Running for time: circadian rhythms and melanoma

Circadian timing system includes an input pathway transmitting environmental signals to a core oscillator that generates circadian signals responsible for the peripheral physiological or behavioural events. Circadian 24-h rhythms regulate diverse physiologic processes. Deregulation of these rhythms is associated with a number of pathogenic conditions including depression, diabetes, metabolic syndrome and cancer. Melanoma is a less common type of skin cancer yet more aggressive often with a lethal ending. However, little is known about circadian control in melanoma and exact functional associations between core clock genes and development of melanoma skin cancer. This paper, therefore, comprehensively analyses current literature data on the involvement of circadian clock components in melanoma development. In particular, the role of circadian rhythm deregulation is discussed in the context of DNA repair mechanisms and influence of UV radiation and artificial light exposure on cancer development. The role of arylalkylamine N-acetyltransferase (AANAT) enzyme and impact of melatonin, as a major output factor of circadian rhythm, and its protective role in melanoma are discussed in details. We hypothesise that further understanding of clock genes’ involvement and circadian regulation might foster discoveries in the field of melanoma diagnostics and treatment.     

The role of nephrologist in treatment of multiple myeloma

Multiple myeloma (MM) is malignant disease caused by proliferation of malignant clone of terminally differentiated plasma-cells. Clinical features may include symptoms of bone disease, unexplained back-pain, fractures, anaemia, kidney failure, oedema, hypercalcaemia, bacterial infections, impaired hemostasis, peripheral neuropathy and hyperviscosity. Impairment of renal function occurs in 50% of patients with different forms of kidney disease. Majority of patients have precipitation of monoclonal immunoglobulins or their fragments in kidney. Hypercalcemia, dehydration, infections and nephrotoxic drugs contribute to development of kidney injury. Treatment consists of chemotherapy for primary disease, with plasma exchange in cases of hyperviscosity. Supportive treatment should include rehydration, treatment of hyperuricemia and hypercalcaemia. Patients with end-stage renal disease could be treated with peritoneal dialysis or haemodialysis. Renal transplantation is rarely offered to this group of patients.     

The cardiorenal syndrome and erythropoietin

The pathophysiological condition, in which combined cardiac and renal dysfunction amplifies a progression in the failure of the individual organ, has been denoted as severe cardiorenal syndrome (SCRS). An interactive network of cardiorenal connectors, i.e., the renin-angiotensin system (RAS), nitric oxide (NO) and reactive oxygen species (ROS) balance, the sympathetic nervous system (SNS), and inflammation, has been proposed as the cornerstones of the pathophysiology of SCRS. Because erythropoietin (Epo) production declinesin chronic renal failure (CRF) and Epo sensitivity might decrease by the cardiorenalconnectors in patients with the SCRS, it is not surprising thatanaemia is a commonly occurring state coinciding with CRF and chronic heart failure (CHF). Epo treatment in patients with SCRS acts via haematopoietic effects, but also may intervenes in the vicious circle of cardiorenal connectors with subsequent deteriorating effects on cardiac, renal, and vascular function. It appears that regular Epo treatment in anaemic patients with diminished renal function improves cardiac performance, delays the progression of kidney disease, and may be of clinical benefit even to patients suffering from CHF with relatively mild anaemia. Despite growing evidence about Epo having positive effects on both renal and cardiac function, little is known about the underlying mechanisms of action.     

Evaluation of novel cyclic analogues of apelin

Apelin regulates various cell signaling processes through interaction with its specific cell-surface receptor, APJ, which is a member of a seven transmembrane G protein-coupled receptor superfamily. To develop a novel apelin analogue, we synthesized cyclic analogues of minimal apelin fragment RPRLSHKGPMPF (apelin-12), and evaluated their bioactivities in a recombinant human APJ-expressed cell line. Three cyclic analogues were synthesized: cyclo apelin-12 (C1) in combination with amino-terminal to carboxy-terminal, cyclourea apelin-12 (C3) in combination with amino-terminal and amino acid side chain at positions 7, and cyclic apelin-12 (C4) in combination with amino acid side chain at positions 7 to carboxy-terminal. All cyclic analogues exhibited dose-dependent inhibitory effects against forskolin-induced cyclic adenosine monophosphate (cAMP) accumulation, and the maximal effects were almost abolished by pertussis toxin (PTx) treatment. Moreover, they could modulate the intracellular signaling pathways composed of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) serine/threonine protein kinases in PTx-sensitive manner. This is the first approach to apply cyclization on apelin, and these results provide the basis for the development of drug-like apelin analogues.     

Chronic Stress Induces Neurotrophin-3 in Rat Submandibular Gland

Purpose

Plasma neurotrophin-3 (NT-3) levels are associated with several neural disorders. We previously reported that neurotrophins were released from salivary glands following acute immobilization stress. While the salivary glands were the source of plasma neurotrophins in that situation, the association between the expression of neurotrophins and the salivary gland under chronic stress conditions is not well understood. In the present study, we investigated whether NT-3 levels in the salivary gland and plasma were influenced by chronic stress.

Materials and Methods

Expressions of NT-3 mRNA and protein were characterized, using real-time polymerase chain reactions, enzyme-linked immunosorbent assay, and immunohistochemistry, in the submandibular glands of male rats exposed to chronic stress (12 h daily for 22 days).

Results

Plasma NT-3 levels were significantly increased by chronic stress (p<0.05), and remained elevated in bilaterally sialoadenectomized rats under the same condition. Since chronic stress increases plasma NT-3 levels in the sialoadenectomized rat model, plasma NT-3 levels were not exclusively dependent on salivary glands.

Conclusion

While the salivary gland was identified in our previous study as the source of plasma neurotrophins during acute stress, the exposure to long-term stress likely affects a variety of organs capable of releasing NT-3 into the bloodstream. In addition, the elevation of plasma NT-3 levels may play important roles in homeostasis under stress conditions.     

Treatment strategies in cavernomas of the brain and spine

The management of brain and spinal cavernomas includes two main options: (i) conservative treatment or (ii) surgical removal. Clinical experience related to cavernoma patients falls into four major categories: the surgical or conservative treatment of incidental or symptomatic cavernomas. In many patients, cavernomas exist as fairly benign lesions, frequently remaining clinically silent for life. This observation argues against the active treatment of all cavernoma patients; rather for the meticulous selection of only those more likely to benefit from surgery. Thus, the most crucial task in successful management of cavernomas is appropriate patient selection. In this review, we present our institutional experience on cavernoma management supplemented with data from the literature.     

A phase III randomized,multicentre, double blind,active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia – the TEAM-ET 2·0 trial

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 10⁹/l (95% confidence interval (CI) 707–936 × 10⁹/l) and 797 × 10⁹/l (95% CI 708–883 × 10⁹/l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 10⁹/l for A-PR (95% CI 254–311) and 305 × 10⁹/l (95% CI 276–337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.