Vincent W. Li

Cancer prevention by targeting angiogenesis

Healthy individuals can harbour microscopic tumours and dysplastic foci in different organs in an undetectable and asymptomatic state for many years. These lesions do not progress in the absence of angiogenesis or inflammation. Targeting both processes before clinical manifestation can prevent tumour growth and progression. Angioprevention is a chemoprevention approach that interrupts the formation of new blood vessels when tumour cell foci are in an indolent state. Many efficacious chemopreventive drugs function by preventing angiogenesis in the tumour microenvironment. Blocking the vascularization of incipient tumours should maintain a dormancy state such that neoplasia or cancer exist without disease. The current limitations of antiangiogenic cancer therapy may well be related to the use of antiangiogenic agents too late in the disease course. In this Review, we suggest mechanisms and strategies for using antiangiogenesis agents in a safe, preventive clinical angioprevention setting, proposing different levels of clinical angioprevention according to risk, and indicate potential drugs to be employed at these levels. Finally, angioprevention may go well beyond cancer in the prevention of a range of chronic disorders where angiogenesis is crucial, including different forms of inflammatory or autoimmune diseases, ocular disorders, and neurodegeneration.

Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients

Background  Pyoderma gangrenosum (PG) is an uncommon and challenging disease, highly associated with comorbidities, but poorly characterized from a diagnostic and therapeutic perspective.

The role of therapeutic angiogenesis in tissue repair and regeneration.

PURPOSE To provide the physician and registered professional nurse with an understanding of angiogenesis and an overview of therapeutic angiogenesis modalities used to manage wounds and other tissue repair situations. TARGET AUDIENCE This continuing education activity is intended for physicians and nurses with an interest in learning more about angiogenesis and therapeutic angiogenesis modalities to manage wounds and other tissue repair situations. OBJECTIVES After reading the article and taking the test, the participant should be able to: Describe the basic principles of angiogenesis and its role in tissue repair and regeneration. Identify the available therapeutic angiogenesis modalities and clinical issues surrounding their use.

Syringolymphoid hyperplasia and follicular mucinosis in a patient with cutaneous T-cell lymphoma

Syringolymphoid hyperplasia with alopecia is an uncommon chronic dermatosis of which 9 cases have been reported, with or without follicular mucinosis or cutaneous T-cell lymphoma. We report a patient with cutaneous T-cell lymphoma and syringolymphoid hyperplasia and follicular mucinosis and review the previously reported cases. All reported cases with syringolymphoid hyperplasia were men (10 of 10), with the clinical findings of alopecia (9 of 10) and anhidrosis (3 of 10). Only 3 of 10 cases had associated follicular mucinosis. Of the 7 cases investigated, 6 were found to hve cutaneous T-cell lymphoma. Three patients were not investigated for cutaneous T-cell lymphoma. Although syringolymphoid hyperplasia can be idiopathic, it can also reflect a syringotropic cutaneous T-cell lymphoma. Careful follow-up with a biopsy of persistent lesions is recommended to evaluate for the presence of lymphoma.

Treatment of Refractory Ulcerative Necrobiosis Lipoidica Diabeticorum With Infliximab: Report of a Case

BACKGROUND Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.

Effects of alpha particles on zebrafish embryos

Dechorionated zebrafish embryos were irradiated at 1.5 h post fertilization (hpf) to low-doses of alpha particles, viz., 1.4, 2.8, 5.6, 11.2 mGy (determined using Monte Carlo simulations). At 24 hpf, these embryos were then examined for apoptotic cells through acridine orange staining. The mean number of apoptotic cells was found to decrease significantly from controls to 1.4-mGy irradiation, and then to increase almost linearly to 2.8, 5.6 and 11.2-mGy irradiation. This trend is a typical characteristic of a hormetic effect.

Leptin: clue to poor appetite in oxygen-starved fish

Hypoxia is the most widespread deleterious consequence of eutrophication and has become a major cause of fishery decline. One feature of chronic exposure to hypoxia in fish is inhibition of feeding. In this study, we investigated if the gene that encodes the appetite-suppressing hormone leptin is regulated by hypoxia in zebrafish (Danio rerio). Exposure of adult zebrafish to hypoxic conditions (1+/-0.2 mg O(2) L(-1)) for 4 and 10 days significantly increased leptin-a (zlep-a) mRNA levels in the liver. To evaluate the role of hypoxia-inducible factor 1 (HIF-1) in regulating zlep-a expression, zebrafish embryos were exposed to cobalt chloride (CoCl(2), a HIF-1 inducer) and overexpressed with HIF-1alpha mRNA. Both CoCl(2) treatment and HIF-1alpha overexpression markedly increased zlep-a expression in developing embryos, indicating the possible involvement of HIF-1 in zlep-a regulation. In vivo promoter analysis indicated that zlep-a promoter activity is found in the muscle fibers of zebrafish embryos and enhanced by CoCl(2). This is the first report to show that leptin gene expression in fish is regulated by hypoxia possibly via the involvement of HIF-1.

Loss of M2 muscarinic receptor function inhibits development of hypoxic bradycardia and alters cardiac β-adrenergic sensitivity in larval zebrafish (Danio rerio)

Fish exposed to hypoxia develop decreased heart rate, or bradycardia, the physiological significance of which remains unknown. The general muscarinic receptor antagonist atropine abolishes the development of this hypoxic bradycardia, suggesting the involvement of muscarinic receptors. In this study, we tested the hypothesis that the hypoxic bradycardia is mediated specifically by stimulation of the M(2) muscarinic receptor, the most abundant subtype in the vertebrate heart. Zebrafish (Danio rerio) were reared at two levels of hypoxia (30 and 40 Torr PO(2)) from the point of fertilization. In hypoxic fish, the heart rate was significantly lower than in normoxic controls from 2 to 10 days postfertilization (dpf). At the more severe level of hypoxia (30 Torr PO(2)), there were significant increases in the relative mRNA expression of M(2) and the cardiac type beta-adrenergic receptors (beta1AR, beta2aAR, and beta2bAR) at 4 dpf. The hypoxic bradycardia was abolished (at 40 Torr PO(2)) or significantly attenuated (at 30 Torr PO(2)) in larvae experiencing M(2) receptor knockdown (using morpholino antisense oligonucleotides). Sham-injected larvae exhibited typical hypoxic bradycardia in both hypoxic regimens. The expression of beta1AR, beta2aAR, beta2bAR, and M(2) mRNA was altered at various stages between 1 and 4 dpf in larvae experiencing M(2) receptor knockdown. Interestingly, M(2) receptor knockdown revealed a cardioinhibitory role for the beta(2)-adrenergic receptor. This is the first study to demonstrate a specific role of the M(2) muscarinic receptor in the initiation of hypoxic bradycardia in fish.

Leptin-Mediated Modulation of Steroidogenic Gene Expression in Hypoxic Zebrafish Embryos: Implications for the Disruption of Sex Steroids

Hypoxia can impair reproduction of fishes through the disruption of sex steroids. Here, using zebrafish (Danio rerio) embryos, we investigated (i) whether hypoxia can directly affect steroidogenesis independent of pituitary regulation via modulation of steroidogenic gene expression, and (ii) the role of leptin in hypoxia-induced disruption of steroidogenesis. Exposure of fertilized zebrafish embryos to hypoxia (1.0 mg O(2) L(-1)) from 0-72 h postfertilization (hpf), a developmental window when steroidogenesis is unregulated by pituitary influence, resulted in the up-regulation of cyp11a, cyp17, and 3β-hsd and the down-regulation of cyp19a. Similar gene expression patterns were observed for embryos exposed to 10 mM cobalt chloride (CoCl(2), a chemical inducer of hypoxia-inducible factor 1, HIF-1), suggesting a regulatory role of HIF-1 in steroidogenesis. Testosterone (T) and estradiol (E2) concentrations in hypoxic embryos were greater and lesser, respectively, relative to the normoxic control, thus leading to an increased T/E2 ratio. Expression of the leptin-a gene (zlep-a) was up-regulated upon both hypoxia and CoCl(2) treatments. Functional assays suggested that under hypoxia, elevated zlep-a expression might activate cyp11a and 3β-hsd and inhibit cyp19a. Overall, this study indicates that hypoxia, possibly via HIF-1-induced leptin expression, modulates sex steroid synthesis by acting directly on steroidogenic gene expression.

Effects of propranolol on heart rate and development in Japanese medaka (Oryzias latipes) and zebrafish (Danio rerio)

Propranolol is a β-adrenergic receptor antagonist (β-blocker) that is frequently used to treat hypertension and other cardiovascular conditions in humans. Detected in surface waters due to discharge of domestic wastewater, propranolol has demonstrated significant species differences in toxicity between fish. The aim of this study was to investigate the effects of propranolol on heart rate and development in embryos of two species of fish; Japanese medaka (JM) Oryzias latipes and zebrafish (ZF) Danio rerio. Parents and fertilized embryos of each species were exposed to nominal (measured) concentrations of 0.1 (0.09), 1 (1.1) and 10 (8.3) μg/L of propranolol. Heart rate was monitored during subsequent exposure in embryos at incremental developmental periods (44, 54, 64 h post-fertilization (hpf) for ZF and 68, 116, 164 hpf for JM). Heart development and morphology was examined using whole mount immunostaining with distance measurements between the sinus venosus (SV) and bulbus arteriosis (BV). Morphological measurements were made at 44 hpf for ZF and 164 hpf for JM. In ZF, a significant reduction in heart rate was observed at 0.08 μg/L propranolol, along with an increase in the SV-BA distance at 44 hpf. Significant reductions in heart rate were also observed in ZF at 54 and 64 hpf at all concentrations of propranolol. For JM, heart rates generally decreased at all developmental timepoints (68, 116 and 164 hpf) after propranolol treatment, with concentration dependent decreases observed at 164 hpf and a lowest observed effect concentration (LOEC) of 0.09 μg/L propranolol at each timepoint. However, significant alterations in cardiac morphology were not observed in JM at 164 hpf. In contrast, heart rates and morphology in ZF were affected with a non-monotonic concentration response in morphology and a LOEC of 0.09 μg/L propranolol for morphological alterations at 44 hpf and for heart rate at each timepoint. These data indicated unique developmental stages of susceptibility between species and that combined parental and embryo exposures may lead to greater impairment of cardiac development and function in offspring than separate exposures of adults and embryos.