Eugenia Yiannakopoulou

Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents - implications for cancer treatment and chemoprevention

BackgroundEpigenetic processes and miRNAs have been recognized as new targets for anticancer drug design. However, old multi-target drugs such as aspirin may also target epigenetic processes.AimThis review aims to provide an overview of our current knowledge on the modulation of epigenetic processes by aspirin and other non steroidal anti-inflammatory agents (NSAIDs) and their implications for cancer treatment and chemoprevention.SynthesisIn vitro and in vivo studies, as well as primary patient data, suggest that aspirin and other NSAIDs reverse tumour suppressor gene hypermethylation in cancer tissues. It must be emphasized that, at this point in time, patient data are limited and DNA hypermethylation reversal has been investigated, but not tumour suppressor gene activation. In addition, evidence from experimental and patient data suggests that aspirin and NSAIDs may also reverse global DNA hypomethylation. At the histone level, both induction and inhibition of deacetylases by aspirin have been reported. Also, direct acetylation of histones by aspirin has been reported, while the natural salicylate anacardic acid has been found to inhibit histone acetyltransferase p300 both in vitro and in vivo, and to regulate gene expression through modulation of histone acetylation. Salicylates and other NSAIDs may also down-regulate miRNAs with oncogene-like functions or up-regulate miRNAs with tumour suppressor-like functions. Up till now, clinical trials have been aimed at investigating the effect of salicylates and NSAIDs on a limited number of miRNAs.ConclusionSo, although the existing evidence is still limited, evidence is accumulating that epigenetic targets may represent nodal targets for the anti-proliferative actions of salicylates and NSAIDs. This, in turn, may have implications for cancer chemoprevention and treatment. Undoubtedly, this notion requires further investigation, but if proved correct, it could lead to the design of less toxic agents that target epigenetic processes as part of existing or novel multi-targeted treatment modalities.

Virtual reality simulators and training in laparoscopic surgery

Virtual reality simulators provide basic skills training without supervision in a controlled environment, free of pressure of operating on patients. Skills obtained through virtual reality simulation training can be transferred on the operating room. However, relative evidence is limited with data available only for basic surgical skills and for laparoscopic cholecystectomy. No data exist on the effect of virtual reality simulation on performance on advanced surgical procedures. Evidence suggests that performance on virtual reality simulators reliably distinguishes experienced from novice surgeons Limited available data suggest that independent approach on virtual reality simulation training is not different from proctored approach. The effect of virtual reality simulators training on acquisition of basic surgical skills does not seem to be different from the effect the physical simulators. Limited data exist on the effect of virtual reality simulation training on the acquisition of visual spatial perception and stress coping skills. Undoubtedly, virtual reality simulation training provides an alternative means of improving performance in laparoscopic surgery. However, future research efforts should focus on the effect of virtual reality simulation on performance in the context of advanced surgical procedure, on standardization of training, on the possibility of synergistic effect of virtual reality simulation training combined with mental training, on personalized training.

Targeting oxidative stress response by green tea polyphenols: clinical implications.

Abstract Green tea polyphenols, the most interesting constituent of green tea leaves, have been shown to have both pro-oxidant and antioxidant properties. Both pro-oxidant and antioxidant properties are expected to contribute to modulation of oxidative stress response under ideal optimal dosage regimens. Exposure to a low concentration of a pro-oxidant prior to exposure to oxidative stress induces the expression of genes that code for proteins that induce adaptation in a subsequent oxidative stress. On the other hand, exposure to an antioxidant concurrently with exposure to the oxidative stress affords protection through free radical scavenging or through other indirect antioxidant mechanisms. In any case, the optimal conditions that afford protection from oxidative stress should be defined for any substance with redox properties. Green tea polyphenols, being naturally occurring substances, seem to be an ideal option for the modulation of oxidative stress response. This paper reviews available data on the pro-oxidant and antioxidant properties of green tea polyphenols focusing on their potential on the modulation of oxidative stress response.

Serious and Long-Term Adverse Events Associated with the Therapeutic and Cosmetic Use of Botulinum Toxin

Although botulinum toxin is generally considered safe, its widespread use and the constantly expanded indications raise safety issues. This study aimed to review the serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin. Serious adverse events included dysphagia, respiratory compromise, generalized muscle weakness, marked bilateral ptosis, pseudoaneurysm of the frontal branch of the temporal artery, necrotizing fasciitis, sarcoidal granuloma, Fournier gangrene, and cervical kyphosis. Death was attributed to botulism or anaphylactic shock. In conclusion, botulinum toxin may cause serious adverse events, which are more common after its therapeutic use, but can also be noticed after its cosmetic use. Thorough knowledge of the anatomy of the treated muscles and of the pharmacology of the drug is imperative to avoid serious adverse events.

Targeting DNA methylation with green tea catechins.

Aberrant epigenetic alterations in the genome such as DNA methylation play a significant role in cancer development. Green tea catechins have been reported to modulate epigenetic processes. This review aims to synthesize evidence on the modulation of DNA methylation by green tea catechins. Green tea catechins have been reported to reverse DNA methylation of tumor suppressor genes and increase transcription of these genes. Green tea catechins and especially epigallocatechin gallate modulate DNA methylation by attenuating the effect of DNA methyltransferase 1 (DNMT1). However, the exact mechanism of DNMT1 inhibition is not delineated. Suggested mechanisms include direct enzymatic inhibition, indirect enzymatic inhibition, reduced DNMT1 expression and translation. The possible effect of green tea catechins on other pathways of DNA methylation, i.e. methyl-CpG binding domain proteins, has not been investigated. Furthermore, the link between redox properties and epigenetic modulation by green tea catechins has not been defined either. Since green tea catechins are natural compounds with a rather acceptable safety profile, further research on their action as inhibitors of DNA methylation seems worthwhile.

Interaction of Green Tea Catechins with Breast Cancer Endocrine Treatment: A Systematic Review

Recent data have shown strong chemopreventive and possibly cancer chemotherapeutic effects of green tea polyphenols and EGCG against breast cancer. This systematic review aims to synthesize data on the possible interaction of green tea catechins with breast cancer endocrine treatment. Electronic databases were searched with the appropriate search terms. Experimental trials suggest a synergistic interaction of green tea catechins with tamoxifen or raloxifene in the treatment of estrogen receptor-positive and estrogen receptor-negative breast cancer through estrogen receptor-dependent and -independent mechanisms. No evidence of an interaction of green tea catechins with aromatase inhibitors or fulvestrant has been reported. As green tea catechins are natural compounds with a rather favorable safety profile, the strategy of co-administrating green tea catechins with tamoxifen seems to be a rational approach in chemoprevention, adjuvant and metastatic breast cancer treatment that needs further investigation. i 2014 S. Karger AG, Basel

Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications.

PurposePharmacogenomics investigates interindividual genetic variability in the DNA sequence of drug targets, drug-metabolizing enzymes or disease genes, RNA expression, or protein translation of genes affecting drug response and drug safety. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications with well-documented variation in patient response in terms of efficacy and safety. This variation may in part be explained by pharmacogenomics.MethodsIn this paper I review data on the pharmacogenomics of aspirin and other NSAIDs focusing on clinical implications.ResultsExisting scientific evidence supports the pharmacogenomic basis of interindividual variation in treatment response to aspirin and NSAIDs, with clinical implications for antiplatelet action, cancer chemoprevention, and drug safety. However, further research efforts are needed before knowledge on the pharmacogenomics of aspirin and NSAIDs can be implemented in clinical practice.ConclusionThe outcome of these research efforts would be anticipated to have added value for both science and society, contributing to the enhanced efficacy and safety of these agents through patient selection.

Modulation of Lymphangiogenesis: A New Target for Aspirin and Other Nonsteroidal Anti‐inflammatory Agents? A Systematic Review

Recent studies have implicated that lymphangiogenesis plays a role in the development of metastasis in experimental cancer models and in certain types of human tumors. Epidemiological and laboratory data suggest that non steroidal anti‐inflammatory agents (NSAIDs) have antitumor activities, although the mechanisms have not been elucidated. This systematic review aimed to synthesize data on the effect of aspirin and other NSAIDs on lymphangiogenesis. In particular, an answer was attempted to be found for the following primary questions: Is there an effect of aspirin and NSAIDs on lymphangiogenesis? If yes, is this effect mediated through COX‐II inhibition or through COX‐II‐independent mechanisms? Electronical databases were searched with the appropriate search terms for the period from 1966 up to and including February 2011. The few identified experimental trials indicated that aspirin and other NSAIDs inhibit lymphangiogenesis, with a potential decrease in metastatic spread, possibly through COX‐II‐dependent regulation of VEGF‐C expression. COX‐II‐independent mechanisms of inhibition of lymphangiogenesis by salicylates and the other NSAIDs have not been investigated. Although further research validation is needed, this proposed effect of NSAIDs might have therapeutic implications in chemoprevention, adjuvant chemotherapy, and treatment of metastatic disease.

Safety Concerns for Sclerotherapy of Telangiectases, Reticular and Varicose Veins

Background: Sclerotherapy has been extensively used in the treatment of valvular insufficiency of superficial veins. Although sclerotherapy seems safe, reports of serious adverse events (AE) have been published. This paper aims to review AE of sclerosing agents. Methods: Electronical databases were searched for identifying articles on local, serious and long-term AE of sclerotherapy. Results: Hyperpigmentation and matting are the most often local AE of sclerotherapy. Other local AE include superficial thrombophlevitis, pyoderma gangrenosum, pain, ulcer formation, and hypertrichosis. Local AE can be serious, that is, it can include cutaneous necrosis, intra-arterial injection with subsequent acute ischemia that can lead to amputation, and necrotizing fasciitis. Most data on systemic AE of sclerotherapy are extracted from case series and case reports. Systemic AE include neurological complications, such as ischemic stroke, transient ischemic attack, visual disturbances and cardiac toxicity, that is, myocardial infarction, Takotsubo cardiomyopathy, chest tightness, pulmonary embolism, deep vein thrombosis, septicemia, anaphylaxis. It is difficult to estimate the frequency of serious systemic AE of sclerotherapy. Conclusion: Physicians practicing sclerotherapy should be aware of the possible local and systemic AE of sclerotherapy, inform patients accordingly and be prepared for the appropriate management of the rare but possibly lethal serious AE.

Methodological issues regarding safety evaluation in randomized controlled trials of the effectiveness of antibiotic prophylaxis for the prevention of post-operative wound infection: systematic review

We are grateful to Dr P. R. Narayanan, Director, and Dr V. Kumaraswami, Scientist ‘F’, at the Tuberculosis Research Centre, Chennai, India, for their encouragement and support. We also thank Mr P. Kumar for technical assistance related to plasma estimations, antiretroviral treatment (ART) medical officers for patient recruitment and clinical and laboratory staff for organizing blood collections at the Government Hospital of Thoracic Medicine, Tambaram, as well as all of the patients who took part in the study.