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Therapy.
Kinds of Therapy. Selected AbstractsDevelopment of microdevices for physioelectrical measurement of biological cellsELECTRONICS & COMMUNICATIONS IN JAPAN, Issue 1 2008Takanori Akagi Abstract Electrical characteristics of biological cells are important indices for obtaining information about the state and function of a cell. In this paper, we report the development of microdevices for physioelectrical measurement of cells by applying nano/microfabrication technologies. These devices enable the highly precise measurement of cell membrane potential and zeta potential of individual cells in a minimally invasive manner. Such a fusion of the microdevice technologies and biotechnologies is expected to provide power diagnostic tools for future cell study and cell therapy. © 2008 Wiley Periodicals, Inc. Electron Comm Jpn, 91(1): 40, 45, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10027 [source] A role for endogenous reverse transcriptase in tumorigenesis and as a target in differentiating cancer therapyGENES, CHROMOSOMES AND CANCER, Issue 1 2006Paola Sinibaldi-Vallebona An unexpected result emerging from completion of the genome sequencing project is that a large portion of mammalian genomes is constituted by retrotransposons. A large body of published data supports the conclusion that retrotransposons are biologically active elements and indicates that retrotransposition is an ongoing process in mammalian genomes. Retroelements can act as insertional mutagens altering the coding integrity of genes and, recently, have been found to also affect the expression of cellular genes at the epigenetic level: in this light, they are a potential threat in that these events can trigger the onset of several pathologies including cancer. Retroelement genes, and particularly the gene coding for reverse transcriptase (RT), are typically expressed at high levels in transformed cells and tumors. In recent work, we have found that drug-mediated inhibition of the endogenous RT activity, or silencing of expression of active retrotransposons of the LINE-1 family by RNA interference, down-regulate cell growth and induce the activation of differentiating functions in several cancer cell lines. Moreover, the inhibition of endogenous RT activity in vivo antagonizes the growth of human tumors in animal models. In this review, we discuss newly emerging concepts on the role of retrotransposons and suggest that an abnormally high level of the RT activity that they encode may contribute to the loss of control in the proliferation and differentiation programs typical of transformed cells. In this light, RT-coding elements may be regarded as promising targets in the development of novel, differentiation-inducing approaches to cancer therapy. © 2005 Wiley-Liss, Inc. [source] Salivary duct carcinoma: A clinical and histologic review with implications for trastuzumab therapyHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2007Vishad Nabili MD Abstract Background Salivary duct carcinoma (SDC) is an aggressive tumor of the head and neck with a poor prognosis. The objective was to study SDC and recommend the use of trastuzumab as adjuvant therapy. Methods A retrospective chart review of patients seen between 1993 and 2006 was performed. Tumor specimens were examined for HER-2 protein overexpression via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. Results Of the 7 patients with SDC, 57% had tumors arising in the parotid gland, the majority having facial nerve paralysis, 71% with nodal disease, and 43% having recurrence. All samples were HER-2 positive on IHC. Three patients had FISH-positive tumors, recurrent disease, and recieved trastuzumab therapy; 1 of the 3 died after 20 months and a second has shown disappearance of metastatic disease. Conclusions Trastuzumab is effective in treating HER-2-positive breast cancer. Given immunohistochemical similarities between SDC and ductal carcinoma of the breast, patients with FISH-positive HER-2/neu SDC should be considered for trastuzumab therapy. © 2007 Wiley Periodicals, Inc. Head Neck 2007 [source] External auditory canal eccrine spiradenocarcinoma: A case report and review of literatureHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2003Tanya K. Meyer MD Abstract Background. Eccrine spiradenocarcinoma is a rare dermal appendage carcinoma believed to arise from transformation of a long-standing benign spiradenoma. This tumor demonstrates highly malignant biologic behavior with a high recurrence rate, frequent lymph node metastases, and overall poor survival. Methods. We report the first case of eccrine spiradenocarcinoma arising in the external auditory canal. The management of this tumor, its histopathologic characteristics, and a review of literature are presented. Results. A literature review identified 17 cases of eccrine spiradenocarcinoma in the head and neck region. Local recurrence occurred in 58.8% of patients, with an average of 23 months from diagnosis. Lymph node metastasis occurred in 35.3%, with an average of 31 months from diagnosis. Other metastatic sites included skin, bone, and lung. Disease-specific mortality was 22.2%. Conclusions. Eccrine spiradenocarcinoma is an aggressive tumor with a poor prognosis. Primary treatment should include wide local excision with or without regional lymphadenectomy. Isolated successful treatments have been documented with adjuvant hormonal manipulation, chemotherapy, and radiation therapy. © 2003 Wiley Periodicals, Inc. Head Neck 25: 505,510, 2003 [source] Free tissue transfer and local flap complications in anterior and anterolateral skull base surgeryHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2002Jason A. Heth MD Abstract Background Advances in reconstructive techniques over the past two decades have allowed the resection of more extensive skull base tumors than had previously been possible. Despite this progress, complications related to these cases remain a concern. Methods Univariate and multivariate analyses were used to determine the relationship of host, tumor, defect, treatment, and reconstructive variables to wound and systemic complications after anterior and anterolateral skull base resections. The study included 67 patients receiving local flap (LF) or free tissue transfer (FTT) reconstructions during an 8-year period. Results Overall, 28% of patients had a major wound complication, and 19% had a major systemic complication. LF and FTT flaps had similar rates of wound complications. LF reconstructions were associated with late wound breakdown problems, and FTT flap complications were primarily acute surgery,related problems. Conclusions The surgical reconstruction of skull base defects should be planned on the basis of the ability of the technique to attain safe closure and maintain integrity after radiation therapy. © 2002 Wiley Periodicals, Inc. Head Neck 24: 00,00, 2002 [source] The sarcomatous guise of cervical ectopic hamartomatous thymoma,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2002Jeff Marschall MD Abstract Background Ectopic hamartomatous thymoma is a rare benign neoplasm occurring in the deep soft tissues adjacent to the sternoclavicular joint. Although clinical presentation and diagnostic imaging can be consistent with a malignant lesion such as a sarcoma, recognition of pathologic features can readily exclude such a diagnosis. However, this remains a challenge caused by their unusual histologic features and diverse composition. Recognition of this tumor is, however, important, because it follows a benign clinical course, and conservative surgical excision is the therapy of choice. Methods A literature review of all reports of ectopic hamartomatous thymoma was undertaken and compared with our indexed case. Results From this review, we identified 26 previous reports. Most patients were men, with a 4.5:1 predominance. There was a wide range of ages at presentation, from 26 to 79 years. All tumors were located in the lower neck, with the exception of one arising presternally. Treatment predominantly consisted of tumor resection, with no reported recurrences on follow-up. Conclusions We conclude that ectopic hamartomatous thymoma is an extremely rare neoplasm usually presenting in the lower neck. Correct identification of this tumor is important, because it follows a benign course, and surgical excision is adequate therapy. © 2002 Wiley Periodicals, Inc. Head Neck 24: 800,804, 2002 [source] Preoperative risk assessment for gastrostomy tube placement in head and neck cancer patientsHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 5 2001John M. Schweinfurth MD Abstract Background The presentation and definitive surgical treatment of head and neck malignancies have varying impact on postoperative recovery and return of swallowing function, which heretofore has not been well defined. Methods We performed a retrospective chart review of 142 patients who underwent extirpative surgery for head and neck cancer. Results Factors significantly associated with the need for long-term postoperative nutritional support (p < .05) included heavy alcohol use, tongue base involvement and surgery, pharyngectomy, composite resection, reconstruction with a myocutaneous flap, radiation therapy, tumor size, and moderately-to-poorly differentiated histology. Heavy alcohol users were at an absolute risk for gastrostomy tube dependence; patients who underwent radiation therapy, flap reconstruction, tongue base resection, and pharyngectomy were at a two to sevenfold increased risk for gastrostomy tube dependence, respectively. Conclusions High-risk patients based on these criteria should receive a feeding gastrostomy at the time of their initial surgical therapy. © 2001 John Wiley & Sons, Inc. Head Neck 23: 376,382, 2001. [source] Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome,HEPATOLOGY, Issue 1 2010André Nazar Terlipressin plus albumin is an effective treatment for type 1 hepatorenal syndrome (HRS), but approximately only half of the patients respond to this therapy. The aim of this study was to assess predictive factors of response to treatment with terlipressin and albumin in patients with type 1 HRS. Thirty-nine patients with cirrhosis and type 1 HRS were treated prospectively with terlipressin and albumin. Demographic, clinical, and laboratory variables obtained before the initiation of treatment as well as changes in arterial pressure during treatment were analyzed for their predictive value. Response to therapy (reduction in serum creatinine <1.5 mg/dL at the end of treatment) was observed in 18 patients (46%) and was associated with an improvement in circulatory function. Independent predictive factors of response to therapy were baseline serum bilirubin and an increase in mean arterial pressure of ,5 mm Hg at day 3 of treatment. The cutoff level of serum bilirubin that best predicted response to treatment was 10 mg/dL (area under the receiver operating characteristic curve, 0.77; P < 0.0001; sensitivity, 89%; specificity, 61%). Response rates in patients with serum bilirubin <10 mg/dL or ,10 mg/dL were 67% and 13%, respectively (P = 0.001). Corresponding values in patients with an increase in mean arterial pressure ,5 mm Hg or <5 mm Hg at day 3 were 73% and 36%, respectively (P = 0.037). Conclusion: Serum bilirubin and an early increase in arterial pressure predict response to treatment with terlipressin and albumin in type 1 HRS. Alternative treatment strategies to terlipressin and albumin should be investigated for patients with type 1 HRS and low likelihood of response to vasoconstrictor therapy. (HEPATOLOGY 2009.) [source] Hepatitis C virus infection and its clearance alter circulating lipids: Implications for long-term follow-up,HEPATOLOGY, Issue 4 2009Kathleen E. Corey Hepatitis C associated hypolipidemia has been demonstrated in studies from Europe and Africa. In two linked studies, we evaluated the relationship between hepatitis C infection and treatment with lipid levels in an American cohort and determined the frequency of clinically significant posttreatment hyperlipidemia. First, a case-control analysis of patients with and without hepatitis C was performed. The HCV Group consisted of 179 infected patients. The Uninfected Control Group consisted of 180 age-matched controls. Fasting cholesterol, low density lipoprotein (LDL), high density lipoprotein and triglycerides were compared. Next was a retrospective cohort study (Treated Hepatitis C Group) of 87 treated hepatitis C patients with lipid data before and after therapy was performed. In the case-control analysis, the HCV Group had significantly lower LDL and cholesterol than the Uninfected Control Group. In the retrospective cohort, patients in the Treated Hepatitis C Group who achieved viral clearance had increased LDL and cholesterol from baseline compared to patients without viral clearance. These results persisted when adjusted for age, sex, and genotype. 13% of patients with viral clearance had increased LDL and 33% experienced increases in cholesterol to levels warranting lipid lowering therapy. Conclusion: Hepatitis C is associated with decreased cholesterol and LDL levels. This hypolipidemia resolves with successful hepatitis C treatment but persists in nonresponders. A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk. Lipids should be carefully monitored in persons receiving antiviral therapy. (HEPATOLOGY 2009;50:1030,1037.) [source] Outcomes of a patient-to-patient outbreak of genotype 3a hepatitis C,HEPATOLOGY, Issue 2 2009Mark E. Mailliard Between March 2000 and July 2001, at least 99 persons acquired a hepatitis C virus genotype 3a (HCV-3a) infection in an oncology clinic. This nosocomial HCV outbreak provided an opportunity to examine the subsequent clinical course in a well-defined cohort. This was a retrospective/prospective observational study of the short-term significant health outcomes of a large, single-source, patient-to-patient HCV-3a outbreak. Outbreak patients or their legal representatives consenting to study were enrolled between September 2002 and December 2007. We measured history and physical examinations, medical records, HCV serology, HCV RNA and genotype, liver enzymes, histology, response to antiviral therapy, and liver-related morbidity and mortality. Sixty-four of the 99 known HCV-3a outbreak patients participated. During a 6-year period, six patients developed life-threatening complications from liver disease, three died, one received a liver transplant, and two were stable after esophageal variceal banding or diuretic therapy of ascites. Thirty-three patients underwent antiviral therapy, with 28 achieving a sustained viral remission. One patient acquired HCV-3a infection sexually from an outbreak patient and was successfully treated. Eleven study patients died of malignancy, including two that had achieved a sustained viral remission after antiviral therapy. Conclusion: Our patient cohort had a nosocomial source and an oncologic or hematologic comorbidity. Compared with previous HCV outcome studies, a patient-to-patient HCV outbreak in an oncology clinic exhibited significant morbidity and mortality. Attention is needed to the public health risk of nosocomial HCV transmission, emphasizing infection control, early diagnosis, and therapy. (HEPATOLOGY 2009.) [source] MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells,HEPATOLOGY, Issue 1 2009Teng Xu Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (HEPATOLOGY 2009.) [source] Acute kidney injury in cirrhosis,HEPATOLOGY, Issue 6 2008Guadalupe Garcia-Tsao Acute renal failure (ARF), recently renamed acute kidney injury (AKI), is a relatively frequent problem, occurring in approximately 20% of hospitalized patients with cirrhosis. Although serum creatinine may underestimate the degree of renal dysfunction in cirrhosis, measures to diagnose and treat AKI should be made in patients in whom serum creatinine rises abruptly by 0.3 mg/dL or more (,26.4 ,mol/L) or increases by 150% or more (1.5-fold) from baseline. The most common causes of ARF (the term is used interchangeably with AKI) in cirrhosis are prerenal azotemia (volume-responsive prerenal AKI), acute tubular necrosis, and hepatorenal syndrome (HRS), a functional type of prerenal AKI exclusive of cirrhosis that does not respond to volume repletion. Because of the progressive vasodilatory state of cirrhosis that leads to relative hypovolemia and decreased renal blood flow, patients with decompensated cirrhosis are very susceptible to developing AKI with events associated with a decrease in effective arterial blood volume. HRS can occur spontaneously but is more frequently precipitated by events that worsen vasodilatation, such as spontaneous bacterial peritonitis. Conclusion: Specific therapies of AKI depend on the most likely cause and mechanism. Vasoconstrictors are useful bridging therapies in HRS. Ultimately, liver transplantation is indicated in otherwise reasonable candidates in whom AKI does not resolve with specific therapy. (HEPATOLOGY 2008;48:2064-2077.) [source] Treating hepatitis C in the prison population is cost-saving,HEPATOLOGY, Issue 5 2008Jennifer A. Tan The prevalence of chronic hepatitis C infection in U.S. prisons is 12% to 31%. Treatment of this substantial portion of the population has been subject to much controversy, both medically and legally. Studies have demonstrated that treatment of chronic hepatitis C with pegylated interferon (PEG IFN) and ribavirin is a cost-effective measure in the general population; however, no study has addressed whether the same is true of the prison population. The aim of this study was to determine the cost-effectiveness of hepatitis C treatment with PEG IFN and ribavirin in the U.S. prison population. Cost-effectiveness was determined via a decision analysis model employing Markov simulation. The cohort of prisoners had a distribution of genotypes and stages of fibrosis in accordance with prior studies evaluating inmate populations. The probability of transitioning from one health state to another, reinfection rates, in-prison and out-of-prison mortality rates, sustained viral response rates, costs, and quality of life weights were also obtained from the literature. Sensitivity analysis was performed. In a strategy without a pretreatment liver biopsy, treatment was cost-effective for all ages and genotypes. This model was robust to rates of disease progression, mortality rates, reinfection rates, sustained viral response rates, and costs. In a strategy employing a pretreatment liver biopsy, treatment was also cost-saving for prisoners of all ages and genotypes with portal fibrosis, bridging fibrosis, or compensated cirrhosis. Treatment was not cost-effective in patients between the ages of 40 and 49 with no fibrosis and genotype 1. Conclusion: Treatment of chronic hepatitis C with PEG IFN and ribavirin in U.S. prisons results in both improved quality of life and savings in cost for almost all segments of the inmate population. If the decision to treat hepatitis C is based on pharmaco-economic measures, this significant proportion of infected individuals should not be denied access to therapy. (HEPATOLOGY 2008.) [source] Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells,HEPATOLOGY, Issue 2 2006Yao-Ming Wu Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression. It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing long-term survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410,419.) [source] Influence of beta-2 adrenergic receptor gene polymorphism on the hemodynamic response to propranolol in patients with cirrhosis,HEPATOLOGY, Issue 1 2006Juan Turnes The beta-2-adrenergic receptor (,2- -AR) has several single-nucleotide polymorphisms. These influence the functional response to adrenergic stimulation; genotypes homozygous for Gly16-Glu27 or Gly16-Gln27 alleles (Gly16-Glu/Gln27 haplotypes) are associated with enhanced response, whereas genotypes homozygous for Arg16-Gln27 alleles (Arg16-Gln27) show a decreased response. We hypothesized that gene polymorphisms at the ,2 -AR may influence the hemodynamic response to propranolol in patients with cirrhosis. The ,2 -AR gene polymorphisms were determined by direct sequencing of the polymerase chain reaction (PCR) products in 48 patients with cirrhosis. All patients also had hepatic and systemic hemodynamic studies before and after propranolol administration. Prevalence of Gly16-Glu/Gln27 haplotypes was 29.1%, Arg16-Gln27 haplotype was 16.7%, and 54.2% were compound heterozygotes. Patients with cirrhosis with Gly16-Glu/Gln27 haplotypes had a greater decrease in heart rate, cardiac index, and hepatic blood flow after propranolol administration than those with Arg16-Gln27 haplotype. However, the HVPG response to propranolol was similar in both groups, whereas estimated hepatic sinusoidal resistance increased significantly in Gly16-Glu/Gln27 haplotypes but not in Arg16-Gln27 (+27.1 ± 17.8% vs -17.9 ± 13.9%, P = .042), suggesting that unopposed vasoconstrictive activity at the intrahepatic circulation hinders the fall in HVPG despite enhanced hemodynamic response to propranolol in Gly16-Glu/Gln27 haplotypes. In conclusion, ,2 -AR gene polymorphisms influence the response to beta-blockade. However, HVPG reduction cannot be predicted from polymorphism analysis. Patients with the Gly16-Glu/Gln27 haplotypes may benefit from the association of hepatic vasodilators to propranolol therapy. (HEPATOLOGY 2005;43:34,41.) [source] New amidino-benzimidazolyl thiophenes: Synthesis and photochemical synthesisHETEROATOM CHEMISTRY, Issue 3 2003Kristina Star New amidino-benzimidazolyl-substituted bis-1,2-(2-thienyl)ethenes (4, 5, and 6) and benzo[1,2- b:4,3- b,]dithiophenes (8, 9, and 10) were prepared by the condensation of amidino-substituted o-phenylene diamines with corresponding dialdehydes (3 and 7). All prepared amidino-benzimidazolyl-substituted compounds are of particular interest, because they can serve as intercalators or groove binders on DNA in anticancer therapy. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:218,222, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10126 [source] Estradiol enhances long term potentiation in hippocampal slices from aged apoE4-TR miceHIPPOCAMPUS, Issue 12 2007Sung Hwan Yun Abstract Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24,27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy. © 2007 Wiley-Liss, Inc. [source] Screening of 25 Italian patients with Niemann-Pick a reveals fourteen new mutations, one common and thirteen private, in SMPD1,,HUMAN MUTATION, Issue 1 2004V. Ricci Abstract Niemann-Pick disease (NPD) results from the deficiency of lysosomal acid sphingomyelinase (SMPD1). To date, out of more than 70-disease associated alleles only a few of them have a significant frequency in various ethnic groups. In contrast, the remainder of the mutations are rare or private. In this paper we report the molecular characterization of an Italian series consisting of twenty-five NPD patients with the severe neurodegenerative A phenotype. Mutation detection identified a total of nineteen different mutations, including 14 novel mutations and five previously reported lesions. The known p.P189fs and the novel p.T542fs were the most frequent mutations accounting for 34% and 18% of the alleles, respectively. Screening the alleles for the three common polymorphisms revealed the variant c.1516G>A (exon 6) and the repeat in exon 1, but not the variant c.965C>T (exon 2). In absence of frequent mutations, the prognostic value of genotyping is limited. However, new genotype/phenotype correlations were observed for this disorder that could in the future facilitate genetic counseling and guide selection of patients for therapy. © 2004 Wiley-Liss, Inc. [source] Cytomegalovirus in inflammatory bowel disease: Pathogen or innocent bystander?INFLAMMATORY BOWEL DISEASES, Issue 9 2010Garrett Lawlor MD Abstract The role of cytomegalovirus (CMV) in exacerbations of inflammatory bowel disease (IBD) remains a topic of ongoing debate. Current data are conflicting as to whether CMV worsens inflammation in those with severe colitis, or is merely a surrogate marker for severe disease. The interpretation of existing results is limited by mostly small, retrospective studies, with varying definitions of disease severity and CMV disease. CMV colitis is rare in patients with Crohn's disease or mild-moderate ulcerative colitis. In patients with severe and/or steroid-refractory ulcerative colitis, local reactivation of CMV can be detected in actively inflamed colonic tissue in about 30% of cases. Where comparisons between CMV+ and CMV, steroid-refractory patients can be made, most, but not all, studies show no difference in outcomes according to CMV status. Treatment with antiviral therapy has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies. This article reviews the immunobiology of CMV disease, the evidence for CMV's role in disease severity, and discusses the outcomes with antiviral therapy. (Inflamm Bowel Dis 2010) [source] PTD4-apoptin protein therapy inhibits tumor growth in vivoINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Jun Sun Abstract Apoptin protein harbors tumor-selective cell death activity, which makes it a potential anticancer therapy candidate. This study reports an apoptin therapy approach based on protein transduction domain 4 (PTD4)-mediated transduction of recombinant apoptin protein. In vitro, the PTD4-apoptin fusion protein is located in the nucleus and induces cell death in, e.g., human hepatocarcinoma HepG2 cells. In normal human L-02 hepatocytes, PTD4-apoptin protein retained mainly cytoplasmic and did not induce detectable levels of cell death, illustrating that the PTD4 domain does not affect apoptin's tumor-selective characteristics. In vivo, liver, cervix and gastric carcinoma xenografts treated with PTD4-apoptin protein for 6 days via the tumor epidermis exhibited a significant tumor growth inhibition because of apoptin-mediated cell death. In addition, treatment of human hepatocarcinoma xenografts during 3 weeks showed that PTD4-apoptin protein has significant anticancer activity, whereas control treatment with PTD4-enhanced green fluorescence protein or saline did not. Cell death and disruption of the tumor integrity were apparent in the PTD4-apoptin transduced xenografted tumors. As important, although PTD4-apoptin protein could be detected in the epidermal tissue covering the subcutaneous tumor tissue and in several organs, such as liver and brain, of the treated mice, no tissue disruption or signs of cell death could be detected. Our in vivo data reveal that apoptin protein delivery constitutes a novel powerful and safe anticancer therapy. © 2009 UICC [source] P53 mutations in stromal fibroblasts sensitize tumors against chemotherapyINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Daniel Lafkas Abstract The efficacy of chemotherapy is usually viewed as the outcome of cancer-cell-autonomous processes while the contribution of stroma is being overseen. Here we show that p53 mutations in stromal fibroblasts, a genetic lesion that is detectable in primary breast, prostate and probably other cancers, while they accelerate tumorigenesis they also sensitize tumours against conventional chemotherapy by doxorubicin and cis -platinum. The mechanism by which p53 of stromal fibroblasts affects the response of a tumour against chemotherapy is likely to involve the induction of senescence in the fibroblasts which in turns results in the production of growth factors acting onto the cancer cells by paracrine mechanisms. Our findings identify stromal fibroblasts as important modulators of the efficacy of anticancer therapy. © 2008 Wiley-Liss, Inc. [source] EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Birgit Geoerger Abstract Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy. © 2008 Wiley-Liss, Inc. [source] Combining adenoviral oncolysis with temozolomide improves cell killing of melanoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Christina Quirin Abstract Oncolytic Adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. Clinical studies with first generation oncolytic adenoviruses have revealed that an increased potency is warranted in order to achieve therapeutic efficacy. One approach towards this end is to combine adenoviral oncolysis with chemotherapy. Here, a fundamental requirement is that chemotherapy does not interfere with adenovirus replication in cancer cells. We have previously developed a melanoma-targeted oncolytic adenovirus, Ad5/3.2xTyr, which features tyrosinase promoter regulated replication and enhanced cell entry into melanoma cells. In this study, we investigated a combination treatment of melanoma cells with Ad5/3.2xTyr and temozolomide (TMZ), which produces the same active metabolite as Dacarbazine/DTIC, the standard chemotherapy for advanced melanoma. We report that TMZ does not inhibit adenovirus replication in melanoma cells. Additive or synergistic cell killing of melanoma cells, dependent on the cell line used, was observed. Enhanced cell binding was not responsible for synergism of adenoviral oncolysis and TMZ treatment. We rather observed that higher numbers of virus genomes are produced in TMZ-treated cells, which also showed a cell cycle arrest in the G2 phase. Our results have important implications for the clinical implementation of adenoviral oncolysis for treatment of malignant melanoma. It suggests that such studies are feasible in the presence of TMZ or DTIC chemotherapy and recommends the investigation of a viro-chemo combination therapy. © 2007 Wiley-Liss, Inc. [source] Autoimmunity as a prognostic factor in melanoma patients treated with adjuvant low-dose interferon alphaINTERNATIONAL JOURNAL OF CANCER, Issue 11 2007Imke Satzger Abstract Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant high-dose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5,79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan,Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy. © 2007 Wiley-Liss, Inc. [source] In vitro and in vivo evaluation and a case report of intense nanosecond pulsed electric field as a local therapy for human malignanciesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Edward B. Garon Abstract When delivered to cells, very short duration, high electric field pulses (nanoelectropulses) induce primarily intracellular events. We present evidence that this emerging modality may have a role as a local cancer therapy. Five hematologic and 16 solid tumor cell lines were pulsed in vitro. Hematologic cells proved particularly sensitive to nanoelectropulses, with more than a 60% decrease in viable cells measured by MTT assay 96 hr after pulsing in 4 of 5 cell lines. In solid tumor cell lines, 10 out of 16 cell lines had more than a 10% decrease in viable cells. AsPC-1, a pancreatic cancer cell line, demonstrated the greatest in vitro sensitivity among solid tumor cell lines, with a 64% decrease in viable cells. When nanoelectropulse therapy was applied to AsPC-1 tumors in athymic nude mice, responses were seen in 4 of 6 tumors, including clinical complete responses in 3 of 6 animals. A single human subject applied nanoelectropulse therapy to his own basal cell carcinoma and had a complete pathologic response. In summary, we demonstrate that electric pulses 20 ns or less kill a wide variety of human cancer cells in vitro, induce tumor regression in vivo, and show efficacy in a single human patient. Therefore, nanoelectropulse therapy deserves further study as a potentially effective cancer therapy. © 2007 Wiley-Liss, Inc. [source] BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHRINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Lu Hao Abstract Cyclin D1 plays an important role in cell cycle progression. In breast cancer, Cyclin D1 expression is deregulated by several mechanisms. We previously showed that in breast cancer cells, overexpression of BRCA1-IRIS induces Cyclin D1 overexpression and increases cell proliferation. BRCA1-IRIS alone or in complex with steroid receptor co-activators was targeted to the cyclin D1 promoter pre-bound by the c-Jun/AP1 and activated its transcription, which could explain the co-overexpression of BRCA1-IRIS and Cyclin D1 in breast cancer cells coupled with their increased proliferation. We report here an alternate or a complementary pathway by which BRCA1-IRIS activates Cyclin D1 expression. BRCA1-IRIS overexpression decreases the expression of the dual specificity phosphatase, DUSP3/VHR, an endogenous inhibitor of several MAPKs, including c-Jun N-terminal kinase. Although, the mechanism by which BRCA1-IRIS overexpression accomplishes that is not yet known, it is sufficient to induce Cyclin D1 overexpression in a human mammary epithelial cell model. Cyclin D1 overexpression could be blocked by co-overexpression of VHR in those cells. Furthermore, in 2 breast cancer cell lines that overexpress both BRCA1-IRIS and Cyclin D1 (MCF-7 and SKBR3) depletion of BRCA1-IRIS by RNA interference attenuated the expression of Cyclin D1 by elevating the expression level of VHR. These data demonstrate a critical role for BRCA1-IRIS in human breast cancer cell-cycle control and suggest that deregulated expression of BRCA1-IRIS is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy. © 2007 Wiley-Liss, Inc. [source] The increased expression of Y box-binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistanceINTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Birgit Schittek Abstract In previous studies we identified the transcription/translation factor Y-box-binding protein (YB-1) as a gene that is upregulated in primary melanoma and melanoma metastases when compared to benign melanocytic nevi. To analyze whether YB-1 expression correlates with melanoma progression in vitro and in vivo, we performed expression analysis on melanoma cell lines representing different stages of melanoma progression and on tissues of melanocytic nevi, primary melanoma and melanoma metastases. Our data indicate that compared to benign melanocytes YB-1 expression is increased in melanoma cells in vitro and in vivo and that YB-1 is translocated into the nucleus in invasive and metastatic melanoma cells. To reveal the functional role of YB-1 in melanoma progression we achieved a stable downregulation of YB-1 using shRNA in metastatic melanoma cells. Interestingly, YB-1 downregulation resulted in a pronounced reduced rate of proliferation and an increased rate of apoptotic cell death. In addition, migration and invasion of melanoma cells in monolayer and in a three-dimensional skin reconstruct in vitro was significantly reduced. These effects were accompanied by downregulation of genes involved in proliferation, survival and migration/invasion of melanoma cells such as MMP-2, bcl-2, Cyclin D1, p53 and p16INK4A. Furthermore, melanoma cells with a reduced YB-1 expression showed a decreased resistance to the chemotherapeutic agents cisplatin and etoposide. These data suggest that YB-1 is involved in malignant transformation of melanocytes and contributes to the stimulation of proliferation, tumor invasion, survival and chemoresistance. Thus, YB-1 may be a promising molecular target in melanoma therapy. © 2007 Wiley-Liss, Inc. [source] Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental modelINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Sven A. Lang Abstract The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1, (HIF-1,). Since mTOR is an upstream regulator of HIF-1,, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1, activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1, activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy. © 2007 Wiley-Liss, Inc. [source] Loss of RAB25 expression in breast cancerINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Ji-Ming Cheng Abstract A novel breast cancer cell line (RAO-3) was established by transduction of the Q61L mutant RAS into human mammary epithelial cells that were immortalized with catalytic subunit of telomerase (hTERT). The cells displayed anchorage-independent growth and proliferation, and formed human mammary spindle cell carcinoma when injected into nude mice. Chromosome locus 1q22-23 was partially duplicated and inverted on one of the 3 chromosomes present in the cell line. We report here that mutations of chromosome 1q22-23 locus have resulted in the loss of RAB25 expression in the breast cancer cell line. Transduction of RAB25 into the breast cancer cell line arrests anchorage-independent growth. We have also demonstrated loss of RAB25 in human breast tumor tissue. These data suggest that loss of RAB25 might contribute to tumorigenesis of breast cancer, and RAB25 is likely to be an important factor in the development of breast cancer. RAB25 could be used as biological marker of breast cancer and provides a target for gene replacement therapy. © 2006 Wiley-Liss, Inc. [source] Steroid hormone receptors and coregulators in endocrine-resistant and estrogen-independent breast cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Nanna Sarvilinna Abstract Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen- and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in anti-estrogen-resistant cells. Estrogen caused PR and ER, upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ER, levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (N-CoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy. © 2005 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||