Constantinos Giaginis

Current clinical status on the preventive effects of cranberry consumption against urinary tract infections.

Urinary tract infections (UTIs) represent a common and quite costly medical problem, primarily affecting the female population which may be due to a shorter urethra. The bacterium Escherichia coli are mainly responsible for most uncomplicated UTIs. Cranberry antibacterial effects have widely been studied in vitro, and laboratory and clinical studies have also been performed to elucidate the mechanisms of cranberry actions and the clinical benefits of cranberry consumption against UTIs. The present review aimed to summarize the proposed mechanisms of cranberry actions against UTIs and the clinical trials that evaluated the efficacy of supplementing cranberry products in different subpopulations. Taking into consideration the existing data, cranberry consumption may prevent bacterial adherence to uroepithelial cells which reduces the development of UTI. Cranberry consumption could also decreasing UTI related symptoms by suppressing inflammatory cascades as an immunologic response to bacteria invasion. The existing clinical trials suggest that the beneficial effects of cranberry against UTIs seem to be prophylactic by preventing the development of infections; however, they exert low effectiveness in populations at increased risk for contracting UTIs. Additional well-designed, double-blind, placebo-controlled clinical trials that use standardized cranberry products are strongly justified in order to determine the efficiency of cranberry on the prevention of UTIs in susceptible populations.

NF-κB signaling at the crossroads of inflammation and atherogenesis: searching for new therapeutic links.

Introduction: NF-κB is a protein complex acting as a primary transcription factor and fast messenger to harmful cellular stimuli, including inflammation. Carotid atherosclerosis is an inflammatory process leading to atheroma formation and ultimately complicating the patient’s condition. This review aims to critically summarize the role of NF-κB in atheroma formation and evolution, also highlighting its potential therapeutic utility. Areas covered: This literature review presents the most recent data in terms of NF-κB, atherosclerosis and implicating factors, with special focus on the carotid artery setting. Results are categorized according to atheroma stage and are discussed for each one respectively, forming an NF-κB mediated atherosclerosis evolvement model per stage. Targeting NF-κB by inhibitors or enhancers and their potential effectiveness are also discussed. Expert opinion: The current data suggest that NF-κB plays a critical role in all stages of plaque evolution toward complexity, implicating genes, membrane and cellular proteins, polypeptides, chemokines and hormones. It also seems capable of assisting several pharmaceutical agents, unfolding either directly or indirectly their anti-inflammatory/anti-atherogenic properties. Targeting NF-κB signaling by specific inhibitors or enhancers may provide new therapeutic strategies against atherogenic inflammatory process.

Histone deacetylase inhibitors and pancreatic cancer:Are there any promising clinical trials?

Pancreatic cancer, although not very frequent, has an exceptionally high mortality rate, making it one of the most common causes of cancer mortality in developed countries. Pancreatic cancer is difficult to diagnose, allowing few patients to have the necessary treatment at a relatively early stage. Despite a marginal benefit in survival, the overall response of pancreatic cancer to current systemic therapy continues to be poor, and new therapies are desperately needed. Histone deacetylase (HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors (HDACIs) have been shown to induce differentiation and cell cycle arrest, activate the extrinsic or intrinsic pathways of apoptosis, and inhibit invasion, migration and angiogenesis in different cancer cell lines. As a result of promising preclinical data, various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies. Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma. The use of HDACIs in clinical trials, in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed. Unfortunately, clinical data for HDACIs in patients with pancreatic cancer are inadequate, because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase II/III trials, among others with advanced solid tumors, is very limited. More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.

Clinical Significance of Ephrin (Eph)-A1, -A2, -A4, -A5 and -A7 Receptors in Pancreatic Ductal Adenocarcinoma

Ephrin (Eph) receptors have been reported to be frequently overexpressed in a wide variety of cancer types, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A1, -A2, -A4, -A5 and -A7 expression in pancreatic ductal adenocarcinoma. Eph-A1, -A2, -A4, -A5 and -A7 expression and staining intensity were assessed immunohistochemically in tumoral samples of 67 pancreatic adenocarcinoma patients and were statistically analyzed in relation to clinicopathological characteristics, tumor proliferative capacity and patients’ survival. Eph receptors were abundantly expressed in pancreatic ductal adenocarcinoma cases examined. Eph-A1 staining intensity was significantly associated with tumor size (pT, p = 0.008) and tumor histopathological stage (pStage, p = 0.012). Eph-A2 expression was significantly associated with patients’ age (p = 0.007), while Eph-A4 and Eph-A5 with tumor proliferative capacity (p = 0.019 and p = 0.011, respectively). Pancreatic adenocarcinoma patients with moderate/intense Eph-A5 or Eph-A7 staining presented significantly shorter survival times compared to those with negative/mild one (log-rank test, p = 0.024 and p = 0.009, respectively). Multivariate analysis identified Eph-A5 and Eph-A7 staining intensity as independent prognostic factors (p = 0.048 and p = 0.004, respectively). In conclusion, the present study revealed that Eph receptors were associated with pancreatic cancer characteristics, supporting evidence for their potential clinical application in management and prognosis of pancreatic adenocarcinoma patients.

Clinical significance of HuR expression in human malignancy

Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of target mRNAs. The aim of the present review was to summarize and present the currently available information in the English literature on HuR expression in various human tumors, verifying its possible clinical significance. HuR function is directly linked to its subcellular localization. In normal cells, HuR is mostly localized in the nucleus, while in malignant cells, an increase in cytoplasmic HuR levels has been noted, in both cell lines and tissue samples. Moreover, in malignancy, elevated HuR expression levels and cytoplasmic immunohistochemical pattern have been correlated with advanced clinicopathological parameters and altered expression levels of proteins implicated in neoplasia. Additionally, elevated HuR expression levels and mainly cytoplasmic immunohistochemical pattern were correlated with decreased patients’ survival rate in various human tumors. HuR is a putative drug target for cancer therapy, since it is expressed ubiquitously in malignant clinical samples and has an apparently consistent role in tumor formation and progression.

Metallothionein expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patient survival

Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, Point D, Tsourouflis G & Sastre‐Garau X
(2011) Histopathology59, 514–525

Expression and Clinical Significance of Focal Adhesion Kinase in the Two Distinct Histological Types, Intestinal and Diffuse, of Human Gastric Adenocarcinoma

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase protein, acts as an early modulator of integrin signaling cascade, regulating basic cellular functions. In transformed cells, unopposed FAK signaling has been considered to promote tumor growth, progression and metastasis. The aim of this study was to assess the clinical significance of FAK expression in the two distinct histological types of human gastric neoplasia. FAK expression was assessed immunohistochemically in tumoral samples of 66 gastric adenocarcinoma cases, 30 intestinal and 36 diffuse type, and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity and patients’ survival. In intestinal type carcinomas, enhanced FAK expression was significantly associated with increased tumor proliferative capacity (P = 0.012). In diffuse type carcinomas, FAK staining intensity was significantly correlated with tumor size (P = 0.026) and disease stage (P = 0.024), presenting also a borderline association with nodal status (P = 0.053). In diffuse type carcinomas, enhanced FAK expression was significantly associated with longer overall survival times (log-rank test, P = 0.014), being also identified as an independent prognostic factor in multivariate analysis (Cox regression, P = 0.016). In contrast, patients with intestinal type tumors and enhanced FAK expression were characterized by shorter overall survival times, without though reaching statistical significance (log-rank test, P = 0.092). The current data support evidence that FAK protein may be considered as a diagnostic and prognostic marker in gastric neoplasia. Further studies conducted on larger clinical samples and highlighting on the distinct impact of the two histological types are warranted to delineate the clinical significance of FAK protein in gastric neoplasia.

Current Evidence on the Anticancer Potential of Chios Mastic Gum

Chios mastic gum derived from the plant Pistacia lentiscus L. variation chia has been shown to exert beneficial effects on a wide range of human disorders. The most comprehensive data so far have indicated that mastic gum provides protection against gastrointestinal malfunctions and bacterial infections. Substantial evidence has also suggested that mastic gum exhibits hepatoprotective and cardioprotective, antiinflammatory/antioxidant, and antiatherogenic properties. In the last decade, an increasing number of studies further evaluated the potential antiproliferative properties of mastic gum against several types of human neoplasia. The present review aims to summarize the current data concerning the anticancer activities of mastic gum and their major constituents, highlighting also the molecular mechanisms through which they exert anticancer function. Mastic gum constituents that belong to the chemical class of triterpenoids appear to be mainly responsible for its anticancer potential. Thus, a brief discussion is dedicated to the anticancer activity of synthetic and naturally occurring triterpenoid analogues with similar chemical structure to mastic gum constituents. Taking into consideration the available data so far, Chios mastic gum could be considered as a conglomeration of effective anticancer drugs.

Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier

Introduction: Placenta plays an obligatory role in fetal growth and development by performing a multitude of functions, including embryo implantation, transport of nutrients and elimination of metabolic waste products and endocrine activity. Drugs and chemicals can transfer across the placental barrier from mother to fetus either by passive diffusion mechanisms and/or via a network of active transporters, which may lead to potential fetotoxicity effects. Placenta also expresses a wide variety of enzymes, being capable of metabolizing a large diversity of drugs and chemicals to metabolites of lower or even higher toxicity than parent compounds. Areas covered: The present review aims to summarize the current toxicological aspects in the emerging topic of drug transport and metabolism across the human placental barrier. Expert opinion: There is an emerging demand for accurate assessment of drug transport and metabolism across the human placental barrier, on the basis of a high throughput screening process in the early stages of drug design, to avoid drug candidates from potential fetotoxicity effects. In this aspect, combined studies, which take into account in vivo and in vitro investigations, as well as the ex vivo perfusion method and the recently developed computer-aided technologies, may significantly contribute to this direction.

Clinical implication of plasma neutrophil gelatinase-associated lipocalin (NGAL) concentrations in patients with advanced carotid atherosclerosis

Abstract Background: Neutrophil gelatinase-associated lipocalin (NGAL) is well established as an early and specific biomarker of kidney disease. Recent evidence further suggests that NGAL may play a crucial role in vascular remodeling and plaque instability during the development of atherosclerosis. Methods: Plasma NGAL concentrations measured using a solid-phase enzyme-linked immunosorbent assay (ELISA) were correlated with medical history, risk factors and medication intake in 141 patients with advanced carotid atherosclerotic lesions who underwent carotid endarterectomy for vascular repair. Results: Plasma NGAL concentrations were associated with patient age (Rs=0.2055, p=0.0144), plasma homocysteine (Rs=0.4274, p<0.00001) and serum creatinine (Rs=0.4640, p<0.00001) concentrations and estimated glomerular filtration rate (eGFR) (Rs=−0.4911, p<0.00001). Hypertensive patients, as well as those receiving therapy with angiotensin converting enzyme (ACE) inhibitors, presented with significantly enhanced plasma NGAL concentrations when compared to normotensive (p=0.0341) patients and those not treated (p=0.0004). Enhanced NGAL concentrations did not meet statistical significance for patients with advanced stenosis grade (p=0.0971) or a history of peripheral artery disease (p=0.0827). Multiple regression analysis identified homocysteine, creatinine, eGFR and treatment with ACE inhibitors (p=0.0019, <0.00001, 0.0005 and 0.0219, respectively) as independent predictors of NGAL concentration. Conclusions: Plasma NGAL concentrations were associated with patient age, hypertension, eGFR, creatinine and homocysteine concentrations and therapy with ACE inhibitors. The role of NGAL in the development of atherosclerosis needs to be further explored taking into consideration the uncontrolled effect of renal disease in atherosclerotic patients with multiple risk factors. Clin Chem Lab Med 2010;48:1035–41.