Metformin in cancer: translational challenges

The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.     

Clinical and epidemiological features of Guillain‐Barré syndrome in the Western Balkans

The aim of this study was to define features of Guillain‐Barré syndrome in a large cohort of patients from three Western Balkans countries. Data from adult Guillain‐Barré syndrome (GBS) cases from 2009 to 2013 were retrospectively obtained from all tertiary health care centers. During the 5‐year period, 327 new cases of GBS were identified with a male to female ratio of 1.7 : 1. The most common GBS variants were demyelinating (65%) and axonal (12%). At nadir 45% of patients were chair‐bound, confined to bed, or required assisted ventilation, while 5% died. The crude incidence of GBS in Serbia and Montenegro was 0.93 per 100,000 population, and age‐adjusted incidence according to the world standard population was 0.86 per 100,000. Incidence was particularly high in 50‐ to 80‐year‐old men. Statistically significant seasonal variations of GBS were not observed. This study of patients with GBS in the Western Balkans allows us to prepare the health system better and to improve the management of patients. This study also opens opportunities for international collaboration and for taking part in the multinational studies on GBS.     

Treatment of Acute Jones Fracture with Ilizarov External Minifixator: Case Series of Six Elite Athletes

No consensus has been reached about the optimal treatment of Jones fractures, especially in elite athletes. Furthermore, only limited experience with external fixation of acute Jones fractures in these patients is available. The aim of the present retrospective study was to report the clinical evaluation of a series of 6 patients—elite athletes—with unilateral acute Jones fracture, who underwent external fixation of the fracture with an Ilizarov minifixator. Treatment success and the intervals to union and the return to full athlete activity were measured for each patient. The mean follow-up duration was 48 (range 24 to 72) months. The average period from surgery to clinical healing of the fracture was 4.1 (range 4.0 to 4.2) weeks, and the interval from surgery to radiographic consolidation of the fracture was 5.8 (range 5.4 to 6.4) weeks. The patients had returned to full athletic activity by 6.7 (range 6.4 to 6.9) weeks postoperatively. No major complications developed. No cases of treatment failure (nonunion, delayed union, or refracture) were observed during the follow-up period. Our results have shown that the Ilizarov external minifixator is a reliable surgical option for the treatment of acute Jones fractures in elite athletes, allowing an early return to full competitive athletic activity. Application of this apparatus is fast and relatively simple, with a percentage of radiographic consolidation and clinical healing comparable to that with screw fixation techniques.     

Successful surgical reconstruction of ruptured renal pelvis following blunt abdominal trauma

A 25-year-old man with occult ureteropelvic obstruction presented with abdominal pain 3 h following blunt abdominal trauma. Isolated rupture of the right renal pelvis was promptly diagnosed and the patient underwent immediate pyeloplasty according to the Anderson-Hynes procedure. The patient made an uneventful recovery. One year after surgery, renal function was satisfactory.     

The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila

Akt (or PKB) is an oncogene involved in the regulation of cell survival. Akt is regulated by phosphatidylinositol 3-OH kinase (PI3'K) signaling and has shown to be hyperactivated through the loss of the PTEN tumor suppressor. In Drosophila, insulin signaling as studied using the Drosophila IRS-4 homolog (Chico) has been shown to be a crucial regulator of cell size. We have studied Drosophila Akt (Dakt1) and have shown that it is also involved in the regulation of cell size. Furthermore we have performed genetic epistasis tests to demonstrate that in Drosophila, PI3'K, PTEN and Akt comprise a signaling cassette that is utilized during multiple stages of development. In addition, we show that this signaling cassette is also involved in the regulation of cell survival during embryogenesis. This study therefore establishes the evolutionary conservation of this signaling pathway in Drosophila. Oncogene (2000) 19, 3971 - 3977.     

In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function

Serotonin(1A) (5-HT(1A)) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT(1A) receptor stimulation using both a within subject design. The effects of 5-HT(1A) receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT(1A) receptor agonist flesinoxan (0-0.3-1.0-3.0 mg/kg s.c.) and tested in either the open-field activity test, the light-dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of flesinoxan in both strains. Our data indicate that the role of 5-HT(1A) receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed.     

Modulation of cellular apoptotic potential: contributions to oncogenesis

The importance of apoptosis as a natural means to eliminate unwanted or damaged cells has been realized over the past decade. Many components required to exercise programmed cell death have been identified and shown to pre-exist in most, if not all, cells. Such ubiquity requires that apoptosis be tightly controlled and suggests the propensity of cells to trigger the cellular death machinery can be regulated. Recently, several signaling pathways have been demonstrated to impact the apoptotic potential of cells, most notably the phosphatidylinositol 3' kinase (PI3'K) pathway. The 3' phosphorylated lipid products generated by this enzyme promote activation of a protein-serine kinase, PKB/AKT, which is necessary and sufficient to confer cell PI3'K-dependent survival signals. The relevance of this pathway to human cancer was revealed by the recent finding that the product of the PTEN tumor suppressor gene acts to antagonize PI3'K. This review focuses on the regulation and mechanisms by which PKB activation protects cells and the oncologic consequences of dysregulation of the pathway.