The endocrine function of osteocalcin regulated by bone resorption. a lesson from reduced and increased bone mass diseases

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans

Bone control of muscle function

Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone–muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton

Twisted Eguchi-Kawai Reduced Chiral Models

We study the twisted Eguchi-Kawai (TEK) reduction procedure for large-N unitary matrix lattice models. In particular, we consider the case of two-dimensional principal chiral models, and use numerical Monte Carlo (MC) simulations to check the conjectured equivalence of TEK reduced model and standard lattice model in the large-N limit. The MC results are compared with the large-N limit of lattice principal chiral models to verify the supposed equivalence. The consistency of the TEK reduction procedure is verified in the strong-coupling region, i.e. for $\beta<\beta_c$ where $\beta_c$ is the location of the large-N phase transition. On the other hand, in the weak-coupling regime $\beta>\beta_c$, relevant for the continuum limit, our MC results do not support the equivalence of the large-N limits of the lattice chiral model and the corresponding TEK reduction. The implications for the correspondence between TEK model and noncommutative field theory are also discussed.Comment: 16 page

Biallelic BIRC3 inactivation in chronic lymphocytic leukaemia patients with 11q deletion identifies a subgroup with very aggressive disease.

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Computed tomography–based body composition in patients with ovarian cancer: association with chemotoxicity and prognosis

PurposeTo assess the association between computed tomography (CT)-derived quantitative measures of body composition profiling and chemotherapy-related complications, in terms of dose reduction, premature discontinuation of chemotherapy, and cycle delays in patients with ovarian cancer. Secondary purposes were to evaluate associations between sarcopenia and survival, and to evaluate differences in body composition profiling at baseline and after neoadjuvant chemotherapy. Materials and MethodsThe study population was retrospectively selected from a database of patients with newly diagnosed ovarian cancer (any stage) referred to our Institution between Feb 2011 and Mar 2020. Clinical data were recorded, and CT images at the level of the 3(rd) lumbar vertebra were stored. By using specific software, skeletal muscle area (SMA), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were extracted. Skeletal muscle index (SMI) was then calculated. Statistical analysis was performed by logistic regression models to identify body composition features predictive of dose reduction, premature end of chemotherapy, and cycle delays. Kaplan-Meier analyses were performed to assess overall survival (OS) and progression-free survival (PFS). The log-rank test was used to determine differences in OS and PFS between sarcopenic and non-sarcopenic patients. Wilcoxon test was performed to compare body composition features before and after neoadjuvant chemotherapy (NACT). ResultsSixty-nine patients were included. A significant association was found between VAT and cycle delays (OR = 1.01, z = 2.01, 95% CI: 1.00-1.02, p &lt; 0.05), between SMA and early discontinuation of chemotherapy (OR = 1.03, z = 2.10, 95% CI: 1.00-1.05, p &lt; 0.05), and between mean SMD and cycle delays (OR = 0.92, z = -2.70, 95%CI: 0.87-0.98, p &lt; 0.01). No significant difference emerged for OS in sarcopenic and non-sarcopenic patients, nor in CT body composition features before and after NACT. ConclusionsIn ovarian cancer patients, CT-derived body composition profiling might predict the risk of chemotoxicity. In particular, VAT and SMD are associated with chemotherapy cycle delays, and SMA with early discontinuation of chemotherapy

high quality genomic dna from human whole blood and mononuclear cells

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Spectrum of confining strings in SU(N) gauge theories

We study the spectrum of the confining strings in four-dimensional SU(N) gauge theories. We compute, for the SU(4) and SU(6) gauge theories formulated on a lattice, the string tensions sigma_k related to sources with Z_N charge k, using Monte Carlo simulations. Our results are consistent with the sine formula sigma_k/sigma = sin k pi/N / sin pi/N for the ratio between sigma_k and the standard string tension sigma. For the SU(4) and SU(6) cases the accuracy is approximately 1% and 2%, respectively. The sine formula is known to emerge in various realizations of supersymmetric SU(N) gauge theories. On the other hand, our results show deviations from Casimir scaling. We also discuss an analogous behavior exhibited by two-dimensional SU(N) x SU(N) chiral models.Comment: Latex, 34 pages, 10 figures. Results of new SU(4) simulations added. The new data are included in the analysis, leading to improved final estimates for SU(4). Conclusions unchange

Relationship between postpartum uterine involution and biomarkers of inflammation and oxidative stress in clinically healthy mares (Equus caballus)

To test the hypothesis that delayed/impaired uterine involution could be associated with oxinflammation, westudied the progression of the uterine involution in association with some biomarkers of inflammation andoxidative stress in clinically healthy mares (N\ubc26) during early postpartum. The examination of the repro-ductive tract was performed on Days 7 and 21 after foaling. Uterine involution was assessed considering: a) theincrease of the gravid uterine horn diameter (GUHD) compared with diameter recorded before pregnancy duringthe previous breeding season; b) the level of endometrial edema (EE); c) the degree of accumulation of intra-uterinefluid (IUFA); d) the status of the cervix (CS). Inflammation and oxidative stress were studied by measuringserum amyloid A (SAA), cortisol, DHEA, AOPP, protein carbonyl groups, malondialdheyde (MDA) and thiols inplasma on Days 7 and 21. By Day 21 after parturition, a significant improvement (P<0.01) was observed forGUHD and EE; while IUFA increased in six animals. Plasma SAA and DHEA concentrations were higher when theclinical parameters indicated a lower degree of uterine involution. On Day 7, the cortisol/DHEA ratio was lower inanimals with higher degree of EE. Plasma AOPP and MDA concentrations were significantly lower (P<0.05) inanimals with the lower GUHD. On Day 21, plasma MDA concentrations were significantly lower (P<0.05) inanimals with the lower IUFA. Our data suggest that a mild condition of inflammation and oxidative stress occur inmares with delayed/impaired uterine involution

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules

Gastric transposition as a valid surgical option for esophageal replacement in pediatric patients: Experience from three Italian medical centers

Background: Esophageal replacement in children is an option that is confined to very few situations including long-gap esophageal atresia and esophageal strictures unresponsive to other therapies (peptic or caustic ingestion). The purpose of our work was to describe the experience of gastric transposition in three Italian centers. Methods: This is a retrospective study. The data were extrapolated from a prospective database. We included all patients who had undergone gastric transposition in the last 15 years. Results: In the 15-year period, eight infants and children (3 males and 5 females) underwent gastric transposition for esophageal replacement. Six patients had long-gap esophageal atresia, and two had caustic esophageal stenosis. There were no deaths in the series. Three patients had an early postoperative complication: Two had a self-limited salivary fistula at three weeks, and one (a patient with jejunostomy) had a jejunal perforation treated surgically. One late complication, anastomotic stricture, was recorded that required two endoscopic dilatations. The median follow-up was 60 months (range: 18-144 months). At final clinical follow-up, six patients had no eating problems, and two patients had some difficulties with eating (jejunostomy in situ), but they underwent logopedic therapy with improved outcomes. All patients had an increase in body weight and height postoperatively. Conclusion: Our small study reports the clinical experience of three Italian centers in which gastric transposition was performed with excellent results, both in terms of surgical technique (simplicity, reproducibility, complication rate) and clinical follow-up (good oral feeding of young patients, normal social life and regular growth curves)