Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF-A induced angiogenesis.

Although beta 2 adrenergic receptors (ß2 ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective ß2 ADR antagonists by inhibiting ß2 ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

Dopamine Prevents Ultraviolet B-induced Development and Progression of Premalignant Cutaneous Lesions through its D2 Receptors.

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. PREVENTION RELEVANCE: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice.

BACKGROUND: Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2-3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated. METHODS: CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo. RESULTS: Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice. CONCLUSION: CI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.

Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis.

Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D2 receptors as significantly more angiogenesis and tumor growth was observed in D2 dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D2 dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.

Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis.

PURPOSE: It has been recently shown that the catecholamine neurotransmitter dopamine (DA) strongly and selectively inhibits vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-induced angiogenesis. Gastric cancer is highly angiogenic and is dependent on VEGF for its growth and progression. Because substantial amounts of DA present in normal stomach tissues has been implicated in several gastric functions, we therefore investigated the role, if any, of this neurotransmitter in the growth and progression of gastric cancer. EXPERIMENTAL DESIGN: Initially, the status of DA and tyrosine hydroxylase, the rate-limiting enzyme required for DA synthesis, were determined in human gastric cancer tissues and in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer tissues of rats. On the basis of our observation of inverse correlation between stomach DA and gastric cancer growth, we determined the effect of pharmacological dose of DA on the angiogenesis and growth of MNNG induced gastric cancer in rats and Hs746T human gastric cancer in nude mice. RESULTS: DA and tyrosine hydroxylase were absent in both human and rat gastric cancer tissues. On the contrary, a low nontoxic pharmacological dose of DA significantly retarded tumor angiogenesis by inhibiting VEGFR-2 phosphorylation in tumor endothelial cells, which expressed DA D(2) receptors. This action of DA was associated with the growth inhibition of both MNNG-induced rat malignant gastric tumors and xenotransplanted human gastric cancer in nude mice. CONCLUSIONS: Our study demonstrates that there is an inverse correlation between endogenous stomach DA and gastric cancer and indicates that DA already in clinical use for other purposes might have a role as an antiangiogenic agent in the treatment of gastric cancer.

Exchange of genetic sequences of long terminal repeat and the env gene by a promiscuous primate type D retrovirus.

Squirrel monkey retrovirus (SMRV) is a New World primate type D retrovirus. It was shown that SMRV-related sequences could be detected in another New World species, the skunk. It was further suggested that SMRV and an Old World primate type C retrovirus, baboon endogenous virus (BaEV), may have exchanged their env gene sequences. In this study, we sought to understand which sequences were exchanged between the genomic DNAs of SMRV and skunk. We also sought to determine the sequences exchanged between SMRV and BaEV. Here, we demonstrate that the long terminal repeat of SMRV is present in the skunk genome. We also show, by nucleotide sequence analysis, that the env gene that encodes the p15E glycoprotein of BaEV was most likely transduced from the corresponding gene of a primate type D retrovirus. Our results demonstrate that SMRV is a promiscuous virus with its pol gene homologous to the pol genes of type A, type B and avian type C viruses and a portion of its env gene homologous to the env genes of primate type C retroviruses. However, the primer binding sequence is unique to type D retroviruses. These kinds of recombination are likely to occur more than once in the evolution of retroviruses. The promiscuous nature of retroviruses and the recent incidence of unintended retroviral integration into a gene therapy patient underscore the importance of understanding how retroviral sequences are recombined among themselves and how they are integrated into the mammalian genome.

Study of mutated p53 protein by immunohistochemistry in urothelial neoplasm of urinary bladder.

It is difficult to predict which urothelial neoplasm would subsequently recur or progress to muscle invasive tumours or produce metastasis.The aim and objective of the study were to evaluate the scope of immunohistochemical expression of p53 in human urothelial neoplasms with regard to grade, stage and outcome of the patients. Eighteen consecutive patients were taken and urothelial tumour samples were obtained from transurethral resection or surgical excision. Histopathological examinations were performed and the grading was done according to the WHO/ISUP consensus classification of urothelial neoplasms. Immunohistochemical staining for p53 was performed on formalin fixed paraffin embedded tissue sections with appropriate positive and negative control. It was found 3 patients with papillary urothelial neoplasm of low malignant potential (PUNLMP), 5 cases of papillary low grade urothelial carcinoma, 10 patients with papillary high grade urothelial carcinoma including 2 cases of invasive urothelial carcinoma. All three PUNLMP cases showed negative results. Four out of 5 low grade papillary urothelial carcinoma had nuclear p53 accumulation, while all of the 10 papillary high grade carcinoma had high p53 index. The finding of negative p53 staining in PUNLMPs and high p53 index in high grade papillary urothelial carcinomas and invasive carcinomas support the notion that mutation of p53 gene might be unrelated to the development of urothelial neoplasms but definitely play a crucial role in progression of the malignancy.

Kappa statistics in the screening of malignancy of prostate.

The optimal upper limit of the normal range for prostate specific antigen (PSA) is suggested, but review of literature reveals that, malignancy of prostate can occur below that range and some benign prostatic diseases are occasionally associated with higher levels. The aim of the study is for early detection of prostatic malignancy. We tried to evaluate digital rectal examination (DRE), estimation of PSA and transrectal ultrasound (TRUS) guided core needle biopsy and histopathological examination in the patients. Seventy-two consecutive patients with lower urinary tract symptoms were taken in this retrospective study from January 2005 to February 2006. PSA level was measured by automated chemilumininescence system. Prostatic biopsies were taken for histopathological examination and stained with haematoxylin and eosin. Gleason grading was applied in case of adenocarcinoma of prostate. For detection of malignancy, sensitivity, specificity, predictive value for positive test and of negative test, percentage of false negatives and false positives, p-values, confidence interval and kappa statistical calculations were done. It was found 19 cases with PSA level > 4 ng/ml had benign diseases of prostate and one person having PSA level < 4 ng/ml had adenocarcinoma of prostate. Seven DRE positive cases had benign disease of the prostate and 5 DRE negative patients had adenocarcinoma of prostate. When compared, serum total PSA value alone and combined PSA and DRE, the later combined approach was found to be more useful. We recommend the study of DRE, PSA and TRUS guided core needle biopsy for detection of prostatic cancer at localised and potentially curable stage.

Dopamine in vivo inhibits VEGF-induced phosphorylation of VEGFR-2, MAPK, and focal adhesion kinase in endothelial cells.

Vascular permeability factor (VPF)/VEGF is a potent multifunctional cytokine and growth factor that has critical roles in vasculogenesis and in both physiological and pathological angiogenesis. Because it has been recently shown that the neurotransmitter dopamine at pharmacological dose can inhibit VEGF/VPF-mediated microvascular permeability, proliferation, and migration of endothelial cells in vitro, we therefore hypothesized that endogenous dopamine may regulate the actions of VPF/VEGF in vivo. We report that VPF/VEGF-induced phosphorylation of VEGF receptor 2, focal adhesion kinase, and MAPK in the endothelial cells is strikingly increased in both dopamine-depleted and dopamine D(2) receptor knockout mice compared with normal controls, thereby indicating that endogenous dopamine regulate these critical signaling cascades required for the in vivo endothelial functions of VPF/VEGF. Together, these observations provide new mechanistic insight into the dopamine-mediated inhibition of the activities of VPF/VEGF and suggest that endogenous neurotransmitter dopamine might be an important physiological regulator of VPF/VEGF activities in vivo.

Fine needle aspiration cytology of thyroid gland and histopathological correlation--revisited.

Fine needle aspiration of the thyroid gland, followed by cytological studies and their correlation with histopathological diagnosis have been undertaken to assess the effectiveness of fine needle aspiration cytology in diagnosing disorders of this gland. The cases in which discrepancies had arisen between these two methods of diagnosis have also been reviewed. Out of the total 100 patients studied, 28 were cases of simple colloid goitre, 17 of adenomatoid goitre, 10 of autoimmune thyroiditis ranging from lymphocytic thyroiditis to Hashimoto's thyroiditis, 28 of follicular neoplasia, 10 of papillary carcinoma, one of medullary carcinoma, 2 of anaplastic carcinoma and 4 of cystic lesions of the thyroid gland. Although, fine needle aspiration cytology of the thyroid gland was diagnostic in 75% of cases, it did not correlate with the histopathological diagnosis in the remaining 25% of cases. Possible reasons behind these discrepancies have been discussed.