Janus kinase (JAK) 2 V617F mutation as the cause of primary thrombocythemia in acromegaly with severe visceromegaly and divergence between growth hormone and insulin-like growth factor-1 concentrations during the follow-up: causal or casual association?

OBJECTIVE: An increased prevalence of hematological abnormalities is reported in acromegaly, but to date no reports about the presence of the Janus Kinase (JAK) 2 mutation in acromegalic patients have been described. DESIGN: We report the complex clinical presentation of the unique case, never described, of acromegaly due to GH-secreting pituitary adenoma associated with JAK2 V617F mutation. RESULTS: The patient shows primary thrombocythemia and myelofibrosis, due to JAK2 V617F mutation, severe visceromegaly and a peculiar clinical course of the disease characterized by discrepant values of GH and IGF-1 during somatostatin analog (SA) treatment despite a significant reduction in pituitary adenoma size and therapeutic resistance both to SA and pegvisomant. CONCLUSIONS: The presence of JAK2 V617F mutation is a cause of primary thrombocythemia and myelofibrosis in acromegaly. In this patient, a peculiar clinical course of acromegaly was observed, with the difficulty in controlling the disease. More data, on a larger cohort of patients, could clarify whether JAK2 V617F mutation has a serious impact on the clinical features and course of acromegaly.OBJECTIVE: An increased prevalence of hematological abnormalities is reported in acromegaly, but to date no reports about the presence of the Janus Kinase (JAK) 2 mutation in acromegalic patients have been described. DESIGN: We report the complex clinical presentation of the unique case, never described, of acromegaly due to GH-secreting pituitary adenoma associated with JAK2 V617F mutation. RESULTS: The patient shows primary thrombocythemia and myelofibrosis, due to JAK2 V617F mutation, severe visceromegaly and a peculiar clinical course of the disease characterized by discrepant values of GH and IGF-1 during somatostatin analog (SA) treatment despite a significant reduction in pituitary adenoma size and therapeutic resistance both to SA and pegvisomant. CONCLUSIONS: The presence of JAK2 V617F mutation is a cause of primary thrombocythemia and myelofibrosis in acromegaly. In this patient, a peculiar clinical course of acromegaly was observed, with the difficulty in controlling the disease. More data, on a larger cohort of patients, could clarify whether JAK2 V617F mutation has a serious impact on the clinical features and course of acromegaly

Stabilizing versus destabilizing the microtubules: A double-edge sword for an effective cancer treatment option?

Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy

CALR MUTATIONS IN SICILIAN ESSENTIAL THROMBOCYTHEMIA AND MYELOFIBROSIS PATIENTS.

Background. Essential thrombocythemia (ET) and primary myelofibrosis (MF) are myeloproliferative neoplasms characterized by the overproduction of mature cells such as platelets (ET) or early bone marrow fibrosis due to scarring induced by highly proliferating myeloid progenitors and pathological stimulation of local fibroblasts (MF). Somatic mutations in CALR gene have recently identified in the majority of JAK2-V617F and MPL negative ET and MF patients. In this study we evaluated the frequency and type of CALR mutations and their clinical and hematological features. Methods. A total of 54 patients, 29 ET and 25 MF patient, was included in this study. All patients were JAK2 V617F and MPL negative. We registered clinical and hematological characteristics of patients i.e. age, hemoglobin level, white blood cell count, platelet count, International Prognostic Scoring System (IPSS), risk of thrombosis. Samples were collected from peripheral blood and DNA was extracted by using the QIAamp DNA mini kit (QIAGEN); CALR mutations were analyzed by direct sequencing method. Results. CALR mutations were present in 20.4 % of patients (4 ET; 7 MF). Four types of CALR mutations were detected; type 1 (p.L367fs*46) was isolated in 6 MF patient, type 2 (p.K385fs*47) was isolated in 3 ET patient; we also found 2 deletion mutations (p.E371fs*49 and D373fs*47), which are less common deletions, in the remaining patients. Patients carrying CALR mutations were younger (mediane age: 50 vs 65; p=0.2) than CALR negative patients. Furthermore, they did not show thrombosis and IPSS high risk. Conclusions. Our observations are in agreement with the findings of literature. We can assert an improved outcome of CALR mutated patients and we can also speculate a possible protective role of CARL mutations given the absence of thrombosis events and of IPSS high risk. However, the cohort of patients with myeloproliferative disease need to be implemented to draw final conclusion

Toilet training started during the first year of life: a report on elimination signals, stool toileting refusal and completion age.

The aim of this study was to examine an international population of children who started toilet training in the first year of life. METHODS: Two hundred eighty-six participants completed an anonymous questionnaire. Main outcomes variables were: presence of elimination signals (ES), elimination pattern consistency (EPC), stool toileting refusal (STR), and toilet training completion age. The analysis included the differences in completion age regarding each of the following variables: start age range, presence of ES, EPC, STR and country of residency for those who completed either bowel or bladder training at the time of survey completion. RESULTS: Over 90% of the respondents reported that their children showed ES. STR was nearly 12%. For those who completed toilet training at the time of survey completion mean completion ages for daytime dryness and bowel control were 17.4 and 15.0 months, respectively; those who initiated toilet training during the first 6 months completed training earlier than those who started later; those who showed STR at the beginning of training completed bowel training later than those who did not (P<0.001); those who exhibited ES for voiding or bowel movements completed day-dryness and bowel training earlier than those who did not (P<0.001). Among countries of residency, those children who resided in the USA and Canada completed bowel training the earliest (P<0.001). CONCLUSION: This is the first report which provides data on the current infant toilet training method, which is based mainly on ES and patterns, and practiced by motivated caregivers. Notable side effects were not observed

Protective effect of erdosteine metabolite I against hydrogen peroxide-induced oxidative DNA-damage in lung epithelial cells

It has been shown that the mucolytic agent erdosteine (N- carboxymethylthioacetyl-homocysteine thiolactone, CAS 84611-23-4) has anti-inflammatory and anti-oxidant properties, and an active metabolite I (MET I) containing pharmacologically active sulphydryl group has been found to have a free radical scavenging activity. The aim of this study was to assess the ability of erdosteine metabolite I to protect A549 human lung adenocarcinoma cell against hydrogen peroxide (H2O2)-mediated oxidative stress and oxidative DNA damage. When A549 cells were pre-treated with the active metabolite I (2.5-5-10 \u3bcg/ml) for 10-30 min and then exposed to H 2O2(1-4 mM) for two additional hours at 37\ub0C, 5% at CO2, the intracellular peroxide production, reflected by dichlorofluorescein (DCF) fluorescence, decreased in a concentration-dependent manner. Furthermore, using a comet assay as an indicator for oxidative DNA damage, it was found that the metabolite I prevented damage to cells exposed to short-term H2O2treatment. The data suggest that this compound is effective in preventing H2O2-induced oxidative stress and DNA damage in A549 cells. The underlying mechanisms involve the scavenging of intracellular reactive oxygen species (ROS)

Genotoxic effects of polychlorinated biphenils (PCB153, 138, 101,118) in a fish cell line (RTG-2)

Polychlorinated biphenyls (PCBs) are persistent pollutants in aquatic environments, often causing the decline or disappearance of wild populations. The primary aim of this study was to investigate the genotoxic effects of some PCBs (PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) and 138 (2,2',3,4,4',5'-hexachloro-biphenyl), both non-dioxin-like compounds, and the pentachlorobiphenyls PCB118 (2,3',4,4',5-) and 101 (2,2',4',5,5'-), the former an ortho-substituted, low-affinity dioxin-like compound and the latter a non-coplanar congener classified as non-dioxin-like) in fish cells (RTG-2). These congeners are mostly present in surface waters and in edible aquatic organisms and the loss of DNA integrity in vitro serves as a sensitive biomarker of cytogenetic alterations and is considered as an initial step for the identification of genotoxic effects.The alkaline comet assay and the micronucleus test show clear genotoxic damage after short and longer exposure (2 and 24 h) to maximum soluble, non-cytotoxic doses, evident sooner with PCBs 101 and 118. Oxidative stress situations involving ROS release, reduction in total GSH, lipid peroxidation and alteration to superoxide dismutase, seen after exposure with all the congeners, though with different kinetics, seem the most likely explanation for the genotoxic damage. This appears to be confirmed by the modified comet assay (pH 10) for detection of oxidized bases using endonuclease III. The increased generation of intracellular ROS might explain the apoptosis seen after treatment with the single PCBs and evaluated on the basis of the rise in 3-7 caspase activity. Therefore both the non-coplanar, non-dioxin-like PCBs (153, 138, 101) and the low-affinity dioxin-like compound PCB118 cause evident genotoxic damage, probably as a consequence of oxidative stress

A joint calibration model for combining predictive distributions

In many research fields, as for example in probabilistic weather forecasting, valuable predictive information about a future random phenomenon may come from several, possibly heterogeneous, sources. Forecast combining methods have been developed over the years in order to deal with ensembles of sources: the aim is to combine several predictions in such a way to improve forecast accuracy and reduce risk of bad forecasts.In this context, we propose the use of a Bayesian approach to information combining, which consists in treating the predictive probability density functions (pdfs) from the individual ensemble members as data in a Bayesian updating problem. The likelihood function is shown to be proportional to the product of the pdfs, adjusted by a joint “calibration function” describing the predicting skill of the sources (Morris, 1977). In this paper, after rephrasing Morris’ algorithm in a predictive context, we propose to model the calibration function in terms of bias, scale and correlation and to estimate its parameters according to the least squares criterion. The performance of our method is investigated and compared with that of Bayesian Model Averaging (Raftery, 2005) on simulated data