an increase in core body temperature and rhabdomyolysis. The associated hyperkalemia and metabolic acidosis may lead to an acute renal, cardiac, and hemostatic failure. Exactly, the same symptoms are noticed in case of the anesthesia-induced malignant hyperthermia (MH), an inherited disorder of the skeletal muscle ryanodine receptor. This receptor is a Ca(2+) channel that is activated by the volatile anesthetic agents and depolarizing muscle relaxant. The presence of MH-associated ryanodine receptor variant in the individuals who suffered from EH and improvement of the symptoms with dantrolene has frequently raised the question as to whether the two disorders actually represent one and the same disease. Nevertheless, an exact explanation of the susceptibility of the genetically predisposed MH individuals to ER remains elusive. We have attempted to review the published clinical reports to explore the possibility that ER and EH represent one and the same disorder. PMID:24948473

  20. Novel Photosensitizers Trigger Rapid Death of Malignant Human Cells and Rodent Tumor Transplants via Lipid Photodamage and Membrane Permeabilization

    PubMed Central

    Moisenovich, Mikhail M.; Ol'shevskaya, Valentina A.; Rokitskaya, Tatyana I.; Ramonova, Alla A.; Nikitina, Roza G.; Tatarskiy, Victor V.; Kaplan, Mikhail A.; Kalinin, Valery N.; Kotova, Elena A.; Uvarov, Oleg V.; Agapov, Igor I.; Antonenko, Yuri N.; Shtil, Alexander A.

    2010-01-01

    Background Apoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities. Methodology/Principal Findings Our novel derivatives of chlorin e6, that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e6 against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 µM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3–4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e6 in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump-induced relaxation of transmembrane current on planar lipid bilayers. Conclusions/Significance The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with

  1. Malignant hyperpyrexia

    PubMed Central

    Isaacs, Hyam; Barlow, M. B.

    1973-01-01

    The history, clinical presentation, and management of malignant hyperpyrexia are presented. The aetiology seems to be associated with some inherited abnormality which affects the movement and binding of calcium ions in the sarcoplasmic reticulum, sarcoplasm, and mitochondria. Whether this is a primary muscular defect or secondary to some trophic neural influence is yet to be established. The subjects carrying the abnormal trait show evidence of a myopathy which is subclinical in most instances and revealed only by estimation of serum CPK or biopsy. In some families where the myopathy is clinically obvious there may be, in addition, a variety of musculoskeletal abnormalities. A plea is made for routine monitoring of temperature during anaesthesia and for procainamide or procaine to be readily available in all operating theatres. A history of anaesthetic deaths in a family calls for special care, and, if the serum CPK is elevated, suxamethonium and halothane are to be avoided. Families with orthopaedic and muscular abnormalities are at increased risk and should have estimation of serum CPK before surgery. As a bonus of this study it is suggested that serum CPK estimations be used to screen pigs for selective breeding and so eliminate the disease, which causes soft exudative pork. Images PMID:4708457

  2. The role of ion channels in the hypoxia-induced aggressiveness of glioblastoma

    PubMed Central

    Sforna, Luigi; Cenciarini, Marta; Belia, Silvia; D’Adamo, Maria Cristina; Pessia, Mauro; Franciolini, Fabio; Catacuzzeno, Luigi

    2015-01-01

    The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca2+ concentration, ultimately leading to cell proliferation, migration or death. In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors. PMID:25642170

  3. [Malignant Pleural Mesotheliomas].

    PubMed

    Biancosino, C; Redwan, B; Krüger, M; Eberlein, M; Bölükbas, S

    2016-09-01

    Malignant pleural mesotheliomas (MPM) are very aggressive tumors, which originate from the mesothelial cells of the pleural surface. The main risk factor associated with MPM is exposure to asbestos. The latency period between asbestos exposure and MPM can be 30-60 years. Clinical symptoms and signs are often nonspecifc. The diagnosis of MPM requires an adequate tissue specimen for pathological examination, and video assisted thoracoscopic surgey (VATS) is associated with the highest diagnostic yield. MPM are histologically classified into epitheloid, sacromatoid and biphasic (mixed) sub-types. Accurate staging with invasive tests, if needed, is an important step before an interdisciplinary team can decide on an optimal (multi-modal) treatment approach. A multi-modal treatment approach (surgery, radiation oncology and chemotherapy) is superior to all approaches relying only on a single modality, if the patient qualifies for it from an oncological and functional standpoint. The goal of the surgical therapy is to achieve macroscopic complete resection. There are two competing surgical approaches and philosophies: extrapleural pneumonectomy (EPP) and radical pleurectomy (RP). Over the last years a paradigm shift from EPP to RP occurred and RP is now often the preferred surgical option. PMID:27612329

  4. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326

    PubMed Central

    Ke, Jing; Yao, Yi-long; Zheng, Jian; Wang, Ping; Liu, Yun-hui; Ma, Jun; Li, Zhen; Liu, Xiao-bai; Li, Zhi-qing; Wang, Zhen-hua; Xue, Yi-xue

    2015-01-01

    Glioma is the most common and aggressive primary adult brain tumor. Long non-coding RNAs (lncRNAs) have important roles in a variety of biological properties of cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA HOTAIR in human glioma U87 and U251 cell lines. Quantitative RT-PCR demonstrated that HOTAIR expression was up-regulated in glioma tissues and cell lines. Knockdown of HOTAIR exerted tumor-suppressive function in glioma cells. Further, HOTAIR was confirmed to be the target of miR-326 and miR-326 mediated the tumor-suppressive effects of HOTAIR knockdown on glioma cell lines. Moreover, over-expressed miR-326 reduced the FGF1 expression which played an oncogenic role in glioma by activating PI3K/AKT and MEK 1/2 pathways. In addition, the in vivo studies also supported the above findings. Taken together, knockdown of HOTAIR up-regulated miR-326 expression, and further inducing the decreased expression of FGF1, these results provided a comprehensive analysis of HOTAIR-miR-326-FGF1 axis in human glioma and provided a new potential therapeutic strategy for glioma treatment. PMID:26183397

  5. Asbestos-related malignancy

    SciTech Connect

    Talcott, J.A.; Antman, K.H.

    1988-05-01

    Asbestos-associated malignancies have received significant attention in the lay and medical literature because of the increasing frequency of two asbestos-associated tumors, lung carcinoma and mesothelioma; the wide distribution of asbestos; its status as a prototype environmental carcinogen; and the many recent legal compensation proceedings, for which medical testimony has been required. The understanding of asbestos-associated carcinogenesis has increased through study of animal models, human epidemiology, and, recently, the application of modern molecular biological techniques. However, the detailed mechanisms of carcinogenesis remain unknown. A wide variety of malignancies have been associated with asbestos, although the strongest evidence for a causal association is confined to lung cancer and mesothelioma. Epidemiological studies have provided evidence that both the type of asbestos fiber and the industry in which the exposure occurs may affect the rates of asbestos-associated cancers. It has been shown that asbestos exerts a carcinogenic effect independent of exposure to cigarette smoking that, for lung cancers, is synergistically enhanced by smoking. Other questions remain controversial, such as whether pulmonary fibrosis necessarily precedes asbestos-associated lung cancer and whether some threshold level of exposure to asbestos (including low-dose exposures that may occur in asbestos-associated public buildings) may be safe. Mesothelioma, the most closely asbestos-associated malignancy, has a dismal natural history and has been highly resistant to therapy. However, investigational multi-modality therapy may offer benefit to some patients. 179 references.

  6. Female competition and aggression: interdisciplinary perspectives

    PubMed Central

    Stockley, Paula; Campbell, Anne

    2013-01-01

    This paper introduces a Theme Issue combining interdisciplinary perspectives in the study of female competition and aggression. Despite a history of being largely overlooked, evidence is now accumulating for the widespread evolutionary significance of female competition. Here, we provide a synthesis of contributions to this Theme Issue on humans and other vertebrates, and highlight directions for future research. Females compete for resources needed to survive and reproduce, and for preferred mates. Although female aggression takes diverse forms, under most circumstances relatively low-risk competitive strategies are favoured, most probably due to constraints of offspring production and care. In social species, dominance relationships and threats of punishment can resolve social conflict without resort to direct aggression, and coalitions or alliances may reduce risk of retaliation. Consistent with these trends, indirect aggression is a low cost but effective form of competition among young women. Costs are also minimized by flexibility in expression of competitive traits, with aggressive behaviour and competitive signalling tailored to social and ecological conditions. Future research on female competition and the proximate mediators of female aggression will be greatly enhanced by opportunities for interdisciplinary exchange, as evidenced by contributions to this Theme Issue. PMID:24167303

  7. A benign maxillary tumour with malignant features.

    PubMed

    Ricalde, Rosario R; Lim, Aimee Caroline E; Lopa, Ramon Antonio B; Carnate, Jose M

    2010-06-01

    Non-specific biopsy results such as chronic inflammation, hemorrhage, necrosis can be frustrating to the clinician. This is especially true if the patient presents with clinical features suggestive of an aggressive tumour. This is a review of the clinical features, diagnostic dilemmas and surgical management of a benign maxillary mass with malignant features - a disease called hematoma-like mass of the maxillary sinus (HLMMS). Our experience with five cases will also be cited. PMID:20502750

  8. MicroRNA dependent regulation of DNMT-1 and tumor suppressor gene expression by Interleukin-6 in human malignant cholangiocytes

    PubMed Central

    Braconi, Chiara; Huang, Nianyuan; Patel, Tushar

    2014-01-01

    Although the inflammation-associated cytokine Interleukin-6 (IL-6) has been implicated in cholangiocarcinoma growth, the relationship between IL-6 and oncogenic changes is unknown. IL-6 can increase expression of DNA methyltransferase 1 (DNMT-1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs). DNMT-1 up-regulation occurs in hepatobiliary cancers and is associated with a poor prognosis. To understand the potential regulation of DNMT-1 by IL-6 dependent miRNAs, we examined the expression of a group of miRNAs which have sequence complementarity to the 3′-UTR of DNMT-1, namely miR-148a, miR-152 and miR-301. The expression of these miRNAs was decreased in cholangiocarcinoma cells. Moreover, the expression of all three miRNAs was decreased in IL-6 over-expressing malignant cholangiocytes in vitro and in tumor cell xenografts. There was a concomitant decrease in expression of the methylation-sensitive tumor suppressor genes Rassf1a, and p16INK4a. Using luciferase reporter constructs, DNMT-1 was verified as a target for miR-148a and miR-152. Precursors to miR-148a and miR-152 decreased DNMT-1 protein expression, increased Rassf1a and p16INK4a expression and reduced cell proliferation. Conclusion These data indicate that IL-6 can regulate the activity of DNMT-1 and expression of methylation-dependent tumor suppressor genes by modulation of miR-148a and miR-152, and provide a link between this inflammation-associated cytokines and oncogenesis in cholangiocarcinoma. PMID:20146264

  9. Radioimmunotherapy of malignancies

    SciTech Connect

    Reilly, R.M. )

    1991-05-01

    The critical issues in radioimmunotherapy are highlighted, and novel ways of improving the therapeutic indexes of radioimmunotherapeutic agents are outlined. The use of radioactively labeled monoclonal antibodies to treat malignant tumors has been investigated in animals and humans. Radionuclides suitable for labeling antibodies for such use include iodine 125, iodine 131, yttrium 90, rhenium 188, and copper 67. Radiobiological factors to be considered in radioimmunotherapy include the size and density of the tumor and the ability of a radiolabeled antibody to penetrate the tumor nodule. The dose of radiation required to destroy a tumor varies; however, the whole-body dose must not exceed 200 rads to avoid irreversible toxicity to the bone marrow. Despite the theoretical inadequacy of radiation doses to tumors indicated by conventional dosimetry, responses have been observed in animals and humans. More reliable and accurate dosimetric methods are under development. The induction of human antimouse antibodies can alter the pharmacokinetics of radiolabeled antibodies. Improving the therapeutic index of radioimmunotherapeutic agents may be achieved through regional therapy, administering a secondary antibody to improve clearance, combining radioimmunotherapy with external-beam irradiation, using an avidin-biotin conjugate system to deliver the radiolabeled antibodies, and addressing the problem of tumor antigen heterogeneity. Researchers are working to reduce or eliminate the clinical problems associated with radioimmunotherapy. Hematologic malignancies, such as lymphomas, are more likely than solid tumors to respond satisfactorily. 110 refs.

  10. Contribution of Soft Substrates to Malignancy and Tumor Suppression during Colon Cancer Cell Division

    PubMed Central

    Rabineau, Morgane; Kocgozlu, Leyla; Dujardin, Denis; Senger, Bernard; Haikel, Youssef; Voegel, Jean-Claude; Freund, Jean-Noel; Schaaf, Pierre; Lavalle, Philippe; Vautier, Dominique

    2013-01-01

    In colon cancer, a highly aggressive disease, progression through the malignant sequence is accompanied by increasingly numerous chromosomal rearrangements. To colonize target organs, invasive cells cross several tissues of various elastic moduli. Whether soft tissue increases malignancy or in contrast limits invasive colon cell spreading remains an open question. Using polyelectrolyte multilayer films mimicking microenvironments of various elastic moduli, we revealed that human SW480 colon cancer cells displayed increasing frequency in chromosomal segregation abnormalities when cultured on substrates with decreasing stiffness. Our results show that, although decreasing stiffness correlates with increased cell lethality, a significant proportion of SW480 cancer cells did escape from the very soft substrates, even when bearing abnormal chromosome segregation, achieve mitosis and undergo a new cycle of replication in contrast to human colonic HCoEpiC cells which died on soft substrates. This observation opens the possibility that the ability of cancer cells to overcome defects in chromosome segregation on very soft substrates could contribute to increasing chromosomal rearrangements and tumor cell aggressiveness. PMID:24167628

  11. Endothelial NOS, estrogen receptor β, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer

    PubMed Central

    Nanni, Simona; Benvenuti, Valentina; Grasselli, Annalisa; Priolo, Carmen; Aiello, Aurora; Mattiussi, Stefania; Colussi, Claudia; Lirangi, Vittoria; Illi, Barbara; D’Eletto, Manuela; Cianciulli, Anna Maria; Gallucci, Michele; De Carli, Piero; Sentinelli, Steno; Mottolese, Marcella; Carlini, Paolo; Strigari, Lidia; Finn, Stephen; Mueller, Elke; Arcangeli, Giorgio; Gaetano, Carlo; Capogrossi, Maurizio C.; Donnorso, Raffaele Perrone; Bacchetti, Silvia; Sacchi, Ada; Pontecorvi, Alfredo; Loda, Massimo; Farsetti, Antonella

    2009-01-01

    The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor β (ERβ). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERβ/eNOS, ERβ/HIF-1α, or ERβ/HIF-2α combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERβ and nuclear eNOS plus HIF-2α being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERβ, and HIF-2α expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases. PMID:19363294

  12. Adolescents’ Aggression to Parents: Longitudinal Links with Parents’ Physical Aggression

    PubMed Central

    Margolin, Gayla; Baucom, Brian R.

    2014-01-01

    Purpose To investigate whether parents’ previous physical aggression (PPA) exhibited during early adolescence is associated with adolescents’ subsequent parent-directed aggression even beyond parents’ concurrent physical aggression (CPA); to investigate whether adolescents’ emotion dysregulation and attitudes condoning child-to-parent aggression moderate associations. Methods Adolescents (N = 93) and their parents participated in a prospective, longitudinal study. Adolescents and parents reported at waves 1–3 on four types of parents’ PPA (mother-to-adolescent, father-to-adolescent, mother-to-father, father-to-mother). Wave 3 assessments also included adolescents’ emotion dysregulation, attitudes condoning aggression, and externalizing behaviors. At waves 4 and 5, adolescents and parents reported on adolescents’ parent-directed physical aggression, property damage, and verbal aggression, and on parents’ CPA Results Parents’ PPA emerged as a significant indicator of adolescents’ parent-directed physical aggression (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.0–1.55; p = .047), property damage (OR: 1.29, 95% CI: 1.1–1.5, p = .002), and verbal aggression (OR: 1.35, 95% CI: 1.15–1.6, p < .001) even controlling for adolescents’ sex, externalizing behaviors, and family income. When controlling for parents’ CPA, previous mother-to-adolescent aggression still predicted adolescents’ parent-directed physical aggression (OR: 5.56, 95% CI: 1.82–17.0, p = .003), and father-to-mother aggression predicted adolescents’ parent-directed verbal aggression (OR: 1.86, 95% CI: 1.0–3.3, p = .036). Emotion dysregulation and attitudes condoning aggression did not produce direct or moderated effects. Conclusions Adolescents’ parent-directed aggression deserves greater attention in discourse about lasting, adverse effects of even minor forms of parents’ physical aggression. Future research should investigate parent-directed aggression as

  13. Analysis of associations between behavioral traits and four types of aggression in Shiba Inu.

    PubMed

    Kaneko, Fumihiro; Arata, Sayaka; Takeuchi, Yukari; Mori, Yuji

    2013-10-01

    Canine aggression is one of the behavioral problems for which veterinary behaviorists are most frequently consulted. Despite this, the classification of canine aggression is controversial, and there are several classification methodologies. While the etiology of canine aggression differs among the types of aggression, the behavioral background underlying aggression is not well understood. Behavior trait-based evaluation of canine aggression would improve the effectiveness and efficiency of managing canine aggression problems. We developed a questionnaire addressing 14 behavioral items and items related to four types of canine aggression (owner-, child-, stranger- and dog-directed aggression) in order to examine the associations between behavioral traits and aggression in Shiba Inu. A total of 400 Shiba Inu owners recruited through dog events (n=134) and veterinary hospitals (n=266) completed the questionnaire. Factor analysis sorted the behavioral items from both the event and clinic samples into four factors: "sociability with humans," "reactivity to stimuli," "chase proneness" and "fear of sounds." While "reactivity to stimuli" correlated significantly positively with all of the four types of aggression (P=0.007 to <0.001), "sociability with humans" correlated significantly negatively with child- and stranger-directed aggression (P<0.001). These results suggest that the behavioral traits involved in canine aggression differ among the types of aggression and that specific behavioral traits are frequently simultaneously involved in several types of aggression. PMID:23719752

  14. A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model

    SciTech Connect

    Fukumoto, Shinya; Hanazono, Kiwamu; Fu, Dah-Renn; Endo, Yoshifumi; Kadosawa, Tsuyoshi; Iwano, Hidetomo; Uchide, Tsuyoshi

    2013-09-13

    Highlights: •LAT1 is highly expressed in tumors but at low levels in normal tissues. •We examine LAT1 expression and function in malignant melanoma (MM). •LAT1 expression in MM tissues and cell lines is higher than those in normal tissues. •LAT1 selective inhibitors inhibit amino acid uptake and cell growth in MM cells. •New chemotherapeutic protocols including LAT1 inhibitors are effective for treatment. -- Abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P < 0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [{sup 3}H]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM

  15. In vitro inhibition of human malignant brain tumour cell line proliferation by anti-urokinase-type plasminogen activator monoclonal antibodies.

    PubMed Central

    Abaza, M. S.; Shaban, F. A.; Narayan, R. K.; Atassi, M. Z.

    1998-01-01

    A brain tumour-associated marker, urokinase (UK), was investigated using rabbit anti-UK polyclonal and murine anti-UK monoclonal antibodies, which were prepared by immunization with low molecular weight UK (LMW-UK) and high molecular weight urokinase (HMW-UK) synthetic peptide respectively. The polyclonal antibody cross-reacted with both LMW-UK and HMW-UK, whereas the murine MAbs were specific for HMW-UK. These immunological probes were used to study urokinase in glioma extracts, tissues, sera and cell lines that had been prepared from primary cultures of freshly dissected gliomas. Radioimmunoassays showed that glioma extracts had much higher level (5- to 44-fold) of UK than normal human brain extracts. This result was confirmed by immunoblotting of electrophoresis gels of glioma and human brain extracts. Immunohistochemical study using anti-UK MAb demonstrated much higher levels of UK in glioma tissue than normal brain tissue. Immunohistochemical study using anti-UK MAbs localized UK on the cell surface of glioma cells. Anti-UK MAbs inhibited the proliferation of AA cell lines and GB cell lines (50% to > 90%) and exerted minor effects (< or = 20%) on normal human liver, intestine and lymphocyte cell lines. Taken together, these results suggest that anti-UK MAbs may have therapeutic potential for human gliomas and cancer metastasis. Images Figure 2 Figure 3 PMID:9862567

  16. Microbiology of aggressive periodontitis.

    PubMed

    Könönen, Eija; Müller, Hans-Peter

    2014-06-01

    For decades, Aggregatibacter actinomycetemcomitans has been considered the most likely etiologic agent in aggressive periodontitis. Implementation of DNA-based microbiologic methodologies has considerably improved our understanding of the composition of subgingival biofilms, and advanced open-ended molecular techniques even allow for genome mapping of the whole bacterial spectrum in a sample and characterization of both the cultivable and not-yet-cultivable microbiota associated with periodontal health and disease. Currently, A. actinomycetemcomitans is regarded as a minor component of the resident oral microbiota and as an opportunistic pathogen in some individuals. Its specific JP2 clone, however, shows properties of a true exogenous pathogen and has an important role in the development of aggressive periodontitis in certain populations. Still, limited data exist on the impact of other microbes specifically in aggressive periodontitis. Despite a wide heterogeneity of bacteria, especially in subgingival samples collected from patients, bacteria of the red complex in particular, and those of the orange complex, are considered as potential pathogens in generalized aggressive periodontitis. These types of bacterial findings closely resemble those found for chronic periodontitis, representing a mixed polymicrobial infection without a clear association with any specific microorganism. In aggressive periodontitis, the role of novel and not-yet-cultivable bacteria has not yet been elucidated. There are geographic and ethnic differences in the carriage of periodontitis-associated microorganisms, and they need to be taken into account when comparing study reports on periodontal microbiology in different study populations. In the present review, we provide an overview on the colonization of potential periodontal pathogens in childhood and adolescence, and on specific microorganisms that have been suspected for their role in the initiation and progression of aggressive

  17. Design and synthesis of a MAO-B-selectively activated prodrug based on MPTP: a mitochondria-targeting chemotherapeutic agent for treatment of human malignant gliomas.

    PubMed

    Sharpe, Martyn A; Han, Junyan; Baskin, Alexandra M; Baskin, David S

    2015-04-01

    Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ≥fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75 μM, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180 μM MP-MUS killed 90-95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis. PMID:25677185

  18. Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma

    PubMed Central

    Ma, Jun; Meng, Fanjie; Li, Shuai; Liu, Libo; Zhao, Lini; Liu, Yunhui; Hu, Yi; Li, Zhen; Yao, Yilong; Xi, Zhuo; Teng, Hao; Xue, Yixue

    2015-01-01

    This study aims to investigate the effect of endothelial-monocyte activating polypeptide II (EMAP II) on human glioblastoma (GBM) cells and glioblastoma stem cells (GSCs) as well as its possible mechanisms. In this study, EMAP II inhibited the cell viability and decreased the mitochondrial membrane potential in human GBM cells and GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) blocked these effects. Autophagic vacuoles were formed in these cells after EMAP II treatment and this phenomenon was blocked by 3-MA. In addition, the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and the down-regulation of autophagic degraded substrate p62/SQSTM1 caused by EMAP II were observed. Cells treated with EMAP-II inhibited the PI3K/Akt/mTOR signal pathway, and PI3K/Akt agonist insulin-like growth factor-1 (IGF-1) blocked the effect of EMAP II on the expression of LC3-II and p62/SQSTM1. Cells exposed to EMAP-II experienced mitophagy and ER stress. Furthermore, the inhibition of cell proliferation, migration and invasion of GBM cells and GSCs were more remarkable by the combination of EMAP II and rapamycin than either agent alone in vitro and in vivo. The current study demonstrated that the cytotoxicity of EMAP II in human GBM cells and GSCs was induced by autophagy, accompanied by the inhibition of PI3K/Akt/mTOR signal pathway, mitophagy and ER stress. The combination of EMAP II with rapamycin demonstrated the inhibitory effect on the malignant biological behaviors of human GBM cells and GSCs in vitro and in vivo. PMID:26648842

  19. Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging

    PubMed Central

    Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

    2014-01-01

    Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2−/−/γc−/− mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which

  20. Effects of Symbolic Modeling on Children's Interpersonal Aggression.

    ERIC Educational Resources Information Center

    Liebert, Robert M.; Baron, Robert A.

    Does exposure to symbolically modeled aggression (aggression in cartoons, movies, stories and simulated television programs) increase children's willingness to engage in behavior which might actually harm another human being? This paper presents a summary of three recent experiments offering affirmative answers to the question. A fourth experiment…

  1. Visible to near-infrared refractive properties of freshly-excised human-liver tissues: marking hepatic malignancies

    NASA Astrophysics Data System (ADS)

    Giannios, Panagiotis; Toutouzas, Konstantinos G.; Matiatou, Maria; Stasinos, Konstantinos; Konstadoulakis, Manousos M.; Zografos, George C.; Moutzouris, Konstantinos

    2016-06-01

    The refractive index is an optical constant that plays a significant role in the description of light-matter interactions. When it comes to biological media, refraction is understudied despite recent advances in the field of bio-optics. In the present article, we report on the measurement of the refractive properties of freshly excised healthy and cancerous human liver samples, by use of a prism-coupling technique covering the visible and near-infrared spectral range. Novel data on the wavelength-dependent complex refractive index of human liver tissues are presented. The magnitude of the real and imaginary part of the refractive index is correlated with hepatic pathology. Notably, the real index contrast is pointed out as a marker of discrimination between normal liver tissue and hepatic metastases. In view of the current progress in optical biosensor technologies, our findings may be exploited for the development of novel surgical and endoscopic tools.

  2. Visible to near-infrared refractive properties of freshly-excised human-liver tissues: marking hepatic malignancies

    PubMed Central

    Giannios, Panagiotis; Toutouzas, Konstantinos G.; Matiatou, Maria; Stasinos, Konstantinos; Konstadoulakis, Manousos M.; Zografos, George C.; Moutzouris, Konstantinos

    2016-01-01

    The refractive index is an optical constant that plays a significant role in the description of light-matter interactions. When it comes to biological media, refraction is understudied despite recent advances in the field of bio-optics. In the present article, we report on the measurement of the refractive properties of freshly excised healthy and cancerous human liver samples, by use of a prism-coupling technique covering the visible and near-infrared spectral range. Novel data on the wavelength-dependent complex refractive index of human liver tissues are presented. The magnitude of the real and imaginary part of the refractive index is correlated with hepatic pathology. Notably, the real index contrast is pointed out as a marker of discrimination between normal liver tissue and hepatic metastases. In view of the current progress in optical biosensor technologies, our findings may be exploited for the development of novel surgical and endoscopic tools. PMID:27297034

  3. Visible to near-infrared refractive properties of freshly-excised human-liver tissues: marking hepatic malignancies.

    PubMed

    Giannios, Panagiotis; Toutouzas, Konstantinos G; Matiatou, Maria; Stasinos, Konstantinos; Konstadoulakis, Manousos M; Zografos, George C; Moutzouris, Konstantinos

    2016-01-01

    The refractive index is an optical constant that plays a significant role in the description of light-matter interactions. When it comes to biological media, refraction is understudied despite recent advances in the field of bio-optics. In the present article, we report on the measurement of the refractive properties of freshly excised healthy and cancerous human liver samples, by use of a prism-coupling technique covering the visible and near-infrared spectral range. Novel data on the wavelength-dependent complex refractive index of human liver tissues are presented. The magnitude of the real and imaginary part of the refractive index is correlated with hepatic pathology. Notably, the real index contrast is pointed out as a marker of discrimination between normal liver tissue and hepatic metastases. In view of the current progress in optical biosensor technologies, our findings may be exploited for the development of novel surgical and endoscopic tools. PMID:27297034

  4. Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.

    PubMed Central

    Walker, A M; Montgomery, D W; Saraiya, S; Ho, T W; Garewal, H S; Wilson, J; Lorand, L

    1995-01-01

    Several lines of evidence indicate that immunoglobulin-bound prolactin found in human serum is not a conventional complex between an anti-prolactin antibody and prolactin but a different type of association of prolactin with the Fab portion of IgG heavy chains. The complex of prolactin with IgG was purified from serum by anti-human prolactin affinity chromatography and was shown to contain close to 1 mole of N epsilon-(gamma-glutamyl)lysine crosslinks per mole of complex, a characteristic feature in structures crosslinked by transglutaminase. Interestingly, the complex caused a proliferation of cells from a subset of patients with chronic lymphocytic leukemia, while it was inactive in a cell proliferation prolactin bioassay. By contrast, human prolactin stimulated the proliferation of cells in the bioassay but had no effect on the complex-responsive cells from the patients. Competition studies with prolactin and free Fc fragment of IgG demonstrated a necessity for engaging both the prolactin and the immunoglobulin receptors for proliferation. More importantly, competition for the growth response by free prolactin and IgG suggests both possible reasons for the slow growth of this neoplasm as well as avenues for control of the disease. Images Fig. 1 Fig. 2 Fig. 4 PMID:7724552

  5. Podocalyxin expression in malignant astrocytic tumors.

    PubMed

    Hayatsu, Norihito; Kaneko, Mika Kato; Mishima, Kazuhiko; Nishikawa, Ryo; Matsutani, Masao; Price, Janet E; Kato, Yukinari

    2008-09-19

    Podocalyxin is an anti-adhesive mucin-like transmembrane sialoglycoprotein that has been implicated in the development of aggressive forms of cancer. Podocalyxin is also known as keratan sulfate (KS) proteoglycan. Recently, we revealed that highly sulfated KS or another mucin-like transmembrane sialoglycoprotein podoplanin/aggrus is upregulated in malignant astrocytic tumors. The aim of this study is to examine the relationship between podocalyxin expression and malignant progression of astrocytic tumors. In this study, 51 astrocytic tumors were investigated for podocalyxin expression using immunohistochemistry, Western blot analysis, and quantitative real-time PCR. Immunohistochemistry detected podocalyxin on the surface of tumor cells in six of 14 anaplastic astrocytomas (42.9%) and in 17 of 31 glioblastomas (54.8%), especially around proliferating endothelial cells. In diffuse astrocytoma, podocalyxin expression was observed only in vascular endothelial cells. Podocalyxin might be associated with the malignant progression of astrocytic tumors, and be a useful prognostic marker for astrocytic tumors. PMID:18639524

  6. Podocalyxin expression in malignant astrocytic tumors

    SciTech Connect

    Hayatsu, Norihito; Kaneko, Mika Kato; Mishima, Kazuhiko; Nishikawa, Ryo; Matsutani, Masao; Price, Janet E.; Kato, Yukinari

    2008-09-19

    Podocalyxin is an anti-adhesive mucin-like transmembrane sialoglycoprotein that has been implicated in the development of aggressive forms of cancer. Podocalyxin is also known as keratan sulfate (KS) proteoglycan. Recently, we revealed that highly sulfated KS or another mucin-like transmembrane sialoglycoprotein podoplanin/aggrus is upregulated in malignant astrocytic tumors. The aim of this study is to examine the relationship between podocalyxin expression and malignant progression of astrocytic tumors. In this study, 51 astrocytic tumors were investigated for podocalyxin expression using immunohistochemistry, Western blot analysis, and quantitative real-time PCR. Immunohistochemistry detected podocalyxin on the surface of tumor cells in six of 14 anaplastic astrocytomas (42.9%) and in 17 of 31 glioblastomas (54.8%), especially around proliferating endothelial cells. In diffuse astrocytoma, podocalyxin expression was observed only in vascular endothelial cells. Podocalyxin might be associated with the malignant progression of astrocytic tumors, and be a useful prognostic marker for astrocytic tumors.

  7. Quetiapine modulates functional connectivity in brain aggression networks.

    PubMed

    Klasen, Martin; Zvyagintsev, Mikhail; Schwenzer, Michael; Mathiak, Krystyna A; Sarkheil, Pegah; Weber, René; Mathiak, Klaus

    2013-07-15

    Aggressive behavior is associated with dysfunctions in an affective regulation network encompassing amygdala and prefrontal areas such as orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC). In particular, prefrontal regions have been postulated to control amygdala activity by inhibitory projections, and this process may be disrupted in aggressive individuals. The atypical antipsychotic quetiapine successfully attenuates aggressive behavior in various disorders; the underlying neural processes, however, are unknown. A strengthened functional coupling in the prefrontal-amygdala system may account for these anti-aggressive effects. An inhibition of this network has been reported for virtual aggression in violent video games as well. However, there have been so far no in-vivo observations of pharmacological influences on corticolimbic projections during human aggressive behavior. In a double-blind, placebo-controlled study, quetiapine and placebo were administered for three successive days prior to an fMRI experiment. In this experiment, functional brain connectivity was assessed during virtual aggressive behavior in a violent video game and an aggression-free control task in a non-violent modification. Quetiapine increased the functional connectivity of ACC and DLPFC with the amygdala during virtual aggression, whereas OFC-amygdala coupling was attenuated. These effects were observed neither for placebo nor for the non-violent control. These results demonstrate for the first time a pharmacological modification of aggression-related human brain networks in a naturalistic setting. The violence-specific modulation of prefrontal-amygdala networks appears to control aggressive behavior and provides a neurobiological model for the anti-aggressive effects of quetiapine. PMID:23501053

  8. Intellectual Competence and Aggression.

    ERIC Educational Resources Information Center

    Huesmann, L. Rowell; Yarmel, Patty Warnick

    Using data from a broader longitudinal study, this investigation explores within-subject and cross-generational stability of intellectual competence and the relationship of such stability to aggressive behavior. Data were gathered three times (when subjects' modal age was 8, 19, and 30 years). Initially, subjects included the entire population…

  9. Relational Aggression among Students

    ERIC Educational Resources Information Center

    Young, Ellie L.; Nelson, David A.; Hottle, America B.; Warburton, Brittney; Young, Bryan K.

    2011-01-01

    "Relational aggression" refers to harm within relationships caused by covert bullying or manipulative behavior. Examples include isolating a youth from his or her group of friends (social exclusion), threatening to stop talking to a friend (the silent treatment), or spreading gossip and rumors by email. This type of bullying tends to be…

  10. Stability of Aggressive Behavior.

    ERIC Educational Resources Information Center

    Eron, Leonard D.; Huesmann, L. Rowell

    As indicated by multiple measures (including overt criminal behavior), stability of aggressive behavior was investigated across 22 years for males and females in a variety of situations. Originally, subjects included the entire population enrolled in the third grade in a semi-rural county in New York State. The sample included approximately 870…

  11. Anonymity, Deindividuation and Aggression.

    ERIC Educational Resources Information Center

    Baron, Robert S.

    Several writers suggest that reducing one's sense of individuality reduces social restraints. The author suggests that the effect of uniformity of appearance on aggression is unclear when anonymity is held constant. This poses a problem of interpretation given that a distinction must be made between lack of individuality and anonymity. One must…

  12. Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses.

    PubMed Central

    Kawamoto, H.; Koizumi, H.; Uchikoshi, T.

    1997-01-01

    We investigated the in vivo expression of cyclin B1 and Cdc2 (key molecules for G2-M transition during the cell cycle) in nonmalignant and cancerous human breast lesions using immunohistochemistry and quantitative proliferative index (PI) analysis. Breast epithelial cells co-expressed cyclin B1 and Cdc2 in their cytoplasm in the G2 phase and in their nuclei in the M phase. Cyclin B1, but not Cdc2, immunostaining rapidly disappeared from the nuclei during the mitotic metaphase to anaphase transition. Static image analysis revealed the mean proliferative index for cyclin B1/cdc2 for each type of lesion to be as follows: normal glands (n = 20), 2.0/2.5%; benign lesions, including typical ductal hyperplasia (n = 76), 2.5/5.8%; atypical ductal hyperplasia (n = 21), 3.0/6.6%; carcinomas in situ (n = 70), 7.4/14.0%; and invasive carcinomas (n = 58), 10.0/22.9%. Proliferative index data for atypical hyperplasia were virtually identical to those for benign lesions and were significantly lower than those for breast cancer, suggesting that expression levels of cyclin B1 and Cdc2 may be used to distinguish premalignant human breast lesions from advanced disease. Furthermore, the proliferative index for cyclin B1 for comedo-type ductal carcinomas in situ agreed with that for invasive ductal carcinomas (mean, 10.1% versus 9.5%), apparently explaining the clinicopathological aggressiveness of this tumor at the molecular level. Images Figure 1 Figure 2 Figure 3 PMID:9006317

  13. Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells

    PubMed Central

    Ovaa, Huib; Kessler, Benedikt M.; Rolén, Ulrika; Galardy, Paul J.; Ploegh, Hidde L.; Masucci, Maria G.

    2004-01-01

    The family of ubiquitin (Ub)-specific proteases (USP) removes Ub from Ub conjugates and regulates a variety of cellular processes. The human genome contains many putative USP-encoding genes, but little is known about USP tissue distribution, pattern of expression, activity, and substrate specificity. We have used a chemistry-based functional proteomics approach to identify active USPs in normal, virus-infected, and tumor-derived human cells. Depending on tissue origin and stage of activation/differentiation, different USP activity profiles were revealed. The activity of specific USPs, including USP5, -7, -9, -13, -15, and -22, was up-regulated by mitogen activation or virus infection in normal T and B lymphocytes. UCH-L1 was highly expressed in tumor cell lines of epithelial and hematopoietic cell origin but was not detected in freshly isolated and mitogen-activated cells. Up-regulation of this USP was a late event in the establishment of Epstein–Barr virus-immortalized lymphoblastoid cell lines and correlated with enhanced proliferation, suggesting a possible role in growth transformation. PMID:14982996

  14. Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells

    PubMed Central

    Devailly, Guillaume; Grandin, Mélodie; Perriaud, Laury; Mathot, Pauline; Delcros, Jean-Guy; Bidet, Yannick; Morel, Anne-Pierre; Bignon, Jean-Yves; Puisieux, Alain; Mehlen, Patrick; Dante, Robert

    2015-01-01

    DNA methylation is thought to induce transcriptional silencing through the combination of two mechanisms: the repulsion of transcriptional activators unable to bind their target sites when methylated, and the recruitment of transcriptional repressors with specific affinity for methylated DNA. The Methyl CpG Binding Domain proteins MeCP2, MBD1 and MBD2 belong to the latter category. Here, we present MBD2 ChIPseq data obtained from the endogenous MBD2 in an isogenic cellular model of oncogenic transformation of human mammary cells. In immortalized (HMEC-hTERT) or transformed (HMLER) cells, MBD2 was found in a large proportion of methylated regions and associated with transcriptional silencing. A redistribution of MBD2 on methylated DNA occurred during oncogenic transformation, frequently independently of local DNA methylation changes. Genes downregulated during HMEC-hTERT transformation preferentially gained MBD2 on their promoter. Furthermore, depletion of MBD2 induced an upregulation of MBD2-bound genes methylated at their promoter regions, in HMLER cells. Among the 3,160 genes downregulated in transformed cells, 380 genes were methylated at their promoter regions in both cell lines, specifically associated by MBD2 in HMLER cells, and upregulated upon MBD2 depletion in HMLER. The transcriptional MBD2-dependent downregulation occurring during oncogenic transformation was also observed in two additional models of mammary cell transformation. Thus, the dynamics of MBD2 deposition across methylated DNA regions was associated with the oncogenic transformation of human mammary cells. PMID:26007656

  15. Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    ERIC Educational Resources Information Center

    Duman, Sarah; Margolin, Gayla

    2007-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

  16. Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

    ERIC Educational Resources Information Center

    Page, Angela; Smith, Lisa F.

    2016-01-01

    Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

  17. From hitting to tattling to gossip: an evolutionary rationale for the development of indirect aggression.

    PubMed

    Ingram, Gordon P D

    2014-01-01

    Adult humans are characterized by low rates of intra-group physical aggression. Since children tend to be more physically aggressive, an evolutionary developmental account shows promise for explaining how physical aggression is suppressed in adults. I argue that this is achieved partly through extended dominance hierarchies, based on indirect reciprocity and linguistic transmission of reputational information, mediated by indirectly aggressive competition. Reviewing the literature on indirect and related forms of aggression provides three pieces of evidence for the claim that evolutionarily old impulses towards physical aggression are socialized into indirect aggression in humans: (i) physical aggression falls in early childhood over the same age range at which indirect aggression increases; (ii) the same individuals engage in both direct and indirect aggression; and (iii) socially dominant individuals practice indirect aggression more frequently. Consideration of the developmental course of indirect aggression is complemented by analysis of similar developments in verbal behaviors that are not always thought of as aggressive, namely tattling and gossip. An important puzzle concerns why indirect aggression becomes more covert, and tattling more derogated, in preadolescence and adolescence. This may be due to the development of new strategies aimed at renegotiating social identity and friendship alliances in the peer group. PMID:25299883

  18. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

    PubMed Central

    IFERE, GODWIN O.; DESMOND, RENEE; DEMARK-WAHNEFRIED, WENDY; NAGY, TIM R.

    High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID:23934233

  19. Analysis of Associations between Behavioral Traits and Four Types of Aggression in Shiba Inu

    PubMed Central

    KANEKO, Fumihiro; ARATA, Sayaka; TAKEUCHI, Yukari; MORI, Yuji

    2013-01-01

    ABSTRACT Canine aggression is one of the behavioral problems for which veterinary behaviorists are most frequently consulted. Despite this, the classification of canine aggression is controversial, and there are several classification methodologies. While the etiology of canine aggression differs among the types of aggression, the behavioral background underlying aggression is not well understood. Behavior trait-based evaluation of canine aggression would improve the effectiveness and efficiency of managing canine aggression problems. We developed a questionnaire addressing 14 behavioral items and items related to four types of canine aggression (owner-, child-, stranger- and dog-directed aggression) in order to examine the associations between behavioral traits and aggression in Shiba Inu. A total of 400 Shiba Inu owners recruited through dog events (n=134) and veterinary hospitals (n=266) completed the questionnaire. Factor analysis sorted the behavioral items from both the event and clinic samples into four factors: “sociability with humans,” “reactivity to stimuli,” “chase proneness” and “fear of sounds.” While “reactivity to stimuli” correlated significantly positively with all of the four types of aggression (P=0.007 to <0.001), “sociability with humans” correlated significantly negatively with child- and stranger-directed aggression (P<0.001). These results suggest that the behavioral traits involved in canine aggression differ among the types of aggression and that specific behavioral traits are frequently simultaneously involved in several types of aggression. PMID:23719752

  20. Reverse Discrimination and Aggressive Behavior.

    ERIC Educational Resources Information Center

    Johnson, Stephen D.

    1980-01-01

    White subjects were aggressive toward Black opponents when contest results appeared to reflect elements of reverse discrimination; but they showed less aggressive behavior toward Black opponents when they thought their loss was due to their opponents' superior ability. (RL)

  1. Coping with Agitation and Aggression

    MedlinePlus

    Alzheimer ’s Caregiving Tips Coping with Agitation and Aggression People with Alzheimer’s disease may become agitated or aggressive as the disease gets worse. Agitation means that a person is restless or worried. ...

  2. Raman spectrosopic characterization of human malignant tissues: implications for a percutaneous optical biopsy technique for in-situ tissue diagnosis

    NASA Astrophysics Data System (ADS)

    Redd, Douglas C. B.; Frank, Christopher J.; Feng, Zhe Chuan; Gansler, Ted S.; McCreery, Richard L.

    1994-01-01

    Recent advancements in the technique of Raman spectroscopy now make it possible to achieve rapid, minimally invasive and non-destructive characterization of tissues. In order to evaluate the efficacy of this technique for diagnosis, the Raman spectra of normal and neoplastic human tissues (e.g., breast, kidney, liver and colon) were obtained utilizing visible and near-IR excitation. Normal breast tissue and colon adenocarcinoma showed major Raman features due to the presence of carotenoids and lipids. In breast carcinoma, the features due to lipids were attenuated and as fibrosis (desmoplasia) increased, new spectral features attributable to collagen were observed. Samples of normal and neoplastic liver and kidney show unique spectral differences sufficient to permit tissue differentiation.

  3. Use of PCR amplification of cDNA to study mechanisms of human cell mutagenesis and malignant transformation

    SciTech Connect

    Maher, V.M.; Yang, Jialing; Chen, Rueyhwa; McGregor, W.G.; Lukash, L.; Scheid, J.M.; Reinhold, D.S.; McCormick, J.J. )

    1991-01-01

    PCR is widely employed to amplify short segments of genomic DNA to determine if a specific change has occurred. But some investigators need to sequence the entire coding region of mammalian genes to determine what specific changes have occurred. In 1989, the authors described a method to copy mRNA of the hypoxanthine (guanine) phosphoribosyl transferase (HPRT) gene directly from the lysate of a clone of 6-thioguanine-resistant mutant diploid human fibroblasts without the need for RNA extraction or DNA template purification. The consensus sequence of the cDNA is determined by direct nucleotide sequencing. Using this method, they have investigated the kinds of mutations induced by carcinogens in the coding region of the HPRT gene and their location in the gene and examined the role of DNA repair were exposed to mutagens in exponential growth or synchronized and exposed at the beginning of S phase or in G{sub 1} phase several hr prior to DNA replication.

  4. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

    PubMed

    Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

    2015-08-14

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  5. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

    PubMed Central

    Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

    2015-01-01

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  6. Calpains: markers of tumor aggressiveness?

    PubMed

    Roumes, Hélène; Leloup, Ludovic; Dargelos, Elise; Brustis, Jean-Jacques; Daury, Laetitia; Cottin, Patrick

    2010-05-15

    Rhabdomyosarcoma (RMS) are soft-tissue sarcoma commonly encountered in childhood. RMS cells can acquire invasive behavior and form metastases. The metastatic dissemination implicates many proteases among which are mu-calpain and m-calpain. Study of calpain expression and activity underline the deregulation of calpain activity in RMS. Analysis of kinetic characteristics of RMS cells, compared to human myoblasts LHCN-M2 cells, shows an important migration velocity in RMS cells. One of the major results of this study is the positive linear correlation between calpain activity and migration velocity presenting calpains as a marker of tumor aggressiveness. The RMS cytoskeleton is disorganized. Specifying the role of mu- and m-calpain using antisense oligonucleotides led to show that both calpains up-regulate alpha- and beta-actin in ARMS cells. Moreover, the invasive behavior of these cells is higher than that of LHCN-M2 cells. However, it is similar to that of non-treated LHCN-M2 cells, when calpains are inhibited. In summary, calpains may be involved in the anarchic adhesion, migration and invasion of RMS. The direct relationship between calpain activity and migration velocities or invasive behavior indicates that calpains could be considered as markers of tumor aggressiveness and as potential targets for limiting development of RMS tumor as well as their metastatic behavior. PMID:20193680

  7. Malignant mesothelioma: development to therapy.

    PubMed

    Thompson, Joyce K; Westbom, Catherine M; Shukla, Arti

    2014-01-01

    Malignant mesothelioma (MM) is an aggressive cancer of the mesothelium caused by asbestos. Asbestos use has been reduced but not completely stopped. In addition, natural or man-made disasters will continue to dislodge asbestos from old buildings into the atmosphere and as long as respirable asbestos is available, MM will continue to be a threat. Due to the long latency period of MM development, it would still take decades to eradicate this disease if asbestos was completely removed from our lives today. Therefore, there is a need for researchers and clinicians to work together to understand this deadly disease and find a solution for early diagnosis and treatment. This article focuses on developmental mechanisms as well as current therapies available for MM. PMID:23959774

  8. Malignant Mesothelioma: Development to Therapy

    PubMed Central

    Thompson, Joyce; Westbom, Catherine; Shukla, Arti

    2013-01-01

    Malignant mesothelioma (MM) is an aggressive cancer of the mesothelium caused by asbestos. Asbestos use has been reduced but not completely stopped. In addition, natural or man-made disasters will continue to dislodge asbestos from old buildings into the atmosphere and as long as respirable asbestos is available, MM will continue to be a threat. Due to the long latency period of MM development, it would still take decades to eradicate this disease if asbestos was completely removed from our lives today. Therefore, there is a need for researchers and clinicians to work together to understand this deadly disease and find a solution for early diagnosis and treatment. This article focuses on developmental mechanisms as well as current therapies available for MM. PMID:23959774

  9. Enhanced induction of cell cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin.

    PubMed

    Ismail, Samhani; Haris, Khalilah; Abdul Ghani, Abdul Rahman Izaini; Abdullah, Jafri Malin; Johan, Muhammad Farid; Mohamed Yusoff, Abdul Aziz

    2013-09-01

    Aloe emodin, one of the active compounds found in Aloe vera leaves, plays an important role in the regulation of cell growth and death. It has been reported to promote the anti-cancer effects in various cancer cells by inducing apoptosis. However, the mechanism of inducing apoptosis by this agent is poorly understood in glioma cells. This research is to investigate the apoptosis and cell cycle arrest inducing by aloe emodin on U87 human malignant glioma cells. Aloe emodin showed a time- and dose-dependent inhibition of U87 cells proliferation and decreased the percentage of viable U87 cells via the induction of apoptosis. Characteristic morphological changes, such as the formation of apoptotic bodies, were observed with confocal microscope by Annexin V-FITC/PI staining, supporting our viability study and flow cytometry analysis results. Our data also demonstrated that aloe emodin arrested the cell cycle in the S phase and promoted the loss of mitochondrial membrane potential in U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway. PMID:23869465

  10. Genetic Alteration of a bispecific ligand directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

    PubMed Central

    Vallera, Daniel A.; Chen, Hua; Sicheneder, Andrew R.; Panoskaltsis-Mortari, Angela; Taras, Elizabeth P.

    2009-01-01

    A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two sFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt’s lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06–0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced preterminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation. PMID:19327829

  11. Serotonin and Aggressiveness in Chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin (5-HT) regulates aggressive behavior in animals. This study examined if 5-HT regulation of aggressiveness is gene-dependent. Chickens from two divergently selected lines KGB and MBB (Kind Gentle Birds and Mean Bad Birds displaying low and high aggressiveness, respectively) and DXL (Dekalb ...

  12. Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model

    PubMed Central

    Minami, Daisuke; Takigawa, Nagio; Kato, Yuka; Kudo, Kenichiro; Isozaki, Hideko; Hashida, Shinsuke; Harada, Daijiro; Ochi, Nobuaki; Fujii, Masanori; Kubo, Toshio; Ohashi, Kadoaki; Sato, Akiko; Tanaka, Takehiro; Hotta, Katsuyuki; Tabata, Masahiro; Toyooka, Shinichi; Tanimoto, Mitsune; Kiura, Katsuyuki

    2015-01-01

    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2′-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further. PMID:26211743

  13. Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model.

    PubMed

    Minami, Daisuke; Takigawa, Nagio; Kato, Yuka; Kudo, Kenichiro; Isozaki, Hideko; Hashida, Shinsuke; Harada, Daijiro; Ochi, Nobuaki; Fujii, Masanori; Kubo, Toshio; Ohashi, Kadoaki; Sato, Akiko; Tanaka, Takehiro; Hotta, Katsuyuki; Tabata, Masahiro; Toyooka, Shinichi; Tanimoto, Mitsune; Kiura, Katsuyuki

    2015-10-01

    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further. PMID:26211743

  14. Local distribution and concentration of intravenously injected sup 131 I-9. 2. 27 monoclonal antibody in human malignant melanoma

    SciTech Connect

    Del Vecchio, S.; Reynolds, J.C.; Carrasquillo, J.A.; Blasberg, R.G.; Neumann, R.D.; Lotze, M.T.; Bryant, G.J.; Farkas, R.J.; Larson, S.M. )

    1989-05-15

    Regional measurements of {sup 131}I-9.2.27 distribution in human melanoma tumors were obtained using quantitative autoradiography. Tumors were removed from patients 72-96 h after they had received an i.v. injection of 9.15 mCi (100 mg) of {sup 131}I-9.2.27. The autoradiographic images showed that the radioactivity reaching the tumor was heterogeneously distributed. Areas of relative high and low uptake were selected in each tumor. Regions of high activity contained from 51 to 1371 nCi/g, while areas with low uptake had radioactivity ranging from 12 to 487 nCi/g. The reliability of the autoradiographic measurements was demonstrated by the strong positive correlation with direct tissue sample counting (r = 0.994 P less than 0.001). Since comparative immunocytochemistry showed a homogeneous and diffuse staining of target antigen on viable tumor cells, variability of monoclonal antibody uptake within individual tumors was not primarily due to heterogeneity of antigen expression in these cases. However, antigen levels accounted for some of the variation from tumor to tumor. When immunoperoxidase staining was repeated on adjacent sections without the addition of 9.2.27, it confirmed the nonuniform distribution of monoclonal antibody found at autoradiography. Thus, quantitative autoradiography gives information about the distribution and the local concentration of radioactive antibody in tumors allowing calculation of the radiation dose delivered to small regions within tumors.

  15. YThe BigH3 Tumor Suppressor Gene in Radiation-Induced Malignant Transformation of Human Bronchial Epithelial Cells

    NASA Astrophysics Data System (ADS)

    Zhao, Y.; Shao, G.; Piao, C.; Hei, T.

    Carcinogenesis is a multi-stage process with sequences of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer Previous studies from this laboratory have identified a 7 fold down- regulation of the novel tumor suppressor Big-h3 among radiation induced tumorigenic BEP2D cells Furthermore ectopic re-expression of this gene suppresses tumorigenic phenotype and promotes the sensitivity of these tumor cells to etoposide-induced apoptosis To extend these studies using a genomically more stable bronchial cell line we ectopically expresses the catalytic subunit of telomerase hTERT in primary human small airway epithelial SAE cells and generated several clonal cell lines that have been continuously in culture for more than 250 population doublings and are considered immortal Comparably-treated control SAE cells infected with only the viral vector senesced after less than 10 population doublings The immortalized clones demonstrated anchorage dependent growth and are non-tumorigenic in nude mice These cells show no alteration in the p53 gene but a decrease in p16 expression Exponentially growing SAEh cells were exposed to graded doses of 1 GeV nucleon of 56 Fe ions accelerated at the Brookhaven National Laboratory Irradiated cells underwent gradual phenotypic alterations after extensive in vitro cultivation Transformed cells developed through a series of successive steps before becoming anchorage independent in semisolid medium These findings indicate

  16. Human epidemiology: a review of fiber type and characteristics in the development of malignant and nonmalignant disease.

    PubMed Central

    Merchant, J A

    1990-01-01

    Consideration of the human epidemiology of diseases arising from exposure to naturally occurring and man-made mineral fibers encompasses the several forms of asbestos (chrysotile, crocidolite, amosite, anthophyllite, tremolite-actinolite), other naturally occurring silicates (talc, sepiolite, erionite, attapulgite, vermiculite, and wollastonite), and man-made mineral fibers (glass continuous filament, glass/rock/slag insulation wools, ceramic and other refractory fibers, and glass microfibers). The diseases arising from exposures to some of these fibers include pleural thickening (plaques, diffuse pleural thickening, and calcification), pulmonary fibrosis, lung cancers, mesothelioma of the pleura and peritoneum, and other cancers). Risk factors important in assessing these diseases include assessment of latency, duration of exposure, cumulative exposure, fiber origin and characteristics (length and diameter), other possible confounding occupational or environmental exposures, and smoking. Methodological issues commonly presenting problems in evaluation of these data include assessment of the adequacy of environmental exposures, particularly in regard to fiber identification, distribution, and concentration over the duration of exposure, and the adequacy of study design to detect health effects (disease frequency, latency, and cohort size). Research priorities include further assessment and standardization of pleural thickening relative to fiber exposure, uniform mesothelioma surveillance, further epidemiological assessment of certain silicate and man-made mineral fiber cohorts with emphasis given to assessment of tremolite and small diameter glass and ceramic fibers. Further assessment of possible health risks of the general public should await improved definition of relevant fiber exposure in ambient air. PMID:2272325

  17. Gastrointestinal malignancy and the microbiome.

    PubMed

    Abreu, Maria T; Peek, Richard M

    2014-05-01

    Microbial species participate in the genesis of a substantial number of malignancies-in conservative estimates, at least 15% of all cancer cases are attributable to infectious agents. Little is known about the contribution of the gastrointestinal microbiome to the development of malignancies. Resident microbes can promote carcinogenesis by inducing inflammation, increasing cell proliferation, altering stem cell dynamics, and producing metabolites such as butyrate, which affect DNA integrity and immune regulation. Studies in human beings and rodent models of cancer have identified effector species and relationships among members of the microbial community in the stomach and colon that increase the risk for malignancy. Strategies to manipulate the microbiome, or the immune response to such bacteria, could be developed to prevent or treat certain gastrointestinal cancers. PMID:24406471

  18. Mesenchymal Stem Cells Modified with a Single-Chain Antibody against EGFRvIII Successfully Inhibit the Growth of Human Xenograft Malignant Glioma

    PubMed Central

    Balyasnikova, Irina V.; Ferguson, Sherise D.; Sengupta, Sadhak; Han, Yu; Lesniak, Maciej S.

    2010-01-01

    Background Glioblastoma multiforme is the most lethal brain tumor with limited therapeutic options. Antigens expressed on the surface of malignant cells are potential targets for antibody-mediated gene/drug delivery. Principal Findings In this study, we investigated the ability of genetically modified human mesenchymal stem cells (hMSCs) expressing a single-chain antibody (scFv) on their surface against a tumor specific antigen, EGFRvIII, to enhance the therapy of EGFRvIII expressing glioma cells in vivo. The growth of U87-EGFRvIII was specifically delayed in co-culture with hMSC-scFvEGFRvIII. A significant down-regulation was observed in the expression of pAkt in EGFRvIII expressing glioma cells upon culture with hMSC-scFvEGFRvIII vs. controls as well as in EGFRvIII expressing glioma cells from brain tumors co-injected with hMSC-scFvEGFRvIII in vivo. hMSC expressing scFvEGFRvIII also demonstrated several fold enhanced retention in EGFRvIII expressing flank and intracranial glioma xenografts vs. control hMSCs. The growth of U87-EGFRvIII flank xenografts was inhibited by 50% in the presence of hMSC-scFvEGFRvIII (p<0.05). Moreover, animals co-injected with U87-EGFRvIII and hMSC-scFvEGFRvIII intracranially showed significantly improved survival compared to animals injected with U87-EGFRvIII glioma cells alone or with control hMSCs. This survival was further improved when the same animals received an additional dosage of hMSC-scFvEGFRvIII two weeks after initial tumor implantation. Of note, EGFRvIII expressing brain tumors co-injected with hMSCs had a lower density of CD31 expressing blood vessels in comparison with control tumors, suggesting a possible role in tumor angiogenesis. Conclusions/Significance The results presented in this study illustrate that genetically modified MSCs may function as a novel therapeutic vehicle for malignant brain tumors. PMID:20305783

  19. Children's normative beliefs about aggression and aggressive behavior.

    PubMed

    Huesmann, L R; Guerra, N G

    1997-02-01

    Normative beliefs have been defined as self-regulating beliefs about the appropriateness of social behaviors. In 2 studies the authors revised their scale for assessing normative beliefs about aggression, found that it is reliable and valid for use with elementary school children, and investigated the longitudinal relation between normative beliefs about aggression and aggressive behavior in a large sample of elementary school children living in poor urban neighborhoods. Using data obtained in 2 waves of observations 1 year apart, the authors found that children tended to approve more of aggression as they grew older and that this increase appeared to be correlated with increases in aggressive behavior. More important, although individual differences in aggressive behavior predicted subsequent differences in normative beliefs in younger children, individual differences in aggressive behavior were predicted by preceding differences in normative beliefs in older children. PMID:9107008

  20. TALENs-directed knockout of the full-length transcription factor Nrf1α that represses malignant behaviour of human hepatocellular carcinoma (HepG2) cells.

    PubMed

    Ren, Yonggang; Qiu, Lu; Lü, Fenglin; Ru, Xufang; Li, Shaojun; Xiang, Yuancai; Yu, Siwang; Zhang, Yiguo

    2016-01-01

    The full-length Nrf1α is processed into distinct isoforms, which together regulate genes essential for maintaining cellular homeostasis and organ integrity, and liver-specific loss of Nrf1 in mice results in spontaneous hepatoma. Herein, we report that the human constitutive Nrf1α, rather than smaller Nrf1β/γ, expression is attenuated or abolished in the case of low-differentiated high-metastatic hepatocellular carcinomas. Therefore, Nrf1α is of importance in the physio-pathological origin and development, but its specific pathobiological function(s) remains elusive. To address this, TALENs-directed knockout of Nrf1α, but not Nrf1β/γ, is created in the human hepatocellular carcinoma (HepG2) cells. The resulting Nrf1α(-/-) cells are elongated, with slender spindle-shapes and enlarged gaps between cells observed under scanning electron microscope. When compared with wild-type controls, the invasive and migratory abilities of Nrf1α(-/-) cells are increased significantly, along with the cell-cycle G2-M arrest and S-phase reduction, as accompanied by suppressed apoptosis. Despite a modest increase in the soft-agar colony formation of Nrf1α(-/-) cells, its loss-of-function markedly promotes malgrowth of the subcutaneous carcinoma xenograft in nude mice with hepatic metastasis. Together with molecular expression results, we thus suppose requirement of Nrf1α (and major derivates) for gene regulatory mechanisms repressing cancer cell process (e.g. EMT) and malignant behaviour (e.g. migration). PMID:27065079

  1. TALENs-directed knockout of the full-length transcription factor Nrf1α that represses malignant behaviour of human hepatocellular carcinoma (HepG2) cells

    PubMed Central

    Ren, Yonggang; Qiu, Lu; Lü, Fenglin; Ru, Xufang; Li, Shaojun; Xiang, Yuancai; Yu, Siwang; Zhang, Yiguo

    2016-01-01

    The full-length Nrf1α is processed into distinct isoforms, which together regulate genes essential for maintaining cellular homeostasis and organ integrity, and liver-specific loss of Nrf1 in mice results in spontaneous hepatoma. Herein, we report that the human constitutive Nrf1α, rather than smaller Nrf1β/γ, expression is attenuated or abolished in the case of low-differentiated high-metastatic hepatocellular carcinomas. Therefore, Nrf1α is of importance in the physio-pathological origin and development, but its specific pathobiological function(s) remains elusive. To address this, TALENs-directed knockout of Nrf1α, but not Nrf1β/γ, is created in the human hepatocellular carcinoma (HepG2) cells. The resulting Nrf1α−/− cells are elongated, with slender spindle-shapes and enlarged gaps between cells observed under scanning electron microscope. When compared with wild-type controls, the invasive and migratory abilities of Nrf1α−/− cells are increased significantly, along with the cell-cycle G2-M arrest and S-phase reduction, as accompanied by suppressed apoptosis. Despite a modest increase in the soft-agar colony formation of Nrf1α−/− cells, its loss-of-function markedly promotes malgrowth of the subcutaneous carcinoma xenograft in nude mice with hepatic metastasis. Together with molecular expression results, we thus suppose requirement of Nrf1α (and major derivates) for gene regulatory mechanisms repressing cancer cell process (e.g. EMT) and malignant behaviour (e.g. migration). PMID:27065079

  2. In vitro evaluation of human hybrid cell lines generated by fusion of B-lymphoblastoid cells and ex vivo tumour cells as candidate vaccines for haematological malignancies.

    PubMed

    Mohamed, Yehia S; Dunnion, Debbie; Teobald, Iryna; Walewska, Renata; Browning, Michael J

    2012-10-12

    Fusions of dendritic cells (DCs) and tumour cells have been shown to induce protective immunity to tumour challenge in animal models, and to represent a promising approach to cancer immunotherapy. The broader clinical application of this approach, however, is potentially constrained by the lack of replicative capacity and limited standardisation of fusion cell preparations. We show here that fusion of ex vivo tumour cells isolated from patients with a range of haematological malignancies with the human B-lymphoblastoid cell line (LCL), HMy2, followed by chemical selection of the hybridomas, generated stable, self-replicating human hybrid cell lines that grew continuously in tissue culture, and survived freeze/thawing cycles. The hybrid cell lines expressed HLA class I and class II molecules, and the major T-cell costimulatory molecules, CD80 and CD86. All but two of 14 hybrid cell lines generated expressed tumour-associated antigens that were not expressed by HMy2 cells, and were therefore derived from the parent tumour cells. The hybrid cell lines stimulated allogeneic T-cell proliferative responses and interferon-gamma release in vitro to a considerably greater degree than their respective parent tumour cells. The enhanced T-cell stimulation was inhibited by CTLA4-Ig fusion protein, and by blocking antibodies to MHC class I and class II molecules. Finally, all of five LCL/tumour hybrid cell lines tested induced tumour antigen-specific cytotoxic T-cell responses in vitro in PBL from healthy, HLA-A2+ individuals, as detected by HLA-A2-peptide pentamer staining and cellular cytotoxicity. These data show that stable hybrid cell lines, with enhanced immunostimulatory properties and potential for therapeutic vaccination, can be generated by in vitro fusion and chemical selection of B-LCL and ex vivo haematological tumour cells. PMID:22939910

  3. Effects of oxytocin on aggressive responding in healthy adult men.

    PubMed

    Alcorn, Joseph L; Green, Charles E; Schmitz, Joy; Lane, Scott D

    2015-12-01

    This study investigated the acute effects of oxytocin (OT) on human aggression using a well-established laboratory measure of state (reactive) aggression to test the hypothesis that OT would decrease the frequency of aggressive responding. In a within-subject design, 17 healthy male volunteers received placebo or 24 IU of intranasal OT. Aggression was measured using the Point Subtraction Aggression Paradigm at 30 min before and 30, 60, and 90 min after dose. Acute OT did not produce a significant main effect on aggressive behavior. OT attenuated the expected rise in diastolic blood pressure from morning to early afternoon observed under placebo, providing a possible indication of biological activity. Examination of individual differences showed that aggressive responding following OT dosing (but not placebo) was positively correlated with psychometric measures of interpersonal manipulation and anger (Pearson's r=0.57), indicating that higher scores on these antisocial personality traits were related to increased aggressive behavior following OT administration. These preliminary results stand in contrast to previous work on the prosocial effects of OT and highlight the need for further understanding of individual differences in aggression following OT administration. Such individual differences may have implications for the therapeutic use of OT in individuals with psychiatric disorders and dysfunctional social behavior. PMID:26241153

  4. Quantitative Genomics of Aggressive Behavior in Drosophila melanogaster

    PubMed Central

    Edwards, Alexis C; Rollmann, Stephanie M; Morgan, Theodore J; Mackay, Trudy F. C

    2006-01-01

    Aggressive behavior is important for animal survival and reproduction, and excessive aggression is an enormous social and economic burden for human society. Although the role of biogenic amines in modulating aggressive behavior is well characterized, other genetic mechanisms affecting this complex behavior remain elusive. Here, we developed an assay to rapidly quantify aggressive behavior in Drosophila melanogaster, and generated replicate selection lines with divergent levels of aggression. The realized heritability of aggressive behavior was approximately 0.10, and the phenotypic response to selection specifically affected aggression. We used whole-genome expression analysis to identify 1,539 probe sets with different expression levels between the selection lines when pooled across replicates, at a false discovery rate of 0.001. We quantified the aggressive behavior of 19 mutations in candidate genes that were generated in a common co-isogenic background, and identified 15 novel genes affecting aggressive behavior. Expression profiling of genetically divergent lines is an effective strategy for identifying genes affecting complex traits. PMID:17044737

  5. Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy.

    PubMed

    Morrone, Fernanda B; Gehring, Marina P; Nicoletti, Natália F

    2016-09-01

    Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calcium-permeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca(2+) activity plays an important role in the regulation of cell proliferation, and Ca(2+) signaling is altered in proliferating tumor cells. A series of previous studies emphasized the importance of the T-type low-voltage-gated calcium channels (VGCC) in different cancer types, including gliomas, and remarkably, pharmacologic inhibition of T-type VGCC caused antiproliferative effects and triggered apoptosis of human glioma cells. Other calcium permeable channels, such as transient receptor potential (TRP) channels, contribute to changes in Ca(2+) by modulating the driving force for Ca(2+) entry, and some TRP channels are required for proliferation and migration in gliomas. Furthermore, recent evidence shows that TRP channels contribute to the progression and survival of the glioblastoma patients. Likewise, the purinergic P2X7 receptor acts as a direct conduit for Ca(2+)-influx and an indirect activator of voltage-gated Ca(2+)-channel. Evidence also shows that P2X7 receptor activation is linked to elevated expression of inflammation promoting factors, tumor cell migration, an increase in intracellular mobilization of Ca(2+), and membrane depolarization in gliomas. Therefore, this review summarizes the recent findings on calcium channels and associated receptors as potential targets to treat malignant gliomas. PMID:27418672

  6. Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors1

    PubMed Central

    Stearns, Mark E; Wang, Min

    2011-01-01

    We have examined whether epigallocatechin-3-gallate (EGCG), and extract of green tea, in combination with taxane (i.e., paclitaxel and docetaxel), exerts a synergistic activity in blocking human prostate PC-3ML tumor cell growth in vitro and in vivo. Growth assays in vitro revealed that the IC50 values were ∼30 µM, ∼3 nM, and ∼6 nM, for EGCG, paclitaxel and docetaxel, respectively. Isobolograms generated from the data clearly indicated that EGCG in combination with paclitaxel or docetaxel had an additive effect in blocking tumor cell growth. EGCG combined with taxane also had an additive effect to increase the expression of apoptotic genes, (p53, p73, p21, and caspase 3) and the percent apoptosis observed in vitro and in tumor modeling studies in severe combined immunodeficient mice. The tumor modeling studies clearly showed that EGCG plus taxane injected intraperitoneally (i.p.) induced a significant increase in apoptosis rates (TUNEL assays) and eliminated preexisting tumors generated from PC-3ML cells implanted i.p., increasing disease-free survival rates to greater than 90%. More importantly, the combination therapy (i.p. biweekly) blocked metastases after intravenous injection of PC-3ML cells through the tail vein. In mice treated with EGCG plus taxane, the disease-free survival rates increased from 0% (in untreated mice) to more than 70% to 80% in treated mice. Taken together, these data demonstrate for the first time that EGCG in combination with taxane may provide a novel therapeutic treatment of advanced prostate cancer. PMID:21633670

  7. Aggressive Metaplastic Carcinoma of the Breast with Osteoclastic Giant Cells

    PubMed Central

    Khong, Kathleen; Zhang, Yanhong; Tomic, Mary; Lindfors, Karen; Aminololama-Shakeri, Shadi

    2015-01-01

    Metaplastic carcinoma of the breast is an uncommon type of malignancy that is aggressive but can mimic other benign breast neoplastic processes on imaging. We present a case of a young female patient who presented with a rapidly progressing metaplastic carcinoma with osteoclastic giant cells subtype. There have been only very rare published reports of this pathologic subtype of metaplastic carcinoma containing osteoclastic giant cells. PMID:26629304

  8. Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells.

    PubMed

    Ho, Shuk-Mei; Lau, Kin-Mang; Mok, Samuel Chi-Ho; Syed, Viqar

    2003-07-01

    Epidemiological data have implicated the pituitary gonadotropin follicle stimulating hormone (FSH) as both a risk factor for and a protective agent against epithelial ovarian cancer. Yet, little is known about how this hormone could play such opposing roles in ovarian carcinogenesis. Complementary DNA microarrays containing 2400 named genes were used to examine FSH-induced gene expression changes in ovarian cancer (OC) and immortalized normal human ovarian surface epithelial (HOSE) cell lines. Two-way t-statistics analyses of array data identified two distinct sets of FSH-regulated genes in HOSE and in established OC cell lines established from patients (OVCA cell lines). Among the HOSE cell lines, FSH increased expression of 57% of the 312 genes and downregulated 43%. In contrast, FSH diminished expression of 92% of the 177 genes in the OVCA cell lines. All but 18 of the genes affected by FSH in HOSE cell lines were different from those altered in OVCA cell lines. Among the 18 overlapping genes, nine genes exhibited the same direction of change following FSH challenge, while the other nine showed discordance in response between HOSE and OVCA cell lines. The FSH-induced differential expression of seven out of nine genes was confirmed by real-time RT-PCR. Gene-specific antisense oligonuleotides (ODNs) were used to inhibit the expression of genes encoding GTPase activating protein (rap1GAP), neogenin, and restin in HOSE and OVCA cells. Antisense ODNs to neogenin and restin, but not an antisense ODN to rap1GAP, were effective in inhibiting OVCA cell growth, diminishing proliferating cell nuclear antigen expression, and increasing caspase 3 activities. Furthermore, the ODN to rap1GAP was further shown to be ineffective in altering migration properties of OVCA cell lines. HOSE cell proliferation was not affected by treatment with any of the antisense ODNs. In summary, gene profiling data reveal for the first time that FSH may exert different biological actions on OVCA

  9. Malignant teratoma (image)

    MedlinePlus

    A malignant teratoma is a type of cancer consisting of cysts that contain one or more of the three primary embryonic germ layers: ectoderm, mesoderm, and endoderm. Because malignant teratomas have usually spread by the time of diagnosis, ...

  10. Primary Spindle Cell Malignant Melanoma of Esophagus: An Unusual Finding

    PubMed Central

    Rawandale, Nirmalkumar A.

    2016-01-01

    Malignant melanoma of esophagus is usually a metastatic tumour rather than a primary tumour. Primary malignant melanoma accounts for less than 0.2% of all esophageal neoplasm. We report a case of primary spindle cell malignant melanoma of esophagus in a 69-year-old male who presented with history of dysphagia since 1 month. Radiological examinations revealed polypoidal growth at lateral aspect of esophagus. Biopsy was reported as grade III squamous cell carcinoma. Video assisted thoracoscopic esophagectomy was performed. Histopathological examination along with immunohistochemistry gave confirmed diagnosis of primary spindle cell malignant melanoma of esophagus. Though a rare entity, due to its aggressive nature and poor prognosis primary malignant melanoma should be one of the differential diagnoses in a patient with polypoidal esophageal mass lesion. Despite radical surgical treatment prognosis is extremely poor. PMID:27042502

  11. Malignant epitheloid angiomyolipoma of the kidney in a child treated with sunitinib, everolimus and axitinib

    PubMed Central

    Citak, Elvan Caglar; Yilmaz, Eda Bengi; Yaman, Emel; Kaya, Simge; Taskinlar, Hakan; Arpaci, Rabia Bozdogan; Apaydin, Demir

    2015-01-01

    The malignant variant of epithelioid angiomyolipoma (EAML) of the kidney is uncommon, extremely aggressive and behaves like a renal cell carcinoma. We present a case of a 12-year-old male with malignant EAML who was treated according to adult treatment protocols. To our knowledge, axitinib has not been used before in children. We conclude that adult protocols, in this rare case, could be safely used in rare childhood malignancies. PMID:26279736

  12. Pediatric Salivary Gland Malignancies.

    PubMed

    Ord, Robert A; Carlson, Eric R

    2016-02-01

    Pediatric malignant salivary gland tumors are extremely rare. The percentage of malignant tumors is higher than that seen in adults, although the outcomes in terms of survival are better in pediatric patients. The mainstay of treatment is surgical excision with negative margins. This article reviews current concepts in demographics, etiology, management, and outcomes of malignant salivary tumors in children. PMID:26614703

  13. Motives in Sexual Aggression: The Chinese Context.

    ERIC Educational Resources Information Center

    Tang, Catherine So-Kum; And Others

    1993-01-01

    Compared sexual and aggressive motives for sexual aggression in Chinese college students. Male undergraduates (N=146) completed self-report measures. Results suggest that sex guilt and aggressive guilt acted as inhibitors for their respective drives and sexual aggression resulted from aggressive, rather than sexual, motives. Sexual aggression may…

  14. Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer.

    PubMed

    Matsuzaki, Koichi; Kitano, Chiaki; Murata, Miki; Sekimoto, Go; Yoshida, Katsunori; Uemura, Yoshiko; Seki, Toshihito; Taketani, Shigeru; Fujisawa, Jun-ichi; Okazaki, Kazuichi

    2009-07-01

    Transforming growth factor (TGF)-beta initially inhibits growth of mature epithelial cells. Later, however, autocrine TGF-beta signaling acts in concert with the Ras pathway to induce a proliferative and invasive phenotype. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also Ras-associated kinases, which differentially phosphorylate the mediators Smad2 and Smad3 to create distinct phosphorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C) and both linker and COOH-terminally phosphorylated Smad2/3 (pSmad2L/C and pSmad3L/C). In this study, we investigated actions of pSmad2L/C and pSmad3L/C in cancer progression. TGF-beta inhibited cell growth by down-regulating c-Myc oncoprotein through the pSmad2C and pSmad3C pathway; TGF-beta signaling, in turn, enhanced cell growth by up-regulating c-Myc through the cyclin-dependent kinase (CDK) 4-dependent pSmad2L/C and pSmad3L/C pathways in cell nuclei. Alternatively, TbetaRI and c-Jun NH2-terminal kinase (JNK) together created cytoplasmic pSmad2L/C, which entered the nucleus and stimulated cell invasion, partly by up-regulating matrix metalloproteinase-9. In 20 clinical samples, pSmad2L/C and pSmad3L/C showed nuclear localization at invasion fronts of all TGF-beta-producing human metastatic colorectal cancers. In vitro kinase assay confirmed that nuclear CDK4 and cytoplasmic JNK obtained from the tumor tissue could phosphorylate Smad2 or Smad3 at their linker regions. We suggest that CDK4, together with JNK, alters tumor-suppressive TGF-beta signaling to malignant characteristics in later stages of human colorectal cancer. The linker phosphorylation of Smad2 and Smad3 may represent a target for intervention in human metastatic cancer. PMID:19531654

  15. Meningioma after radiotherapy for malignancy.

    PubMed

    Morgenstern, Peter F; Shah, Kalee; Dunkel,