Biomedical subjects

Sreelatha Meleth

Publications and source records attributed to Sreelatha Meleth.

At least 19 recordsLinked to original sources

PubMed2006

Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods.

AIMS: Non-potassium-sparing diuretics are commonly used in heart failure (HF). They activate the neurohormonal system, and are potentially harmful. Yet, the long-term effects of chronic diuretic use in HF are largely unknown. We retrospectively analysed the Digitalis Investigation Group (DIG) data to determine the effects of diuretics on HF outcomes. METHODS AND RESULTS: Propensity scores for diuretic use were calculated for each of the 7788 DIG participants using a non-parsimonious multivariable logistic regression model, and were used to match 1391 (81%) no-diuretic patients with 1391 diuretic patients. Effects of diuretics on mortality and hospitalization at 40 months of median follow-up were assessed using matched Cox regression models. All-cause mortality was 21% for no-diuretic patients and 29% for diuretic patients [hazard ratio (HR) 1.31; 95% confidence interval (CI) 1.11-1.55; P = 0.002]. HF hospitalizations occurred in 18% of no-diuretic patients and 23% of diuretic patients (HR 1.37; 95% CI 1.13-1.65; P = 0.001). CONCLUSION: Chronic diuretic use was associated with increased long-term mortality and hospitalizations in a wide spectrum of ambulatory chronic systolic and diastolic HF patients. The findings of the current study challenge the wisdom of routine chronic use of diuretics in HF patients who are asymptomatic or minimally symptomatic without fluid retention, and are on complete neurohormonal blockade. These findings, based on a non-randomized design, need to be further studied in randomized trials.

Adult↗

PubMed2006

Association of SULT2A1 allelic variants with plasma adrenal androgens and prostate cancer in African American men.

Dehydroepiandrosterone (DHEA) sulfate which is present at micromolar levels in the plasma, can be desulfated to supply free DHEA for metabolism to androgens or estrogens in peripheral tissues. Human cytosolic sulfotransferase (SULT) 2A1 catalyzes DHEA sulfation in the adrenal cortex. Three SULT2A1 nonsynonymous coding single nucleotide polymorphisms (SNPs), identified only in African Americans (AA), are associated with decreased levels of activity and expression as compared to wild-type cDNA when expressed in COS cells. To test whether the SNPs are associated with decreased plasma androgens, 124 normal AA men were genotyped and plasma DHEA, DHEA-sulfate and testosterone levels determined. The two SNPs identified in these participants occurred at allelic frequencies of 0.044 (G187C) and 0.101 (G781A). The G187C SNP was highly linked to the G781A SNP. Although no differences in hormone levels were associated with the individual SNPs, a significant increase in the DHEA:DHEA-sulfate ratio was observed in participants with a heterozygous G187C/G781A genotype. Increased free DHEA levels may result in increased testosterone synthesis and stimulation in the prostate, therefore a group of AA prostate cancer (PC) patients and controls were genotyped. No significant association of the presence of the different SULT2A1 alleles with the occurrence of PC was detected.

Androgens↗

PubMed2006

Proteomics analysis of the actions of grape seed extract in rat brain: technological and biological implications for the study of the actions of psychoactive compounds.

Grape seed extract (GSE) is a commonly available dietary supplement taken for the anti-oxidant activity that's attributed to its proanthocyanidin (oligomers of monomeric polyphenols) content. Similar polyphenol-enriched preparations from blueberries and soy have shown protection against ovariectomy-induced or age-related cognitive deficits, suggesting that the molecular changes induced by these polyphenol preparations correlated with behavioral benefit. We hypothesized that ingestion of polyphenol-enriched preparations such as GSE would be manifested as protein changes that would be consistent with neuroprotection. Proteomics technology, namely 2D gel electrophoresis and mass spectrometry, identified quantitative changes in specific proteins induced in adult rat brain following ingestion of a powdered preparation of GSE. As recently reported [Deshane, J., Chaves, L., Sarikonda, K.V., Isbell, S., Wilson, L., Kirk, M., Grubbs, C., Barnes, S., Meleth, S. and Kim, H., 2004. Proteomics analysis of rat brain protein modulations by grape seed extract. Journal of Agricultural and Food Chemistry 52, 7872-7883.], the direction of change for the majority of the affected proteins was opposite to the direction the proteins were changed in either Alzheimer disease or in transgenic mouse models of dementia. A conservative conclusion is that GSE has neuroprotective activity, by affecting specific proteins in particular ways. In this chapter, elements of proteomics-type analysis are discussed that demonstrate the power of the technology to enable discovery of proteins involved in the response of the brain to a stimulus whether it be a dietary supplement, or a psychoactive drug. The fact that GSE affects proteins implicated in cognitive disorders suggests moreover that GSE may have impact on the actions of psychoactive drugs by maintaining an overall viability of the nervous system.

Animals↗

PubMed2006

Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with experimental brain tumors.

Previous studies have described in vitro serial passage of a Deltagamma(1)34.5 herpes simplex virus type 1 (HSV-1) strain in SK-N-SH neuroblastoma cells and selection of mutants that have acquired the ability to infect and replicate in this previously nonpermissive cell line. Here we describe the selection of a mutant HSV-1 strain by in vivo serial passage, which prolongs survival in two separate experimental murine brain tumor models. Two conditionally replication-competent Deltagamma(1)34.5 viruses, M002, which expresses murine interleukin-12, and its parent virus, R3659, were serially passaged within human malignant glioma D54-MG cell lines in vitro or flank tumor xenografts in vivo. The major findings are (i) viruses passaged in vivo demonstrate decreased neurovirulence, whereas those passaged in vitro demonstrate a partial recovery of the neurovirulence associated with HSV-1; and (ii) vvD54-M002, the virus selected after in vivo serial passage of M002 in D54-MG tumors, improves survival in two independent murine brain tumor models compared to the parent (unpassaged) M002. Additionally, in vitro-passaged, but not in vivo-passaged, M002 displayed changes in the protein synthesis profile in previously nonpermissive cell lines, as well as early U(S)11 transcription. Thus, a mutant HSV-1 strain expressing a foreign gene can be selected for enhanced antitumor efficacy via in vivo serial passage within flank D54-MG tumor xenografts. The enhanced antitumor efficacy of vvD54-M002 is not due to restoration of protein synthesis or early U(S)11 expression. This finding emphasizes the contribution of the in vivo tumor environment for selecting novel oncolytic HSV specifically adapted for tumor cell destruction in vivo.

Animals↗

PubMed2006

Interleukin-12-deficient mice are at greater risk of UV radiation-induced skin tumors and malignant transformation of papillomas to carcinomas.

Solar UV radiation-induced immunosuppression is a risk factor for nonmelanoma skin cancer. Interleukin (IL)-12 has been shown to possess antitumor activity and inhibit the immunosuppressive effects of UV radiation in mice. In this study, we generated IL-12 knockout (KO) mice on a C3H/HeN background to characterize the role of IL-12 in photocarcinogenesis. After exposure of the mice to UVB (180 mJ/cm2) radiation thrice a week for 35 weeks, the development of UV-induced tumors was more rapid and the tumor multiplicity and tumor size were significantly higher in IL-12 KO mice than their wild-type (WT) counterparts (P < 0.05-0.001). Moreover, the malignant transformation of UVB-induced papillomas to carcinomas was higher in IL-12 KO mice in terms of carcinoma incidence (55%, P < 0.001), carcinoma multiplicity (77%, P < 0.001), and carcinoma size (81%, P < 0.001). As IL-12 has the ability to repair UV-induced DNA damage, we determined this effect in our in vivo IL-12 KO mouse model. We found that UVB-induced DNA damage in the form of cyclobutane pyrimidine dimers was removed or repaired more rapidly in WT mice than IL-12 KO mice. Similarly, the UVB-induced sunburn cell formation is primarily a consequence of DNA damage. It was observed that UVB-induced sunburn cells were repaired rapidly in WT mice compared with IL-12 KO mice. The rapid removal or repair of UV-induced cyclobutane pyrimidine dimers or sunburn cells will result in reduced risk of photocarcinogenesis. Taken together, our data show that IL-12 deficiency is associated with the greater risk of photocarcinogenesis in mice, and this may be due to reduction in damaged DNA repair ability.

Animals↗

PubMed2005

Effect of insulin on plasma vascular endothelial growth factor in children with new-onset diabetes.

CONTEXT: Considerable experimental evidence inculpates vascular endothelial growth factor (VEGF) as one of the candidate factors providing a mechanistic link between hyperglycemia and diabetic complications. AIM: The aim of the study was to assess the effect of insulin treatment and glycemic control on plasma VEGF levels in children with new-onset diabetes. METHODS: This prospective study assessed the changes in plasma VEGF levels after treatment of diabetes with insulin. We also aimed to ascertain whether there was any correlation between plasma VEGF levels and simultaneous random plasma glucose. The study comprised 19 children with new-onset diabetes mellitus between the ages of 3 and 18 yr. The control group comprised 55 healthy nondiabetic children with idiopathic short stature. RESULTS: Plasma VEGF concentrations were significantly elevated in children at diagnosis of diabetes, compared with healthy controls (P < 0.0002). Plasma VEGF levels (P < 0.01) and hemoglobin A(1C) (P < 0.0001) declined in diabetic children after insulin treatment. There was a highly significant correlation between reduction in plasma VEGF levels and hemoglobin A1C levels (r = 0.65, P = 0.0037). We did not find any correlation between the simultaneous plasma glucose values and basal VEGF. CONCLUSIONS: Presence of hyperglycemia and/ or insulin deficiency in children with new-onset of diabetes is associated with plasma VEGF elevation, even at the outset of disease, and this can be mitigated by insulin therapy.

Acidosis↗

PubMed2005

Growth inhibitory and antimetastatic effect of green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems.

PURPOSE: Breast cancer is the second leading cause of cancer-related deaths among females. Dietary habits may have a role in breast cancer risk and prevention as well. Here, we examined the effect of green tea polyphenols (GTP) on growth and metastasis of highly metastatic mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. EXPERIMENTAL DESIGN: 4T1 cells were treated with (-)-epigallocatechin-3-gallate (EGCG), and the effect was determined on cellular proliferation, induction of apoptosis, proapoptosis, and antiapoptotic proteins of Bcl-2 family, and caspase 3 and poly(ADP-ribose) polymerase activation following 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Western blot analysis. Anticarcinogenic and antimetastatic effect of GTP in 4T1 cells was assessed in immunocompetent BALB/c mice. RESULTS: Treatment of 4T1 cells with EGCG resulted in inhibition of cell proliferation, induction of apoptosis in dose- and time-dependent manner. The increase in apoptosis was accompanied with decrease in the protein expression of Bcl-2 concomitantly increase in Bax, cytochrome c release, Apaf-1, and cleavage of caspase 3 and PARP proteins. Treatment of EGCG-rich GTP in drinking water to 4T1 cells bearing BALB/c mice resulted in reduction of tumor growth accompanied with increase in Bax/Bcl-2 ratio, reduction in proliferating cell nuclear antigen and activation of caspase 3 in tumors. Metastasis of tumor cells to lungs was inhibited and survival period of animals was increased after green tea treatment. CONCLUSION: This study suggests that GTP have the ability to prevent the development of breast cancer and its metastasis; however, further in vivo studies are required to identify the molecular targets.

Administration, Oral↗

PubMed2005

The case for well-conducted experiments to validate statistical protocols for 2D gels: different pre-processing = different lists of significant proteins.

BACKGROUND: The proteomics literature has seen a proliferation of publications that seek to apply the rapidly improving technology of 2D gels to study various biological systems. However, there is a dearth of systematic studies that have investigated appropriate statistical approaches to analyse the data from these experiments. RESULTS: Comparison of the effects of statistical pre-processing on the results of two sample t-tests suggests that the results of 2D gel experiments and by extension the conclusions derived from these experiments are not independent of the statistical protocol used. CONCLUSIONS: This study suggests that there is a need for well-conducted validation studies to establish optimal statistical techniques to be used on such data sets.

Animals↗

PubMed2005

Activating FLT3 mutations are rare in children with juvenile myelomonocytic leukemia.

BACKGROUND: Activating mutations of FLT3 have been identified in multiple myeloid malignancies. Two types of activating mutations have been described: (1) the internal tandem duplication (FLT3-ITD) and (2) point mutations within the activating loop (FLT3-ALM). Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood. Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities. We investigated whether FLT3 mutations might also contribute to JMML pathogenesis, and if present, whether FLT3 status would correlate with disease natural history and prognosis. PROCEDURES: Genomic DNA was isolated from peripheral blood and bone marrow samples of 60 patients meeting international JMML diagnostic criteria. Samples were analyzed for FLT3-ITD and FLT3-ALM using polymerase chain reaction and restriction endonuclease digestion. RESULTS: FLT3-ALM was found in 1/60 (1.7%) patients analyzed. Direct sequencing confirmed a C836G mutation. Clinical and laboratory characteristics of the JMML patient with the FLT3-ALM did not differ from the remainder of the cohort. No FLT3-ITD mutations were detected. CONCLUSIONS: This first reported mutational analysis for both FLT3-ITD and FLT3-ALM performed in JMML documents the presence of FLT3 mutations within JMML, but at a sufficiently low prevalence as to be clinically insignificant for most patients. Despite the poor prognosis and limited therapeutic options for JMML patients with refractory disease, compassionate therapy with targeted FLT3 inhibitors should not be considered in this patient population until adequate safety and efficacy data become available.

Child↗

PubMed2005

Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor.

Antiangiogenic gene transfer has the potential to be more efficacious than protein-based therapies or pharmacotherapies for the control of solid tumor growth, invasion and metastasis. For a sustained antiangiogenic effect, a vector capable of long-term expression without vector-associated immunity or toxicity is advantageous. The present study evaluated the potential of a recombinant adeno-associated virus-2 (rAAV) encoding the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1), which functions by both sequestering vascular endothelial growth factor (VEGF) and forming inactive heterodimers with other membrane-spanning VEGF receptors, in vitro and in vivo. Results indicated significant growth inhibitory activity of the transgenic factor in a human umbilical vein endothelial cell proliferation assay in vitro and protection against the growth of an angiogenesis-dependent human ovarian cancer cell line, SKOV3.ip1, xenograft in vivo with increased disease-free survival. Stable expression of the secretory factor and transgene persistence were confirmed by immunohistochemistry and in situ hybridization analyses, respectively. Increased therapeutic effects on both the growth index of the implanted tumor cells and tumor-free survival also correlated with an increasing dose of the vector used. These studies indicate that rAAV-mediated sFlt-1 gene therapy may be a feasible approach for inhibiting tumor angiogenesis, particularly as an adjuvant/therapy.

Angiogenesis Inhibitors↗

PubMed2005

Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12.

Herpes simplex viruses type 1 (HSV-1) that lack the gamma(1)34.5 gene are unable to replicate in the central nervous system (CNS), but maintain replication competence in actively dividing tumors. To determine if antitumor therapy by M002, a gamma(1)34.5(-) HSV that expresses interleukin-12 (IL-12), could be augmented by combinatorial therapy with another gamma(1)34.5-deleted HSV-1 engineered to express the chemokine CCL2, Neuro-2a tumors were established subcutaneously in the syngeneic A/J mouse strain. Tumors received multiple injections intratumorally either of saline, the parent, non-cytokine-expressing virus R3659, M002, M010 (gamma(1)34.5(-) HSV expressing CCL2), or a combination of M002 and M010. Efficacies were evaluated by monitoring inhibition of tumor growth over time. Results demonstrated the following: (1) inhibition of tumor growth was most pronounced in tumors treated with a combination of M002 and M010; (2) enhanced tumor growth inhibition for the combinatorial treatment group was statistically significant compared to either M002 or M010 alone; and (3) the variability between slopes of the tumor growth rates within an individual treatment group appeared to be virus-dependent, and was reproducible between experiments. Our results demonstrate that combinatorial cytokine/chemokine gamma(1)34.5(-) HSV therapies can provide superior antitumor effects in experimental tumors as a model for malignancies arising in the brain.

Animals↗

PubMed2005

Recurrence and survival predictive value of phenotypic expression of Bcl-2 varies with tumor stage of colorectal adenocarcinoma.

Although decreased or lack of expression of Bcl-2 has been correlated with advanced tumor stage and shortened patient survival in colorectal cancer (CRC), its value in predicting the recurrence has not been well explored. Therefore, we assessed the usefulness of phenotypic expression of Bcl-2 in non-Hispanic Caucasian patients with CRCs in identifying risk of recurrence. Archival tissues of 92 Stage II and 66 Stage III primary CRCs were evaluated for immunohistochemical expression of Bcl-2. None of these patients received either pre- or post-surgical adjuvant therapies. Kaplan-Meier and Cox proportional hazards methods were used to estimate the rates of recurrence and survival according to Bcl-2 expression. Decreased expression of Bcl-2 was associated with an increased rate of recurrence in patients with Stage II CRCs (5-year log-rank test P=0.0015; Hazard Ratio (HR)=3.90, 95%C.I.:1.55-9.77) but not with Stage III CRCs (5-year log-rank test P=0.6058; HR=1.07, 95%C.I.:0.47-2.45) after adjusting for other demographic and clinicopathological features. Furthermore, decreased expression of Bcl-2 was an indicator of short survival in patients with Stage II CRCs but not with Stage III CRCs. Thus, decreased or lack of Bcl-2 expression in primary CRCs may serve as a molecular biomarker of high risk of recurrence for Caucasian patients with Stage II CRCs. These findings might be useful in identifying biologically aggressive phenotypes of Stage II CRCs, and may aid the oncologist in designing maximally appropriate therapeutic regimens.

Adenocarcinoma↗

PubMed2004

Proteomics analysis of rat brain protein modulations by grape seed extract.

Dietary supplements such as grape seed extract (GSE) enriched in proanthocyanidins (PA) (oligomeric polyphenols) have been suggested to have multiple health benefits, due to antioxidant and other beneficial activities of the PA. However, a systematic analysis of the molecular basis of these benefits has not been demonstrated. Because the brain is vulnerable to age-related oxidative damage and other insults including inflammation, it was hypothesized that rats ingesting GSE would experience changes in expression or modifications of specific brain proteins that might protect against pathologic events. Normal adult female rats were fed diets supplemented with 5% GSE for 6 weeks. Proteomics analysis (2D electrophoresis and mass spectrometry) of brain homogenates from these animals identified 13 proteins that were altered in amount and/or charge. Because many of these changes were quantitatively in the opposite direction from previous findings for the same proteins in either Alzheimer disease or mouse models of neurodegeneration, the data suggest that these identified proteins may mediate the neuroprotective actions of GSE. This is the first identification and quantitation of specific proteins in mammalian tissues modulated by a dietary supplement, as well as the first to demonstrate links of such proteins with any disease.

Amino Acid Sequence↗

PubMed2004

Folate is associated with the natural history of high-risk human papillomaviruses.

Several micronutrients have been implicated in cervical carcinogenesis. However, their mode of action is still a matter of speculation. In particular, it is unclear whether certain nutrients reduce the probability of acquiring high-risk human papillomavirus (HPV) or whether they facilitate the clearance of high-risk HPV. We conducted a 24-month prospective follow-up study to test the hypothesis that systemic concentrations of folate are associated with the occurrence and duration of high-risk HPV infections after controlling for other micronutrients (vitamins B(12), A, E, and C, total carotene) and known risk factors for high-risk HPV infections and cervical cancer. Circulating concentrations of these micronutrients and risk factors for cervical cancer were determined in a cohort of 345 women who were at risk of developing cervical intraepithelial neoplasia. Using the hybrid capture 2 (HC-2) assay, high-risk HPV status was evaluated at 6-month intervals up to 24 months. All women had at least three consecutive visit high-risk HPV test results. Higher folate status was inversely associated with becoming HC-2 test-positive [odds ratio (OR): 0.27; 95% confidence interval (CI), 0.08-0.91; P = 0.04]. Women with higher folate status were significantly less likely to be repeatedly HC-2 test-positive (OR: 0.33; 95% CI, 0.13-0.86; P = 0.02) and more likely to become test-negative during the study (OR: 2.50; 95% CI, 1.18-5.30; P = 0.02). To our knowledge, this is the first long-term prospective follow-up study reporting an independent protective role of higher folate status on several aspects of the natural history of high-risk HPV after controlling for known risk factors and other micronutrients. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.

Adult↗

PubMed2004

Initial treatment of melanoma brain metastases using gamma knife radiosurgery: an evaluation of efficacy and toxicity.

BACKGROUND: Melanoma is the primary malignancy that is most likely to metastasize to the brain. Because such an event carries an almost uniformly poor prognosis, the current study reviewed outcomes and identified associated prognostic indicators for 51 consecutive patients receiving gamma knife (GK) radiosurgery in the initial treatment of 188 intracranial melanoma metastases. METHODS: Data were collected retrospectively from a single-center GK radiosurgery database and from primary patient medical records and radiographs. RESULTS: At presentation, 71% of patients had multiple intracranial metastases, and extracranial metastases were present in 66% of patients. Thirty-two patients (63%) were initially treated with GK radiosurgery alone, whereas the remainder received GK radiosurgery in combination with surgery and/or whole-brain radiotherapy (WBRT). Overall median survival from time of GK radiosurgery was 26 weeks. Subgroup analysis revealed a median survival of 77 weeks for patients presenting with a single lesion, compared with 20 weeks for patients presenting with multiple lesions (P = 0.003). Patients in recursive partitioning analysis (RPA) Class I survived a median of 57 weeks, compared with a median survival of 20 weeks for patients in RPA Class II or III (P = 0.002). Although long-term imaging follow-up revealed that a majority of patients experienced distant brain metastases, multivariate analysis showed that distant metastases occurred significantly sooner in patients with extracranial metastases (P = 0.0004). Addition of initial WBRT had no significant effect on the time to development of new brain metastases (P = 0.13). Local control (crude) was observed in 81% of lesions initially treated with GK. Patients experienced improved or stable symptoms for a median of 37 weeks post-GK radiosurgery. CONCLUSIONS: Survival analyses supported the use of GK radiosurgery in the initial treatment of patients with melanoma brain metastases, with best results occurring in patients presenting with a single lesion.

Brain Neoplasms↗

PubMed2004

Postsurgical disparity in survival between African Americans and Caucasians with colonic adenocarcinoma.

BACKGROUND: Studies of colorectal adenocarcinoma (CRC) indicate a higher mortality rate for African Americans compared with Caucasians in the United States. In the current study, the authors evaluated the racial differences in survival based on tumor location and pathologic stage between African-American patients and Caucasian patients who underwent surgery alone for CRC. METHODS: All 199 African American patients and 292 randomly selected, non-Hispanic Caucasian patients who underwent surgery between 1981 and 1993 for first primary sporadic CRC at the University of Alabama-Birmingham (Birmingham, AL) or an affiliated Veterans Affairs hospital were assessed for differences in survival. None of these patients received preoperative or postoperative neoadjuvant or adjuvant therapy. Survival curves were generated using the Kaplan-Meier method, and hazard ratios with 95% confidence intervals (95% CI) were estimated from Cox proportional hazards models, adjusting for demographic and tumor characteristics. RESULTS: African Americans were 1.67 (95% CI, 1.21-2.33) and 1.52 (95% CI, 1.12-2.07) times more likely to die of colonic adenocarcinoma (CAC) within 5 years and 10 years of surgery, respectively, compared with Caucasians. Racial differences in survival were observed among patients with Stage II, III, and IV CAC; however, the strongest and statistically significant association was observed among patients with Stage II CAC. There were no significant racial differences in survival in patients with rectal adenocarcinomas. CONCLUSIONS: The current findings suggest that the decreased overall survival at 5 years and 10 years postsurgery observed in African-American patients with CAC may not be attributable to tumor stage at diagnosis or treatment but may be due to differences in other biologic or genetic characteristics between African-American patients and Caucasian patients.

Adenocarcinoma↗

PubMed2004

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor.

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.

Angiogenesis Inhibitors↗

PubMed2004

Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage.

PURPOSE: Although the decreased expression of p27(kip-1), a cyclin-dependent kinase inhibitor, has been correlated with advanced tumor stage and short survival of patients with colorectal adenocarcinomas (CRCs), its prognostic value based on the tumor site, tumor stage, and patient ethnicity was not assessed. Therefore, in this study, we investigated whether the prognostic value of p27(kip-1) expression varies with the tumor site, tumor stage and patient ethnicity. EXPERIMENTAL DESIGN: We evaluated 206 (85 African Americans and 121 Caucasians) archival tissue specimens of first primary CRCs for immunohistochemical expression of p27(kip-1), and its prognostic significance was analyzed using univariate Kaplan-Meier and multivariate Cox regression survival methods. RESULTS: Although, similar proportion of CRCs with decreased p27(kip-1) expression was observed in all stages (range, 26-36%), the decreased p27(kip-1) expression has been shown as a marker of poor prognosis only for patients with stage III tumors both in univariate (log-rank test, P = 0.014) and multivariate (hazard ratio = 3.2, 95% confidence interval = 1.3-7.7; P = 0.01) survival analyses. The decreased expression of p27(kip-1) was associated with a high histologic grade (P = 0.016) in stage II CRCs, and with distal tumors (P = 0.001), tumor invasion (P = 0.044), and with local recurrence (P = 0.008) in stage III CRCs. CONCLUSIONS: No prognostic significance was found for p27(kip-1) expression in stages I, II, or IV CRCs, and its prognostic value was not associated with either ethnicity or tumor location. These studies suggest that decreased expression of p27(kip-1) is an indicator of poor prognosis and aids in identifying a subset of patients with aggressive forms of stage III CRCs.

Adenocarcinoma↗