Angiogenic cytokines profile in smoldering multiple myeloma: No difference compared to MGUS but altered compared to symptomatic myeloma

Background: Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM. Material/Methods We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS. Results: The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories. Conclusions: SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents

TECHNICAL AND TACTICAL ANALYSIS OF GOAL SCORING PATTERNS IN THE 2018 FIFA WORLD CUP IN RUSSIA

The aims of this research are to record and analyze the goals scored during the 64 matches in the 21st World Cup in Russia in 2018, to highlight those factors that are directly related to the teams’ effectiveness in scoring, to record the goals approved after the use of the new technologies, video assistant referee and goal line technology, as well as their effect on the outcome of the game. Chi-square and univariate general linear methods were used for the data analysis. Statistical difference is observed in the number of goals scored between the two halves (X²=8.699, p<0.005). A comparable percentage of scoring in most of the periods with exceptions of the periods in over time, the period 16th to 30th min, the addition time of the first and second half and the period 76th to 90th min of the game is determined (p<0.01). The teams that scored first won 71.4% matches, lost 9.5% and had a tie 19% of the matches (X²=42.000, p<0.001). Most of the goals were scored following a corner kick (24), penalty (22) and free kick scored non-directly (16), which were significantly different from free kick scored directly (6) and throw in (2) (X²=26.857, p<0.001). 19 goals were scored from cross, 19 from a long-range shot (8 of them with the “inner foot”), 18 from a forward pass and 12 from cutback. Statistical differences between the first four groups and all of the others are determined (X²=27.818, p<0.01). Significant differences were found between the goals that “began” from the offensive third, the middle and the defensive third (X²=73.645, p<0.001). 58.9% of the goals are scored following positional play, which is significantly different compared to counter attack (29.5%) and direct play (11.6%) (X²=32.611, p<0.001). Over 59 goals were scored from “the inner part of the foot” or “place”, and 31 from header, which were significantly different from the other types of shot (X²=89.254, p<0.001)

Pulmonary hypertension in patients with sickle cell/β thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations

Background and Objectives Pulmonary hypertension (PH) is increasingly observed in sickle cell disease (SCD) and β-thalassemia (β-thal), but there is no information on its prevalence in patients with HbS/β-thal. The amino-terminal fragment of B-type natriuretic peptide (NT-proBNP) is considered as an independent prognostic factor in PH. The aim of this study was to evaluate the incidence of PH and its correlation with clinical and laboratory findings, including NT-proBNP, in patients with HbS/β-thal.Design and Methods We studied 84 HbS/β-thal patients; 51% had been receiving hydroxyurea for a median time of 9 years. The presence of PH was evaluated using Doppler echocardiography and NT-proBNP serum levels were determined by an electrochemiluminescence immunoassay.Results The incidence of PH in our cohort of HbS/β-thal patients was 33%. PH patients had elevated values of NT-proBNP, reticulocyte counts and serum ferritin compared with patients without PH. However, even patients without PH had elevated concentrations of NT-proBNP compared with controls. An NT-proBNP level of 153.6 pg/mL had the highest sensitivity (85.7%) and specificity (94.6%) for detecting PH in our patients. NT-proBNP levels correlated with measures of pulmonary artery systolic pressure (tricuspid regurgitant jet velocity and right ventricular systolic pressure), left atrial area and diastolic dysfunction. The administration of hydroxyurea did not affect the presence of PH.Interpretation and Conclusions The incidence of PH in patients with HbS/β-thal is similar to that observed in patients with SCD. Serum NT-proBNP is a strong indicator of PH in HbS/β-thal. The correlation between PH and reticulocyte counts and ferritin suggests that the degree of hemolysis and iron overload is implicated in the pathogenesis of PH in HbS/β-thal

The effect of beach volleyball training on muscle performance of indoor volleyball players

BACKGROUND: Beach volleyball is frequently used as a conditioning activity for indoor volleyball players, but little information exists regarding any performance benefits when transitioning from sand to hard court. The present study examined the effect of 12 weeks beach volleyball training on muscle performance of indoor volleyball players. METHODS: Eleven athletes who completed an indoor volleyball season and were willing to train and compete at beach volleyball, participated in the study. Muscle endurance of knee extensors and plantar flexors (torque at 120°·s-1 following 40 contractions), muscle strength of knee extensors/ flexors (60, 180, 300°·s-1), dorsi/plantar flexors (torque at 60, 120, 180°·s-1) trunk flexors (60, 90, 180°·s-1) and power (squat [SJ] and countermovement [CMJ] jumps performed on sand and hard court surfaces) were assessed pre- and post-12 weeks of beach volleyball training. RESULTS: Knee extensors and plantar flexors endurance was higher post-12 weeks, as less torque decrease was found after 40 contractions for both muscle groups at post-12-week-time points. Knee extensors strength was higher post-12-weeks for 60 and 300°·s-1, while dorsi flexors strength was higher post-12 weeks for all speeds. SJ and CMJ vertical jump height was improved when measured on sand and on hard court. CONCLUSIONS: Twelve weeks of systematic training and competition at beach volleyball can improve muscular endurance of lower limbs and jumping height in indoor volleyball players. More importantly, these improvements are transferrable to hard court, making beach volleyball a very attractive alternative for conditioning indoor volleyball players during the off-indoor volleyball season

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/␤ 0 -thal, and 165 with HbS/␤ ؉ -thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P ‫؍‬ .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/ HbS, HbS/␤ 0 -thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients. (Blood

Effects of proteasome inhibitors on bone cancer.

Bone metastasis is a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer, while bone disease is also the characteristic clinical feature of multiple myeloma. Skeletal-related events can be devastating, with major effect on the quality of life and survival. Bisphosphonates are the mainstay of therapeutic management of bone disease of solid tumors and myeloma, and denosumab has recently been approved for patients with bone metastases. Both act through inhibition of the osteoclast activity but do not restore bone formation. Proteasome inhibition has direct bone anabolic effects. Proteasome inhibitors have been used in the management of patients with multiple myeloma and mantle-cell lymphoma during the last decade. In multiple myeloma, bortezomib, the first-in-class proteasome inhibitor, has shown both in vitro and in vivo regulation of bone remodeling by inhibiting osteoclast function and promoting osteoblast activity. Bortezomib also reduces bone resorption but more importantly increases bone formation and bone mineral density, at least, in subsets of myeloma patients. Thus, bortezomib is recommended for myeloma patients with extended bone disease in combination with bisphosphonates. This review focuses on the effects of the proteasome system on bone metabolism and the implications into the better management of patients with cancer and bone disease

Study of bone metabolism in multiple myeloma

Multiple myeloma (MM) is a malignancy of B-cells characterized by monoclonal development of plasma cells in the bone marrow. The main clinical feature is bone disease characterized by the presence of lytic lesions. The purpose of this study was to detect and measure the levels of cytokines and molecules involved in the pathogenesis of bone disease, correlate them with clinical data and explore their alterations when administering therapy. The measurement of the above molecules was made in the serum of patients with MM, using ELISA methodology. Patients with MM at diagnosis have both increased osteoclast activity and bone resorption, as reflected by increased levels of activation markers of osteoclasts (sRANKL, sRANKL/OPG, CCL-3, OPN) and bone resorption (CTX, NTX, TRACP-5b) and partly suppressed osteoblast function and bone formation, as reflected by the elevated values of inhibitors of osteoblasts (Dkk-1, activin-A, sclerostin) and the reduced levels of markers of bone synthesis (bALP and OC). The increased angiogenic cytokines (VEGF, VEGF-A, bFGF, angiogenin, angiopoetin-2) reflect the importance of angiogenesis in the pathogenesis of MM. The diffuse pattern of bone marrow infiltration on MRI is associated with increased angiogenesis, negative clinical features and is an independent predictor of lower survival even in patients treated with novel agents, suggesting the use of more aggressive therapy in these patients. The combination of thalidomide-dexamethasone (TD) in patients with refractory/relapsed MM suppresses osteoclasts and significantly reduces the sRANKL/OPG ratio and subsequently bone resorption markers with no effect on osteoblasts since there are no changes in markers of bone formation. The combination of lenalidomide-dexamethasone (RD) in patients with refractory/relapsed MM reduces osteoclast activity and bone resorption but only in patients who responded to treatment, with no positive effect on osteoblasts. The administration of bortezomib in patients with refractory/relapsed MM significantly reduces osteoblast inhibitors Dkk-1 and sclerostin, resulting in an increase in bone formation as reflected by the increase in serum osteocalcin and bALP.Το πολλαπλούν μυέλωμα (ΠΜ) είναι μια κακοήθεια των Β-κυττάρων που χαρακτηρίζεται από μονοκλωνική ανάπτυξη στο μυελό των οστών παθολογικών πλασματοκυττάρων με κύριο κλινικό γνώρισμά του την οστική νόσο που χαρακτηρίζεται από την παρουσία λυτικών εστιών. Σκοπός της παρούσας μελέτης ήταν η εμβάθυνση στην παθοφυσιολογία της οστικής νόσου με την ανίχνευση και μέτρηση των επιπέδων κυτταροκινών και μορίων που ενέχονται στην παθογένειά της, τη συσχέτισή τους με κλινικά δεδομένα και τη μεταβολή τους κατά τη χορήγηση αντιμυελωματικής θεραπείας. Η μέτρηση των προαναφερθέντων παραγόντων έγινε στον ορό ασθενών με ΠΜ με μεθοδολογία ELISA. Οι ασθενείς με ΠΜ στη διάγνωση έχουν αφενός αυξημένη οστεοκλαστική δραστηριότητα και οστική αποδόμηση όπως αυτό αντανακλάται από τις αυξημένες τιμές των δεικτών ενεργοποίησης των οστεοκλαστών (sRANKL, sRANKL/OPG, CCL-3, OPN) και οστικής απορρόφησης (CTX, NTX, TRACP-5b) και αφετέρου κατασταλμένη οστεοβλαστική λειτουργία και οστικό σχηματισμό, όπως αυτό αντικατοπτρίζεται από τις αυξημένες τιμές των αναστολέων των οστεοβλαστών (Dkk-1, ακτιβίνης-Α, σκληροστίνης) και τις ελαττωμένες τιμές των δεικτών οστικής σύνθεσης (bALP και OC). Οι αυξημένες των αγγειογενετικών κυτταροκινών (VEGF, VEGF-A, bFGF, αγγειογενίνης, αγγειοποιητίνης-2) αντικατοπτρίζουν τη σημασία της αγγειογένεσης στην παθογένεια του ΠΜ. Ο διάχυτος τύπος διήθησης στην MRI σχετίζεται με αυξημένη αγγειογένεση, αρνητικά κλινικά χαρακτηριστικά και αποτελεί ανεξάρτητο προγνωστικό παράγοντα κατώτερης επιβίωσης σε ασθενείς που έλαβαν θεραπεία με νεότερους αντιμυελωματικούς παράγοντες, υποδεικνύοντας τη χρήση πιο επιθετικών θεραπειών στους ασθενείς αυτούς. Ο συνδυασμός θαλιδομίδης-δεξαμεθαζόνης (TD) σε ασθενείς με ανθεκτικό/υποτροπιάζων ΠΜ καταστέλλει τους οστεοκλάστες και ελαττώνει σημαντικά το λόγο sRANKL/OPG και επακόλουθα τους δείκτες οστικής απορρόφησης χωρίς καμία επίδραση στους οστεοβλάστες καθώς δεν παρατηρήθηκαν μεταβολές των δεικτών οστικού σχηματισμού. Ο συνδυασμός λεναλιδομίδης-δεξαμεθαζόνης (RD) σε ασθενείς με ανθεκτικό/υποτροπιάζων ΠΜ ελαττώνει την οστεοκλαστική δραστηριότητα και οστική απορρόφηση αλλά μόνο σε ασθενείς που ανταποκρίθηκαν στη θεραπεία, χωρίς καμία θετική επίδραση στους οστεοβλάστες. Η χορήγηση βορτεζομίδης σε ασθενείς με ανθεκτικό/υποτροπιάζων ΠΜ ελαττώνει σημαντικά τους αναστολείς των οστεοβλαστών Dkk-1 και σκληροστίνη, με αποτέλεσμα αύξηση του οστικού σχηματισμού όπως αυτό φαίνεται από την αύξηση στον ορό των bALP και οστεοκαλσίνης